US 12,686,690 B2Granted

Macrocyclic urea orexin receptor agonists

AssigneeMerck Sharp & Dohme Corp.

InventorsKira A. Armacost, Maria Irina Chiriac, Danielle M. Hurzy, Jeffrey C. Kern, Jian Liu, Peter J. Manley, Vanessa L. Rada, Michael T. Rudd, Craig A. Stump, Zhe Wu, Dong Xiao

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Abstract

The present invention is directed to macrocyclic urea compounds which are agonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

Claims14

Dependent claims

A compound of the formula I:

wherein:
A is N or C(R8)n;
D is N or C(R8)n;
E is N or C(R8)n;
G is N or C(R8)n;
J is Nor C(R8)n;
W is N or C(R8)n;
when J is N, m is 1 but when J is C(R8)n, m is 1 or 2;
n is 0 or 1;
X is —O— or —CH2—;
Y is phenyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyridofuranyl, oxazolyl, thiazolyl, which is unsubstituted or substituted with one to three groups selected from R4;
Z is
R is independently selected from H or C1-6alkyl;
R1 is selected from:
1) Hydrogen,
2) CN,
3) —C(O)NR2—,
4) —CH2OCH2CF3—,
5) —CH2OCH2CHCF2—, and
6) C1-6alkyl, which is substituted with 0, 1, or 3 independently selected from:
a) C1-6alkyl,
b) halogen,
c) hydroxyl,
d) —O—C1-6alkyl which is substituted with 0, 1, or 3 substituents selected from halogen, or C3-6cycloalkyl which is unsubstituted or substituted with halogen, C1-6alkyl, or C1-6alkylfluoro,
e) C3-6cycloalkyl, which is which is substituted with 0, 1, or 3 of R4,
f) Heteroaryl, which is substituted with 0, 1, or 3 of R4,
g) Heterocyclyl, which is substituted with 0, 1, or 3 R4,
h) CN, and
i) S(O)2R;
R2 is selected from
1) Linear or branched C1-10alkyl or C4-8alkenyl, 2) —(CR2)1-6—O—(CR2)1-6—;
3) —(CR2)1-6—N(R9)—(CR2)1-6—, wherein R9 is hydrogen or —C1-6alkyl, where the —C1-6alkyl is unsubstituted or substituted with halogen,
4) —(CR2)1-6C3-6cycloalkyl-(CR2)1-6—, where the —C3-6cycloalkyl is unsubstituted or substituted with —C1-6alkyl or halogen, and
5) Piperidinyl, pyrrolidinyl, oxaxolyl, oxadiazolyl or thiazolyl ring, which is unsubstituted or substituted with —C1-6alkyl or halogen;
R3 is selected from a direct bond, —S—, —NR—, —O—C1-6alkyl-, —S—C1-6alkyl-, and —S(O)2—C1-6alkyl-;
R4 is selected from:
(1) hydrogen,
(2) hydroxyl,
(3) halogen,
(4) —C1-6alkyl, which is unsubstituted or substituted with one to six fluoro,
(5) —O—C1-6alkyl, which is unsubstituted or substituted with one to six fluoro, and
(6) C3-6cycloalkyl;
R5 and R6 are independently selected from:
(1) hydrogen, and
(2) —C1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from halogen,
or R5 and R6 and the carbon atom to which they are attached may be joined together to form a —C3-6cycloalkyl group;
R7 is selected from:
(1) hydrogen,
(2) —C1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from halogen, and
(3) —C3-6cycloalkyl, where the —C3-6cycloalkyl is unsubstituted or substituted with —C1-6alkyl or halogen;
R8 is selected from:
(1) hydrogen,
(2) halogen, and
(3) —C1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from halogen;
or a pharmaceutically acceptable salt thereof.

