Novel Cyclopropabenzofuranyl Pyridopyrazinediones
Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I wherein X, R 1 , R 2a , R 2b , R 4a , R 4b , R 5a , R 5b , R 6 , R 7 , R 10 , R 11 , and y are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
1 . A compound having the structure of Formula I:
or pharmaceutically acceptable salts thereof, wherein:
X is a (5- to 14-membered)heteroaryl containing 1-3 heteroatoms;
R 1 , where chemically permissible, is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, oxo, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , and —C(═O)—OR 4 ;
R 2a and R 2b , where chemically permissible, at each occurrence, are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted phenyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , and —C(═O)—OR 4 ; or R 2a and R 2b together with the carbon atom(s) to which they are attached form a (C 3 -C 8 )cycloalkyl or a (4- to 10-membered)heterocycloalkyl, wherein the (C 3 -C 8 )cycloalkyl and the (4- to 10-membered)heterocycloalkyl are optionally substituted with one to three R 8 ;
R 4a and R 4b , where chemically permissible, are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, oxo, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted phenyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , and —C(═O)—OR 4 ; or R 4a and R 4b together with the carbon atom to which they are attached form a (C 3 -C 8 )cycloalkyl, wherein the (C 3 -C 8 )cycloalkyl is optionally substituted with one to three R 8 ;
R 5a and R 5b , at each occurrence, are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, oxo, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted phenyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , and —C(═O)—OR 4 ; or R 5a and R 5b together with the carbon atom to which they are attached form a (C 3 -C 8 )cycloalkyl, wherein said (C 3 -C 8 )cycloalkyl is optionally substituted with one to three R 8 ;
R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, cyano, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted phenyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , —C(═O)—OR 4 , and —OR 9 ; provided that R 6 and R 7 cannot both be hydroxy;
R 8 , at each occurrence, is independently selected from the group consisting of cyano, halogen, hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, and optionally substituted (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
R 9 is selected from the group consisting of hydrogen and optionally substituted (C 1 -C 6 )alkyl;
y is an integer selected from 1, 2, 3 or 4;
ring B is optionally substituted with one to three R 10 , wherein each R 10 is independently selected from the group consisting of halogen, cyano, hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , and —C(═O)—OR 4 ; or two R 10 substituents taken together with the carbon atom(s) to which they are attached form an optionally substituted (C 3 -C 8 )cycloalkyl;
ring D is optionally substituted with one to four R 11 , wherein each R 11 is independently selected from the group consisting of halogen, cyano, hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (4- to 6-membered)heterocycloalkyl; —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , —C(═O)—OR 4 ; and
R 4 and R 5 , at each occurrence, are each independently selected from hydrogen or optionally substituted (C 1 -C 6 )alkyl;
provided that the compound is not 7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione.
2 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is represented by:
Xi) a (5- to 6-membered)heteroaryl containing 1-3 heteroatoms;
Xii) a (6-membered)heteroaryl containing 1-3 heteroatoms; or
Xiii) a (5-membered)heteroaryl containing 1-3 heteroatoms.
3 . The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein X is a (5-membered)heteroaryl selected from the group consisting of triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, and oxazolyl.
4 . The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein X is imidazolyl.
5 . The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein X is triazolyl.