52 more elements

A compound which is selected from:

(10R,E)-9-ethyl-10-methyl-3-oxa-7,9-diaza-2(6,8)-imidazo[1,2-a]pyrazina-1(1,3)-benzena-4(1,3)-cyclopentanacyclodecaphan-8-one;
(12R)-13-ethyl-12-methyl-12,13,16,17,19,20-hexahydro-6,22-(azeno)-11,7-(metheno)imidazo[1,2-o][1,18,4,6, 15]dioxatriazacycloicosin-14(15H)-one;
(12R)-13-ethyl-12-methyl-18-(propan-2-yl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[1,2-r][1,4,7,9,18]oxatetraazacycloicosin-14-one;
(12R)-13-ethyl-12-methyl-12,13,15,16,17,18,21,22,22a,23-decahydro-14H,20H-6,25-(azeno)-11,7-(metheno)imidazo[1,2-s]pyrrolo[2,1-c][1,4,8,10,19]oxatetraazacyclohenicosin-14-one;
(7R)-8-ethyl-7-methyl-18-oxa-8,10,13,21,24,26-hexaazapentacyclo-[17.6.1.1-2,6-1-13,17.0-20,24-]octacosa-1(25),2(28),3,5,19(26),20,22-heptaen-9-one;
(12R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,20,21-octahydro-14H-6,23-(azeno)-11,7-(metheno)imidazo[2,1-f][1,4,7,13,16,18]dioxatetraazacyclohenicosin-14-one;
(12R)-13-ethyl-8-methoxy-12-methyl-12,13,15,16,17,18,20,21-octahydro-14H-6,23-(azeno)-11,7-(metheno)imidazo[2,1-f][1,4,7,13,16,18]dioxatetraazacyclohenicosin-14-one;
(12R)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,20,21-hexahydro-19H-6,23-(azeno)-11,7-(metheno)imidazo[1,2-o][1,18,4,6,9,15]dioxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-12,16-dimethyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(R,E)-4-ethyl-3-methyl-13-oxa-4,6,9-triaza-1(6,8)-imidazo[1,2-a]pyrazina-2(1,3)-benzenacyclotridecaphan-5-one;
(12R)-13-ethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[1,2-s][1,4,8,10,19]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13, 15]oxatriazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-12,19,19-trimethyl-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13,15]oxatriazacycloicosin-14-one;
(12R)-13-ethyl-12-methyl-12,13,15,16,17,18,20,21-octahydro-14H-6,23-(azeno)-11,7-(metheno)imidazo[2,1-f][1,4,7,16,18]dioxatriazacyclohenicosin-14-one;
(12R)-13,18-diethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13,15,18]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-12,18,21-trimethyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13,15,18]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-12-methyl-12,13,16,17,20,21-hexahydro-19H-6,23-(azeno)-11,7-(metheno)imidazo[1,2-o][1,18,4,6,15]dioxatriazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-12,16-dimethyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13,15]oxatriazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-12-methyl-16-(1,3-thiazol-4-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13,15]oxatriazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-12-methyl-16-(1,2-oxazol-3-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13,15]oxatriazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,20,21-hexahydro-19H-6,23-(azeno)-11,7-(metheno)imidazo[1,2-o][1,18,4,6,9,15]dioxatetraazacyclohenicosin-14(15H)-one;
(R,27E,62Z)-10-ethyl-11-methyl-3-oxa-8,10-diaza-6(4,2)-thiazola-2(6,8)-imidazo[1,2-a]pyrazina-1(1,3)-benzenacycloundecaphan-9-one;
(R,27E,54Z)-10-ethyl-11-methyl-3-oxa-8,10-diaza-5(3,5)-oxadiazola-2(6,8)-imidazo[1,2-a]pyrazina-1(1,3)-benzenacycloundecaphan-9-one;
(3R,E)-4-ethyl-3,9-dimethyl-8-(trifluoromethyl)-12-oxa-4,6,9-triaza-1(6,8)-imidazo[1,2-a]pyrazina-2(1,3)-benzenacyclododecaphan-5-one;
(3R,E)-4-ethyl-3,9-dimethyl-8-(trifluoromethyl)-13-oxa-4,6,9-triaza-1(6,8)-imidazo[1,2-a]pyrazina-2(1,3)-benzenacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(3,5)-pyridinacyclododecaphan-5-one;
(3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(3,5)-pyridinacyclotridecaphan-5-one;
(12S,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloicosin-14-one;
(12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13, 15]oxatetraazacycloicosin-14-one;
(12S,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(17E,3R,7S,9Z)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(1,3)-benzenacyclododecaphan-9-en-5-one;
(3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(1,3)-benzenacyclododecaphan-5-one;
(16S,18Z)-13-ethyl-8-methoxy-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,20-hexahydro-14H-6,22-(azeno)-11,7-(metheno)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloicosin-14-one;
(16R)-13-ethyl-8-methoxy-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)[1,2,4]triazolo [5,1-c][1,4,10,13,15]oxatetraazacycloicosin-14-one;
(16R)-13-ethyl-8-methoxy-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)[1,2,4]triazolo[5,1-c][1,4,10,13, 15]oxatetraazacycloicosin-14-one;
13-ethyl-8-methoxy-12-(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloicosin-14-one;
(16R)-13-ethyl-8-methoxy-2-methyl-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloicosin-14-one;
(16R)-13-ethyl-8-methoxy-12,16-bis (trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloicosin-14-one;
(16R)-13-ethyl-8-methoxy-16-(2,2,2-trifluoroethyl)-12-(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloicosin-14-one;
(16R)-13-ethyl-8-methoxy-12,16-bis (trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloicosin-14-one;
(12S,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloicosin-14-one;
(12R,18Z)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,20-hexahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13,15]oxatriazacycloicosin-14-one;
(12R)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13, 15]oxatriazacycloicosin-14-one;
(16R)-13-ethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13,15]oxatriazacycloicosin-14-one;
(16R)-13-ethyl-8-methoxy-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13,15]oxatriazacycloicosin-14-one;
(16R)-13-ethyl-8-methoxy-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloicosin-14-one;
(3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(3,5)-pyridinacyclododecaphan-5-one;
(3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(3,5)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-3,9-dimethyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(1,3)-benzenacyclododecaphan-5-one;
(12R)-13-ethyl-12-methyl-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,13,15]oxatriazacycloicosin-14-one;
(7R)-8-ethyl-14,14-difluoro-3-methoxy-7-methyl-11-(3,3,3-trifluoropropyl)-17-oxa-5,8,10,20,23,25-hexazatetracyclo(12R)[16.6.1.12,6.019,23]hexacosa-1(24),2(26),3,5,18(25), 19,21-heptaen-9-one;
(3R,7R,E)-4-ethyl-23-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]yridine-2(2,6)-pyridinacyclotridecaphan-5-one;
(16R)-13-ethyl-8-methoxy-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,9,13, 15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13,16-diethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-12-methyl-16-(2-methylpropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-12-methyl-16-propyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-16-(cyclopropylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-16-(2-methoxyethyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-16-cyclopropyl-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-16-(methoxymethyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-16-[(2,2-difluorocyclopropyl) methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclo henicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-16-(3-methoxypropyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-16-(cyclobutylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-16-(ethoxymethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-16-tert-butyl-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-16-(2-ethylbutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-16-(cyclopentylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-12-methyl-16-{[1-(trifluoromethyl)cyclopropyl]methyl}-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-12-methyl-16-[(oxolan-3-yl)methyl]-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-12-methyl-16-(oxan-4-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-16-[(3,3-difluorocyclobutyl) methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-16-{[1-(difluoromethyl)cyclopropyl]methyl}-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-16-(3-fluoro-3-methylbutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-16-(3-fluorobutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-12-methyl-16-[2-(trifluoromethoxy)ethyl]-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(9R,E)-12-ethyl-13-methyl-9-(3,3,3-trifluoropropyl)-3-oxa-10,12-diaza-1(7,5)-furo[3,2-b]pyridina-2(6,8)-imidazo[1,2-a]pyrazinacyclotridecaphan-11-one;
(10R)-7-ethyl-6,19-dimethyl-10-(3,3,3-trifluoropropyl)-6,7,10,11,12,13,14,15-octahydro-23,17-(azeno)-5,24-(metheno)furo[2,3-h]imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-8(9H)-one;
(10R)-7-ethyl-6,19-dimethyl-10-(3,3,3-trifluoropropyl)-6,7,10,11,12,13,14, 15-octahydro-23,17-(azeno)-5,24-(metheno)furo[2,3-h]imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-8(9H)-one;
(10R)-7-ethyl-6,20-dimethyl-10-(3,3,3-trifluoropropyl)-6,7,10,11,12,13,14,15-octahydro-23,17-(azeno)-5,24-(metheno)furo[2,3-h]imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-8(9H)-one;
(10R)-7-ethyl-6,20-dimethyl-10-(3,3,3-trifluoropropyl)-6,7,10,11,12,13,14,15-octahydro-23,17-(azeno)-5,24-(metheno)furo[2,3-h]imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-8(9H)-one;