6 . The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 , where chemically permissible, is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, oxo, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , and —C(═O)—OR 4 ;
R 2a and R 2b , where chemically permissible, at each occurrence, are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted phenyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , and —C(═O)—OR 4 ; or R 2a and R 2b together with the carbon atom(s) to which they are attached form a (C 3 -C 8 )cycloalkyl or a (4- to 10-membered)heterocycloalkyl, wherein the (C 3 -C 8 )cycloalkyl and the (4- to 10-membered)heterocycloalkyl are optionally substituted with one to three R 8 ;
R 4a and R 4b , where chemically permissible, are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, oxo, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted phenyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , and —C(═O)—OR 4 ; or R 4a and R 4b together with the carbon atom to which they are attached form a (C 3 -C 8 )cycloalkyl, wherein the (C 3 -C 8 )cycloalkyl is optionally substituted with one to three R 8 ;
R 5a and R 5b , at each occurrence, are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, oxo, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted phenyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , and —C(═O)—OR 4 ; or R 5a and R 5b together with the carbon atom to which they are attached form a (C 3 -C 8 )cycloalkyl, wherein said (C 3 -C 8 )cycloalkyl is optionally substituted with one to three R 8 ;
R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, cyano, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted phenyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , —C(═O)—OR 4 , and —OR 9 ; provided that R 6 and R 7 cannot both be hydroxy;
R 8 , at each occurrence, is independently selected from the group consisting of cyano, halogen, hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, and optionally substituted (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
R 9 is selected from the group consisting of hydrogen and optionally substituted (C 1 -C 6 )alkyl;
y is an integer selected from 1, 2, 3 or 4;
ring B is optionally substituted with one to three R 10 , wherein each R 10 is independently selected from the group consisting of halogen, cyano, hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , —C(═O)—OR 4 ; or two R 10 substituents taken together with the carbon atom(s) to which they are attached form an optionally substituted (C 3 -C 8 )cycloalkyl;
ring D is optionally substituted with one to four R 11 , wherein each R 11 is independently selected from the group consisting of halogen, cyano, hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted thio(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (4- to 6-membered)heterocycloalkyl; —N(R 4 )(R 5 ), —N(R 4 )(C═(O)R 5 ), —C(═O)N(R 4 )(R 5 ), —O—C(═O)N(R 4 )(R 5 ), —C(═O)—R 4 , —C(═O)—OR 4 ; and
R 4 and R 5 , at each occurrence, are each independently selected from hydrogen or optionally substituted (C 1 -C 6 )alkyl.
7 . The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy; wherein the (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one to three substituents selected from halogen, oxo, cyano, hydroxy, or —SF 5 ;
R 2a and R 2b are each independently selected from hydrogen, halogen, cyano, hydroxy or optionally substituted (C 1 -C 6 )alkyl;
R 4a , R 4b , R 5a and R 5b are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, oxo, —SF 5 , optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy, wherein the (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one to three substituents selected from halogen, oxo, cyano, hydroxy, or —SF 5 ;
R 6 and R 7 are each independently selected from the group consisting of hydrogen, cyano, halogen, —SF 5 , optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy, wherein the (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one to three substituents selected from halogen, oxo, cyano, hydroxy, or —SF 5 ;
y is 1;
ring B is optionally substituted with one to two R 10 , wherein each R 10 is independently selected from halogen, cyano, hydroxy, —SF 5 , optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy, wherein the (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one to three substituents selected from halogen, oxo, cyano, hydroxy, or —SF 5 ; and
ring D is optionally substituted with one to three R 11 , wherein each R 11 is independently selected from the group consisting of halogen, cyano, hydroxy, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, —SF 5 , —N(R 4 )(R 5 ), nitro, and optionally substituted (C 3 -C 8 )cycloalkyl, wherein the (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 3 -C 8 )cycloalkyl are optionally substituted with one to three substituents independently selected from halogen, cyano, hydroxy, —SF 5 , and optionally substituted (C 1 -C 6 )alkyl, wherein R 4 and R 5 are each independently selected from hydrogen or optionally substituted (C 1 -C 6 )alkyl.
8 . The compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is an optionally substituted (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is substituted with one to three substituents selected from halogen, oxo, cyano, hydroxy, or —SF 5 ; and
R 2a , R 2b , R 4a , R 4b , R 5a and R 5b are each independently
i) hydrogen; or
ii) optionally substituted (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is substituted with one to three substituents selected from halogen, oxo, cyano, hydroxy, or —SF 5 .
9 . The compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl; and R 2a , R 2b , R 4a , R 4b , R 5a and R 5b are each independently hydrogen.
10 . The compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl; R 2a , R 2b , R 5a and R 5b are each independently hydrogen; and one of R 4a and R 4b is hydrogen and the other is methyl.
11 . The compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl; one of R 2a and R 2b is hydrogen and the other is methyl; R 4a , R 4b , R 5a and R 5b are each independently hydrogen.
12 . A compound having the structure of Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy; wherein the (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one to three substituents selected from halogen, oxo, cyano, hydroxy, or —SF 5 ;
R 2a , R 2b , R 4a , R 4b , R 5a and R 5b are each independently selected from hydrogen, halogen, cyano, hydroxy or optionally substituted (C 1 -C 6 )alkyl;
ring B is optionally substituted with one to two R 10 , wherein each R 10 is independently selected from halogen or optionally substituted (C 1 -C 6 )alkyl; and
ring D is optionally substituted with one to three R 11 , wherein each R 11 is independently selected from halogen, optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy;
provided that the compound is not 7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione.