(12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(trifluoromethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-8,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-8,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-10,6-(azeno)-5,22-(metheno)pyrazolo[1,5-c][1,3,9,13,15]oxatetraazacyclohenicosin-13(14H)-one;
(12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20,21,22-decahydro-14H-6,23-(azeno)-11,7-(metheno)imidazo[1,2-1][1,3,6,12]tetraazacyclohenicosin-14-one;
(12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-16-(3,3-difluorobutyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-16-(3,3-difluorobutyl)-13-ethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-8-methoxy-5,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,9,13, 15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,5,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-5,22-(azeno)-10,6-(metheno)pyrazolo[1,5-c][1,3,10,13,15]oxatetraazacyclohenicosin-13(14H)-one;
(12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(metheno)imidazo[2,1-c][1,4,5,9,13, 15]oxapentaazacyclohenicosin-14(15H)-one;
(16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azeno)imidazo[2,1-c][1,4,13,15]oxatriazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(metheno)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(16R)-13-ethyl-10,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12S,16R)-13-ethyl-8,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azeno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azeno)-7,10-epithioimidazo[2,1-c][1,4,8,12,14]oxatetraazacycloicosin-13(14H)-one;
(16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(metheno)imidazo[2,1-c][1,4,8,10,13,15]oxapentaazacyclohenicosin-14(15H)-one;
(16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(metheno)imidazo[2,1-c][1,4,8,10,13,15]oxapentaazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azeno)imidazo[2,1-c][1,4,13,15]oxatriazacyclohenicosin-14(15H)-one;
(11R,15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-5,22-(azeno)-10,6-(metheno)pyrazolo[1,5-c][1,3,5,10,13,15]oxapentaazacyclohenicosin-13 (14H)-one;
(12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,5,9,13,15]oxapentaazacyclohenicosin-14(15H)-one;
(11R,15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-5,22:10,6-di(metheno)pyrazolo[1,5-c][1,3,5,10,13,15]oxapentaazacyclohenicosin-13(14H)-one;
(12R,16R)-13-ethyl-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,5,10,13,15]oxapentaazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,5,10,13,15]oxapentaazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azeno)-7,10-epoxyimidazo[2,1-c][1,4,8,12,14]oxatetraazacycloicosin-13(14H)-one;
(15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22:10,7-di(azeno)imidazo[2,1-c][1,8,4,12,14]dioxatriazacycloicosin-13(14H)-one;
(12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20,21,22-decahydro-14H-11,7-(azeno)-6,23-(metheno)imidazo[1,2-1][1,3,12]triazacyclohenicosin-14-one;
(12S,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azeno)-7,10-epoxyimidazo[2,1-c][1,4,9,12,14]oxatetraazacycloicosin-13(14H)-one;
(3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-14-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotetradecaphan-5-one;
(3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,8,10,13,15]oxapentaazacyclohenicosin-14(15H)-one;
(16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,8,10,13,15]oxapentaazacyclohenicosin-14(15H)-one;
(12S,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16S)-13-ethyl-8-methoxy-12-methyl-16-(trifluoromethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,9,10,13, 15]oxapentaazacyclohenicosin-14(15H)-one;
(12S,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azeno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azeno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12S,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(12S,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,8,10,13,15]oxapentaazacyclohenicosin-14(15H)-one;
(12R,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,8,10,13,15]oxapentaazacyclohenicosin-14(15H)-one;
(16R)-13-ethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azeno)-11,7-(metheno)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclohenicosin-14(15H)-one;
(3R,E)-7-(2,2-difluorobutyl)-4-ethyl-25,3-dimethyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-16,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-17,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(R,E)-7-(3,3-difluorobutyl)-4-ethyl-22-methoxy-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(3,5)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-7-(fluoromethyl)-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-7-(3,3-difluoropropyl)-4-ethyl-25-fluoro-3-methyl-10,13-dioxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-25-chloro-7-(3,3-difluoropropyl)-4-ethyl-3-methyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25,3-dimethyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((R)-3,3,3-trifluoro-2-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((S)-3,3,3-trifluoro-2-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((R)-3,3,3-trifluoro-1-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((S)-3,3,3-trifluoro-1-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-10-thia-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-10-thia-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one 10,10-dioxide;
(3R,7S,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-10-hydroxy-22,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(3,5)-pyridinacyclotridecaphan-5-one;
(3R,7R,Z)-4-ethyl-23-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-4,6-diaza-1(6,8)-imidazo[1,2-a]pyridina-2(2,6)-pyridinacyclododecaphan-5-one;
(3R,7R,E)-4-ethyl-23-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(2,6)-pyrazinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-26-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(5,7)-pyrazolo[1,5-a]pyridina-2(5,3)-pyridazinacyclotridecaphan-5-one;
(3R,7S,E)-4-ethyl-8,8-difluoro-25-methoxy-3,7-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(R,E)-4-ethyl-3,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridina-7(1,2)-cyclopropanacyclododecaphan-5-one;
(3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-22,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(3,5)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyrimidinacyclotridecaphan-5-one;
(3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-22-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(3,5)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-b]pyridazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyridina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-7-(2,2-difluoropropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3-methylpyrazin-2-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25,3-dimethyl-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(2-(methylsulfonyl) ethyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(5,7)-pyrazolo[1,5-a]pyridina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-quinolina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-3,4-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(5,3)-pyridazinacyclotridecaphan-5-one;
(3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-15,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(2,4)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(2,4)-pyridinacyclotridecaphan-5-one;
(3R,7R)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-naphthyridina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-naphthyridina-2(4,2)-pyridinacyclotridecaphan-9-en-5-one;
(3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-12,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-b]pyridazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-4-ethyl-25-methoxy-13,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-b]pyridazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(7,5)-[1,2,4]triazolo[1,5-c]pyrimidina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-9,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-15,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-4-ethyl-23-fluoro-3-methyl-7-(3,3,3-trifluoropropyl)-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(7,5)-[1,2,4]triazolo[1,5-c]pyrimidina-2(4,2)-pyridinacyclotridecaphan-5-one;
(R,E)-4-ethyl-25-methoxy-3-methyl-14-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotetradecaphan-5-one;
(R,E)-4-ethyl-25-methoxy-3-methyl-11-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacycloundecaphan-5-one;
(7S,E)-4-ethyl-23-fluoro-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-3-methyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-3-methyl-10,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-(2-(difluoromethoxy) ethyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-7-((1-fluorocyclopropyl) methyl)-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-(4,4-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-7-(isopropoxymethyl)-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-(2,2-difluoroethyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-7-(2,2,3,3-tetrafluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-7-((2,2,2-trifluoroethoxy) methyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-7-(tetrahydrofuran-3-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-((2,2-difluoroethoxy) methyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-7-(1-methoxyethyl)-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-(2,2-difluorocyclopropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-7-(tetrahydrofuran-2-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