13 . The compound according to claim 12 , wherein:
R 1 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy; wherein the (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one to three fluoro atoms;
R 2a , R 2b , R 4a , R 4b , R 5a and R 5b are each independently selected from hydrogen or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is methyl;
ring B is optionally substituted with one to two R 10 , wherein each R 10 is selected from:
i) halogen selected from fluoro or chloro, or
ii) (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is methyl; and
ring D is optionally substituted with one to three R 11 , wherein each R 11 is selected from:
i) halogen selected from fluoro or chloro;
ii) optionally substituted (C 1 -C 6 )alkyl selected from the group consisting of fluoromethyl, difluoromethyl, and trifluoromethyl; and
iii) optionally substituted (C 1 -C 6 )alkoxy, wherein the optionally substituted (C 1 -C 6 )alkoxy is selected from the group consisting of fluoromethoxy, difluoromethoxy, trifluoromethoxy.
14 . The compound according to claim 12 , wherein R 1 is a (C 1 -C 6 )alkyl wherein the alkyl is methyl.
15 . A compound having the structure of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy; wherein the (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one to three substituents selected from halogen, oxo, cyano, hydroxy, or —SF 5 ;
R 2a , R 2b , R 4a , R 4b , R 5a and R 5b are each independently selected from hydrogen, halogen, cyano, hydroxy or optionally substituted (C 1 -C 6 )alkyl;
ring B is optionally substituted with one to two R 10 , wherein each R 10 is independently selected from halogen or optionally substituted (C 1 -C 6 )alkyl; and
ring D is optionally substituted with one to three R 11 , wherein each R 11 is independently selected from halogen, optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy.
16 . The compound according to claim 15 , wherein:
R 1 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy; wherein the (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with one to three fluoro atoms;
R 2a , R 2b , R 4a , R 4b , R 5a and R 5b are each independently selected from hydrogen or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is methyl;
ring B is optionally substituted with one to two R 10 , wherein each R 10 is selected from:
i) halogen selected from fluoro or chloro, or
ii) (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is methyl; and
ring D is optionally substituted with one to three R 11 , wherein each R 11 is selected from:
i) halogen selected from fluoro or chloro;
ii) optionally substituted (C 1 -C 6 )alkyl selected from the group consisting of fluoromethyl, difluoromethyl, and trifluoromethyl; and
iii) optionally substituted (C 1 -C 6 )alkoxy, wherein the optionally substituted (C 1 -C 6 )alkoxy is selected from the group consisting of fluoromethoxy, difluoromethoxy, and trifluoromethoxy.
17 . A compound selected from the group consisting of:
7-(4-methyl-1H-imidazol-1-yl)-2-{[1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aS,6bS)-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aR,6bR)-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-3-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(3-methyl-1H-1,2,4-triazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-4-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-4-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-5-(difluoromethoxy)-4-fluoro-1a-methyl-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-[4-(hydroxymethyl)-1H-imidazol-1-yl]-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aS,6bS)-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
7-(4-methyl-1H-imidazol-1-yl)-2-{[(1aR,6bR)-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-3-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-3-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aS,6bS)-3-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione;
2-{[(1aR,6bR)-3-chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione; or the
pharmaceutically acceptable salts thereof.
18 . 2-{[(1aS,6bS)-4-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
19 . 2-{[(1aR,6bR)-4-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
20 . 2-{[(1aS,6bS)-3-Fluoro-1a-methyl-5-(trifluoromethoxy)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
21 . 2-{[(1aR,6bR)-3-Fluoro-1a-methyl-5-(trifluoromethoxy)-1, 1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
22 . 2-{[(1aS,6bS)-4-Chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
23 . 2-{[(1aR,6bR)-4-Chloro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b][1]benzofuran-6b-yl]methyl}-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
24 . 2-(((1aS,6bS)-4-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b]benzofuran-6b-yl)methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
25 . 2-(((1aR,6bR)-4-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b]benzofuran-6b-yl)methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
26 . 2-(((1aS,6bS)-3-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b]benzofuran-6b-yl)methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
27 . 2-(((1aR,6bR)-3-fluoro-1a-methyl-5-(trifluoromethyl)-1,1a-dihydro-6bH-cyclopropa[b]benzofuran-6b-yl)methyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione, or a pharmaceutically acceptable salt thereof.
28 . A method for reducing the production of amyloid beta (Aβ) peptides, in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
29 . A method for reducing the production of amyloid beta Aβ42 peptide, in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
30 . A method of modulating the gamma-secretase complex in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
31 . A method for treating Alzheimer's disease in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
32 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.