2-((3R,E)-4-ethyl-25-methoxy-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphane-7-yl)acetonitrile;
(3R,E)-7-(3,3-difluorocyclobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
3-((3R,E)-4-ethyl-25-methoxy-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphane-7-yl)propanenitrile;
(3R,E)-25-cyclopropyl-7-(3,3-difluoropropyl)-4-ethyl-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-25-chloro-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-fluoro-7-(methoxymethyl)-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-(3,3-difluoropropyl)-4-ethyl-25,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-(3,3-difluoropropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-(bicyclo[1.1.1]pentan-1-ylmethyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-(3,3-difluoropropyl)-4-ethyl-25-fluoro-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-b]pyridazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-cyclopropyl-7-(3,3-difluoropropyl)-25-fluoro-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-7-((1-methylcyclopropyl) methyl)-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-7-(2,2-difluoropropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3S,E)-7-(3,3-difluoropropyl)-4-ethyl-25-methoxy-3-(trifluoromethyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(9R,13R,E)-14-Cyclopropyl-12-ethyl-13-methyl-9-(3,3,3-trifluoropropyl)-3-oxa-10,12-diaza-1(5,2)-thiazola-2(6,8)-imidazo[1,2-a]pyrazinacyclotridecaphan-11-one;
(16E,22E,7R)-25-cyclopropyl-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-21H-13-oxa-4,6-diaza-1(5,7)-pyrazolo[1,5-a]pyridina-2(1,3)-pyrazolacyclotridecaphan-5-one;
(9R,13R,E)-14-Cyclopropyl-12-ethyl-13-methyl-9-(3,3,3-trifluoropropyl)-3-oxa-10,12-diaza-1(5,2)-oxazola-2(6,8)-imidazo[1,2-a]pyrazinacyclotridecaphan-11-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-74-(trifluoromethyl)-11-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridina-7 (3,1)-pyrrolidinacycloundecaphan-5-one;
(3R,E)-4-ethyl-74,74-difluoro-3-methyl-11-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-7(3,1)-pyrrolidina-2(1,3)-benzenacycloundecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-74-(trifluoromethyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridina-7(3,1)-pyrrolidinacyclododecaphan-5-one;
(3R,E)-4-ethyl-22-methoxy-3-methyl-7-(2-methylthiazol-4-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(3,5)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-7-(2-methylthiazol-5-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-7-(1-methyl-1H-tetrazol-5-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-7-(4-methylthiazol-2-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-7-(1-methyl-1H-1,2,4-triazol-5-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(17E,3R,8E)-4-ethyl-11,11-difluoro-25-methoxy-3,7-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-8-en-5-one;
(3R,7S,E)-4-ethyl-11,11-difluoro-25-methoxy-3,7-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan-5-one;
(3′R,7'S,7′E,8′E)-4′-ethyl-5′-methoxy-3′,7′-dimethyl-2,3,5,6-tetrahydrospiro[pyran-4,11′-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphanen]-8′-en-5′-one;
(3′R,7'S,E)-4′-ethyl-5′-methoxy-3′,7′-dimethyl-2,3,5,6-tetrahydrospiro[pyran-4,11′-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphan]-5′-one;
(3R,E)-4-ethyl-25-methoxy-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphane-7-carbonitrile;
and
(3R,E)-4-ethyl-25-fluoro-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazina-2(4,2)-pyridinacyclotridecaphane-7-carboxamide;
or a pharmaceutically acceptable salt thereof.

231 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/250,267Filed 28 Oct 2021 · us provisional application
Priority: 2 Nov 2020
Published: US 2023/0391795 A17 Dec 2023
Granted: 21 Jul 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 498/18
In which the condensed system contains three hetero rings: bridged systems
A61P 25/00
Drugs for disorders of the nervous system
C07D 498/22
Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
C07D 513/22
Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero…