MODIFIER OF FOUR-MEMBERED RING DERIVATIVE, PREPARATION METHOD AND APPLICATION THEREOF

Abstract

Provided is a modifier of a four-membered ring derivative, a preparation method and application thereof. In particular, provided is a compound represented by the general formula (IX-A), a preparation method thereof, a pharmaceutical composition containing the compound, and a use thereof as a G protein-coupled receptor modulator in the treatment or prevention of central nervous system diseases and/or mental diseases. The definition of each substituents in the general formula (IX-A) is same as the definition in the specification.

##STR00001##

Claims

1. A compound of formula (IX-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ##STR00209## wherein: R.sup.4 is selected from the group consisting of 5 to 6 membered N-containing heterocyclyl, ##STR00210## ##STR00211## ##STR00212## ##STR00213## ##STR00214## the 5 to 6 membered N-containing heterocyclyl is preferably an oxazolidinonyl; R.sub.a is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C.sub.1-.sub.6 alkyl, C.sub.1-.sub.6 deuterated alkyl, C.sub.1-.sub.6 haloalkyl, C.sub.1-.sub.6 alkoxy, C.sub.1-.sub.6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl and 5 to 12 membered heteroaryl; R.sub.b is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C.sub.1-.sub.6 alkyl, C.sub.1-.sub.6 deuterated alkyl, C.sub.1-.sub.6 haloalkyl, C.sub.1-.sub.6 alkoxy, C.sub.1-.sub.6 hydroxyalkyl, C.sub.1-.sub.6 haloalkoxy, C.sub.2-.sub.6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl and 5 to 12 membered heteroaryl, wherein the amino, C.sub.1-.sub.6 alkyl, C.sub.1-.sub.6 deuterated alkyl, C.sub.1-.sub.6 haloalkyl, C.sub.1-.sub.6 alkoxy, C.sub.1-.sub.6 haloalkoxy, C.sub.2-.sub.6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl and 5 to 12 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxy, cyano, C.sub.1-.sub.6 alkyl, C.sub.1-.sub.6 deuterated alkyl, C.sub.1-.sub.6 haloalkyl, C.sub.1-.sub.6 alkoxy, C.sub.1-.sub.6 haloalkoxy, C.sub.2-.sub.6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl and 5 to 12 membered heteroaryl; R.sup.5 is selected from the group consisting of hydrogen, deuterium, C.sub.1-.sub.6 alkyl, C.sub.1-.sub.6 deuterated alkyl, C.sub.1-.sub.6 haloalkyl, C.sub.1-.sub.6 alkoxy, C.sub.1-.sub.6 haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C.sub.2-.sub.6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl and 5 to 12 membered heteroaryl; preferably, R.sub.5 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-.sub.3 alkyl, C.sub.1-.sub.3 haloalkyl, C.sub.1-.sub.3 alkoxy and C.sub.3-.sub.6 cycloalkyl, and more preferably selected from the group consisting of hydrogen and chlorine; or, any adjacent two R.sub.5 are bonded to form a 5 to 6 membered heterocyclyl or 5 to 6 membered heteroaryl, preferably a 5 to 6 membered heteroaryl containing 1 to 2 N, S or O heteroatoms, and more preferably thienyl; r is 0, 1 or 2; m is 0 or 1; and t is 0, 1, 2 or 3, and preferably 2; ##STR00215## ##STR00216## and m is 1, then R.sup.4 is not ##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221## NHC(O)C.sub.2H.sub.5, -NHC(O)N(CH.sub.3).sub.2, -NHC(O)NHCH.sub.3, -NHC(O)N(C.sub.2H.sub.5)CH.sub.3, -NHC(O)NHC.sub.2H.sub.5, ##STR00222## ##STR00223## ##STR00224## ##STR00225## ##STR00226## ##STR00227## ##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232## ##STR00233## when m is 2, then R.sup.4 is not -NHC(O)N(CH.sub.3).sub.2.

2. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is further as shown in formula (X) or formula (X-A): ##STR00234## ##STR00235## .

3. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 wherein R.sub.4 is selected from the group consisting of 5 to 6 membered N-containing heterocyclyl, ##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240## the 5 to 6 membered N-containing heterocyclyl is preferably an oxazolidinonyl; R.sub.a is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-.sub.3 alkyl, C.sub.1-.sub.3 haloalkyl, C.sub.1-.sub.3 alkoxy and C.sub.3-.sub.6 cycloalkyl; preferably, R.sub.a is selected from the group consisting of hydrogen and methyl; R.sub.b is selected from the group consisting of amino, C.sub.1-.sub.3 alkyl, C.sub.1-.sub.3 alkoxy, C.sub.1-.sub.3 hydroxyalkyl, C.sub.3-.sub.6 cycloalkyl, 3 to 6 membered heterocyclyl, C.sub.6-.sub.10 aryl and 5 to 10 membered heteroaryl, optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C.sub.1-.sub.3 alkyl and C.sub.1-.sub.3 alkoxy; preferably, R.sub.b is selected from the group consisting of amino, methyl, ethyl, methoxy, hydroxyisopropyl, cyclopropyl, azetidinyl, phenyl, pyridyl, furanyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl, indolyl, quinolyl and benzoxazolyl, optionally further substituted by one or more substituents selected from the group consisting of fluorine, cyano, hydroxy, methyl and methoxy; and r is 0, 1 or 2.

4. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is further as shown in formula (XI): ##STR00241## wherein: R.sub.6 is selected from the group consisting of hydrogen, deuterium, C.sub.1-.sub.6 alkyl, C.sub.1-.sub.6 deuterated alkyl, C.sub.1-.sub.6 haloalkyl, C.sub.1-.sub.6 alkoxy, C.sub.1-.sub.6 haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C.sub.2-.sub.6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl and 5 to 12 membered heteroaryl; R.sub.7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C.sub.1-.sub.6 alkyl, C.sub.1-.sub.6 deuterated alkyl, C.sub.1-.sub.6 haloalkyl, C.sub.1-.sub.6 alkoxy, C.sub.1-.sub.6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl, 5 to 12 membered heteroaryl, R.sub.ee, -C(O)(CH.sub.2).sub.n2R.sub.ee, -(CH.sub.2).sub.n2C(O)NR.sub.eeR.sub.ff, -C(O)NR.sub.eeR.sub.ff, -(CH2)n2C(O)NReeC(O)Rff, -(CH.sub.2).sub.n2S(O).sub.m2R.sub.ee, -(CH.sub.2).sub.n2NR.sub.eeS(O).sub.m2R.sub.ff, -(CH.sub.2).sub.n2S(O).sub.m2NR.sub.eeR.sub.ff, -(CH.sub.2).sub.n1S(O).sub.m2NR.sub.eeR.sub.ff, -(CH.sub.2).sub.n2OR.sub.ee, -C(O)NRee(CH2)n2Rff, -C(O)(CH.sub.2).sub.n2OR.sub.ee, -(CH2)n2SRee, -(CH.sub.2).sub.n2C(O)OR.sub.ee, -P(O)R.sub.eeR.sub.ff, -(CH.sub.2).sub.n2NR.sub.eeC(O)R.sub.ff and -(CH.sub.2).sub.n2NR.sub.eeS(O).sub.m2R.sub.ff, wherein the C.sub.1-6 alkyl, C.sub.1-6 deuterated alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-.sub.6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl and 5 to 12 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxy, cyano, C.sub.1-6 alkyl, C.sub.1-6 deuterated alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-.sub.6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl and 5 to 12 membered heteroaryl; preferably, R.sub.7 is selected from the group consisting of R.sub.ee, -C(O)(CH.sub.2).sub.n2R.sub.ee, -C(O)NR.sub.eeR.sub.ff, -C(O)NRff(CH2)n2Ree, -S(O).sub.m2R.sub.ee and -S(O).sub.m2NR.sub.eeR.sub.ff; R.sub.ee and R.sub.ff are each independently selected from the group consisting of hydrogen, amino, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.14 aryl and 5 to 14 membered heteroaryl, wherein the amino, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.1-6 alkoxy; preferably, R.sub.ee and R.sub.ff are each independently selected from the group consisting of amino, C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl, C.sub.3-.sub.6 cycloalkyl, phenyl, naphthyl, biphenyl, 4 to 6-membered heterocyclyl containing 1 to 2 nitrogen atoms and 5 to 10 membered heteroaryl containing 1 to 2 oxygen, nitrogen, sulfur atoms, optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; and more preferably, R.sub.ee and R.sub.ff are each independently selected from the group consisting of: (CH.sub.3).sub.2N-, CH.sub.3NH-, CH.sub.3-, CH.sub.3CH.sub.2-, CH.sub.3CH.sub.2NH-, CH.sub.3CH.sub.2NCH.sub.3-, (CH.sub.3).sub.2C(OH)-, (CH.sub.3).sub.2C(OH)CH.sub.2-, CH.sub.3OCH.sub.2-, ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## n2 is selected from the group consisting of 0, 1 and 2; m2 is selected from the group consisting of 0, 1 and 2; and m is selected from the group consisting of 0, 1 and 2.

5. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4, wherein R.sub.ee and R.sub.ff are each independently selected from the group consisting of hydrogen and the following substituents: ##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## .

6. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4, wherein, R.sub.6 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C.sub.1-3 alkyl, C.sub.1-3 deuterated alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkoxy, C.sub.2- .sub.3 alkenyl and C.sub.2-.sub.3 alkynyl, and preferably hydrogen; R.sub.7 is selected from the group consisting of R.sub.ee, -C(O)(CH.sub.2).sub.n2R.sub.ee, -C(O)NR.sub.eeR.sub.ff, -C(O)NRff(CH2)n2Ree, -S(O).sub.m2R.sub.ee and -S(O).sub.m2NR.sub.eeR.sub.ff; R.sub.ee is selected from the group consisting of hydrogen, amino, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.14 aryl and 5 to 14 membered heteroaryl, wherein the amino, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.1-6 alkoxy; preferably, R.sub.ee is selected from the group consisting of amino, C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl, C.sub.3-6 cycloalkyl, phenyl, naphthyl, biphenyl, 4 to 6-membered heterocyclyl containing 1 to 2 oxygen, nitrogen, sulfur heteroatoms and 5 to 10 membered heteroaryl containing 1 to 2 oxygen, nitrogen, sulfur heteroatoms, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; and more preferably, R.sub.ee is selected from the group consisting of: (CH.sub.3).sub.2N-, CH.sub.3NH-, CH.sub.3-, CH.sub.3CH.sub.2-, CH.sub.3CH.sub.2NH-, CH.sub.3CH.sub.2NCH.sub.3-, (CH.sub.3).sub.2C(OH)-, (CH.sub.3).sub.2C(OH)CH.sub.2-, CH.sub.3OCH.sub.2-, ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279## R.sub.ff is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C.sub.1-6 alkyl, C.sub.1-6 deuterated alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2- .sub.6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl and 5 to 12 membered heteroaryl; preferably, R.sub.ff is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy and C.sub.3-.sub.6 cycloalkyl; and more preferably, R.sub.ff is selected from the group consisting of hydrogen and methyl; n2 is selected from the group consisting of 0, 1 and 2; and m2 is selected from the group consisting of 0, 1 and 2.

7. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4, wherein the compound is further as shown in formula (XI-A) or formula (XI-B): ##STR00280## ##STR00281## .

8. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4 , wherein ##STR00282## selected from the group consisting of ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292## ##STR00293## ##STR00294## .

9. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4 , wherein ##STR00295## selected from the group consisting of ##STR00296## ##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302## .

10. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 4, wherein the compound is further as shown in formula (XII): ##STR00303## wherein: R.sub.8 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C.sub.1-6 alkyl, C.sub.1-6 deuterated alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-.sub.6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-.sub.8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-12 aryl and 5 to 12 membered heteroaryl, wherein the amino, C.sub.1-6 alkyl, C.sub.1-6 deuterated alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-.sub.6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl and 5 to 12 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxy, cyano, C.sub.1-6 alkyl, C.sub.1-6 deuterated alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-.sub.6 alkenyl, C.sub.2-.sub.6 alkynyl, C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-.sub.12 aryl and 5 to 12 membered heteroaryl; preferably, R.sub.8 is selected from the group consisting of amino, C.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C.sub.6-10 aryl and 5 to 10 membered heteroaryl, wherein the amino, C.sub.1-3 alkyl, C.sub.1-3 hydroxyalkyl, C.sub.3-.sub.6 cycloalkyl, 3 to 6 membered heterocyclyl, C.sub.6-10 aryl and 5 to 10 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of hydroxy, cyano, C.sub.1-3 alkyl, C.sub.1-3 alkoxy and C.sub.3- .sub.6 cycloalkyl; and more preferably, R.sub.8 is further selected from the group consisting of: CH.sub.3O-, HOC(CH.sub.3).sub.2-, ##STR00304## ##STR00305## ##STR00306## ##STR00307## v is 0 or 1; when v is 0, then R.sub.8 is not -C.sub.2H.sub.5, -N(CH.sub.3).sub.2, -NHCH.sub.3, -NC.sub.2H.sub.5CH.sub.3, -NHC.sub.2H.sub.5, ##STR00308## ##STR00309## ##STR00310## when v is 1, then R.sub.8 is not phenyl.

11. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 10, wherein the compound of formula (XII) is further as shown in formula (XII-A) or formula (XII-B): ##STR00311## ##STR00312## .

12. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sub.4 is ##STR00313## R.sub.b is selected from the group consisting of C.sub.3-.sub.6 cycloalkyl and 5 to 10 membered heteroaryl containing 1 to 2 nitrogen, oxygen, sulfur atoms, optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxy, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy and C.sub.1-3 haloalkoxy; R.sub.5 is selected from the group consisting of hydrogen, halogen and C.sub.1-3 alkyl; m is 1; t is 1, 2 or 3; when r is 0 and R.sub.b is ##STR00314## then R.sub.b is substituted by at least one substituent; when r is 0 and R.sub.b is ##STR00315## then R.sub.b is substituted by at least one substituent.

13. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 12, wherein R.sub.b is selected from the group consisting of C.sub.3-6 cycloalkyl, 5 to 6 membered heteroaryl containing nitrogen or oxygen and 9 to 10 membered fused heteroaryl containing nitrogen, optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy and C.sub.1-3 haloalkoxy; and preferably, R.sub.b is selected from the group consisting of cyclopropyl, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolyl and quinolyl, optionally further substituted by one or more substituents selected from the group consisting of halogen, C.sub.1-3 alkyl and C.sub.1-3 haloalkyl.

14. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the specific structure of the compound is as follows: ##STR00316## ##STR00317## ##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332## ##STR00333## ##STR00334## ##STR00335## ##STR00336## ##STR00337## ##STR00338## ##STR00339## ##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## .

15. A method for preparing the compound of formula (XII), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 10, comprising the following step of, ##STR00388## reacting a compound of formula (XII-1) with an acyl chloride or carboxylic acid of formula (XII-2) to obtain the compound of formula (XII), the stereoisomer thereof or the pharmaceutically acceptable salt thereof.

16. A compound of formula (XII-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ##STR00389## .

17. A method for preparing the compound of formula (XII-1), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 16, comprising the following step of, ##STR00390## deprotecting a compound of formula (XII-3) to obtain the compound of formula (XII-1), the stereoisomer thereof or the pharmaceutically acceptable salt thereof; wherein: Pg.sub.1 is an amino protecting group, selected from the group consisting of allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, fluorenemethoxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl and p-methoxyphenyl, and preferably tert-butoxycarbonyl; optionally, reacting a compound of formula (XII-4) with a compound of formula (XII-5) to obtain the compound of formula (XII-3), the stereoisomer thereof or the pharmaceutically acceptable salt thereof; ##STR00391## Pg.sub.2 is a hydroxy protecting group, selected from the group consisting of methyl, tert-butyl, triphenyl, methylthiomethyl ether, 2-methoxyethoxymethyl ether, methoxymethyl ether, p-methoxybenzyl ether, pivaloyl, benzyl ether group, methoxymethyl, trimethylsilyl, tetrahydrofuranyl, tert-butyldisilyl, acetyl, benzoyl and p-toluenesulfonyl, and preferably p-toluenesulfonyl.

18. A pharmaceutical composition, comprising a therapeutically effective dose of the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, and one or more pharmaceutically acceptable carriers, diluents or excipients.

19. The pharmaceutical composition according to claim 18, wherein the therapeutically effective dose is 0.1 to 500 mg .

20. Use of the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a G protein-coupled receptor modulator medicament .

21. Use of the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating or preventing a central nervous system disease or psychiatric disease or .

Description

DEFINITIONS

[0092] Unless otherwise stated, the terms used in the specification and claims have the meanings described below.

[0093] The term “alkyl” refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group comprising 1 to 20 carbon atoms, preferably an alkyl having 1 to 8 carbon atoms, more preferably an alkyl having 1 to 6 carbon atoms, and most preferably an alkyl having 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferably, the alkyl group is a lower alkyl having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. The alkyl group can be substituted or unsubstituted. When substituted, the substituent group(s) can be substituted at any available connection point. The substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl. The alkyl of the present invention is preferably selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

[0094] The term “alkylene” refers to an alkyl of which a hydrogen atom is further substituted, for example, “methylene” refers to -CH.sub.2-, “ethylene” refers to -(CH.sub.2).sub.2-, “propylene” refers to -(CH.sub.2).sub.3-, “butylene” refers to -(CH.sub.2).sub.4- and the like. The term “alkenyl” refers to an alkyl as defined above that consists of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like. The alkenyl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocyclylthio.

[0095] The term “cycloalkyl” refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring. The cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl, and more preferably cyclopropyl, cyclobutyl and cyclohexyl.

[0096] The term “spiro cycloalkyl” refers to a 5 to 20 membered polycyclic group with individual rings connected through one shared carbon atom (called a spiro atom), wherein the rings can contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. The spiro cycloalkyl is preferably a 6 to 14 membered spiro cycloalkyl, and more preferably a 7 to 10 membered spiro cycloalkyl. According to the number of the spiro atoms shared between the rings, the spiro cycloalkyl can be divided into a mono-spiro cycloalkyl, a di-spiro cycloalkyl, or a poly-spiro cycloalkyl, and the spiro cycloalkyl is preferably a mono-spiro cycloalkyl or di-spiro cycloalkyl, and more preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro cycloalkyl. Non-limiting examples of spiro cycloalkyl include:

##STR00117##

and also include spiro cycloalkyl in which a cycloalkyl and a heterocyclyl are connected through one spiro atom, non-limiting examples thereof include:

##STR00118##

[0097] The term “fused cycloalkyl” refers to a 5 to 20 membered all-carbon polycyclic group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. The fused cycloalkyl is preferably a 6 to 14 membered fused cycloalkyl, and more preferably a 7 to 10 membered fused cycloalkyl. According to the number of membered rings, the fused cycloalkyl can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and the fused cycloalkyl is preferably a bicyclic or tricyclic fused cycloalkyl, and more preferably a 4-membered/4-membered, 5-membered/5-membered or 5-membered/6-membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl include:

##STR00119##

[0098] The term “bridged cycloalkyl” refers to a 5 to 20 membered all-carbon polycyclic group, wherein every two rings in the system share two disconnected carbon atoms, the rings can have one or more double bonds, but none of the rings has a completely conjugated π-electron system. The bridged cycloalkyl is preferably a 6 to 14 membered bridged cycloalkyl, and more preferably a 7 to 10 membered bridged cycloalkyl. According to the number of membered rings, the bridged cycloalkyl can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and the bridged cycloalkyl is preferably a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, and more preferably a bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl include:

##STR00120##

##STR00121##

[0099] The cycloalkyl ring can be fused to the ring of aryl, heteroaryl or heterocyclyl, wherein the ring bound to the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl and the like. The cycloalkyl can be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl.

[0100] The term “heterocyclyl” refers to a 3 to 20 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, boron, phosphorus, S(O).sub.m (wherein m is an integer of 0 to 2) and P(O).sub.n (wherein n is an integer of 0 to 2), but excluding -O-O-, -O-S- or -S-S- in the ring, with the remaining ring atoms being carbon atoms. Preferably, the heterocyclyl has 3 to 12 ring atoms wherein 1 to 4 atoms are heteroatoms; more preferably, 3 to 8 ring atoms; and most preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl include oxacyclobutyl, oxacyclobutyl, pyrrolidinyl, oxazolidin-2-one group, azepinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, preferably oxacyclobutyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, oxazolidin-2-one group, morpholinyl, piperazinyl and azepinyl, and more preferably oxacyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl and oxazolidin-2-one group. Polycyclic heterocyclyl includes a heterocyclyl having a spiro ring, fused ring or bridged ring. The heterocyclyl having a spiro ring, fused ring or bridged ring is optionally bonded to other group via a single bond, or further bonded to other cycloalkyl, heterocyclyl, aryl and heteroaryl via any two or more atoms on the ring.

[0101] The term “spiro heterocyclyl” refers to a 3 to 20 membered polycyclic heterocyclyl group with individual rings connected through one shared atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, boron, phosphorus, S(O).sub.m (wherein m is an integer of 0 to 2) and P(O).sub.n (wherein n is an integer of 0 to 2), with the remaining ring atoms being carbon atoms, and the rings can contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. The spiro heterocyclyl is preferably a 6 to 14 membered spiro heterocyclyl, and more preferably a 7 to 10 membered spiro heterocyclyl. According to the number of the spiro atoms shared between the rings, the spiro heterocyclyl can be divided into a mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and the spiro heterocyclyl is preferably a mono-spiro heterocyclyl or di-spiro heterocyclyl, and more preferably a 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl. Non-limiting examples of spiro heterocyclyl include:

##STR00122##

and the like.

[0102] The term “fused heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of atoms with another ring, one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and S(O).sub.m (wherein m is an integer of 0 to 2), with the remaining ring atoms being carbon atoms. The fused heterocyclyl is preferably a 6 to 14 membered fused heterocyclyl, and more preferably a 7 to 10 membered fused heterocyclyl. According to the number of membered rings, the fused heterocyclyl can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, and preferably a bicyclic or tricyclic fused heterocyclyl, and more preferably a 3-membered/5-membered, 4-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl include:

##STR00123##

##STR00124##

the like.

[0103] The term “bridged heterocyclyl” refers to a 5 to 14 membered polycyclic heterocyclyl group, wherein every two rings in the system share two disconnected atoms, wherein the rings can have one or more double bond(s), but none of the rings has a completely conjugated π-electron system, and one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and S(O).sub.m (wherein m is an integer of 0 to 2), with the remaining ring atoms being carbon atoms. The bridged heterocyclyl is preferably a 6 to 14 membered bridged heterocyclyl, and more preferably a 7 to 10 membered bridged heterocyclyl. According to the number of membered rings, the bridged heterocyclyl can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and the bridged heterocyclyl is preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably a bicyclic or tricyclic bridged heterocyclyl. Non-limiting examples of bridged heterocyclyl include:

##STR00125##

##STR00126##

[0104] The heterocyclyl ring can be fused to the ring of aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl. Non-limiting examples thereof include:

##STR00127##

and the like.

[0105] The heterocyclyl can be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl.

[0106] The term “aryl” refers to a 6 to 14 membered all-carbon monocyclic ring or polycyclic fused ring (i.e. each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) having a conjugated π-electron system, preferably a 6 to 10 membered aryl, for example, phenyl and naphthyl. The aryl is more preferably phenyl. The aryl ring can be fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to the parent structure is aryl ring. Non-limiting examples thereof include:

##STR00128##

##STR00129##

##STR00130##

[0107] The aryl can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

[0108] The term “heteroaryl” refers to a 5 to 14 membered heteroaromatic system having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl is preferably a 5 to 12 membered heteroaryl, more preferably a 5 to 10 membered heteroaryl, and further preferably a 5 or 6 membered heteroaryl, wherein the heteroatom is 1 to 2 heteroatom(s) selected from the group consisting of oxygen, sulfur and nitrogen atom, for example imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, isoxazolyl, oxadiazolyl, pyrazinyl and the like, preferably pyridyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, pyrimidinyl and thiazolyl, and more preferably pyridyl, thiazolyl, oxazolyl, isoxazolyl, furanyl and pyrimidinyl. The heteroaryl ring can be fused to the ring of aryl, heterocyclyl or cycloalkyl, wherein the ring bound to the parent structure is heteroaryl ring. Non-limiting examples thereof include:

##STR00131##

[0109] The heteroaryl can be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

[0110] The term “alkoxy” refers to an -O-(alkyl) or an -O-(unsubstituted cycloalkyl) group, wherein the alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy. The alkoxy can be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

[0111] “Haloalkyl” refers to an alkyl group substituted by one or more halogen(s), wherein the alkyl is as defined above.

[0112] “Haloalkoxy” refers to an alkoxy group substituted by one or more halogen(s), wherein the alkoxy is as defined above.

[0113] “Hydroxyalkyl” refers to an alkyl group substituted by hydroxy(s), wherein the alkyl is as defined above.

[0114] “Alkenyl” refers to a chain alkenyl, also known as alkene group. The alkenyl can be further substituted by other related group, for example alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy or alkoxycarbonyl.

[0115] “Alkynyl” refers to (CH=C-). The alkynyl can be further substituted by other related group, for example alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy or alkoxycarbonyl.

[0116] “Hydroxy” refers to an -OH group.

[0117] “Halogen” refers to fluorine, chlorine, bromine or iodine.

[0118] “Amino” refers to a -NH.sub.2 group.

[0119] “Cyano” refers to a -CN group.

[0120] “Nitro” refers to a -NO.sub.2 group.

[0121] “Carboxy” refers to a -C(O)OH group.

[0122] “THF” refers to tetrahydrofuran.

[0123] “EtOAc” refers to ethyl acetate.

[0124] “MeOH” refers to methanol.

[0125] “DMF” refers to N,N-dimethylformamide.

[0126] “DIPEA” refers to diisopropylethylamine.

[0127] “TFA” refers to trifluoroacetic acid.

[0128] “MeCN” refers to acetonitrile.

[0129] “DMA” refers to N,N-dimethylacetamide.

[0130] “Et.sub.2O” refers to diethyl ether.

[0131] “DCE” refers to 1,2-dichloroethane.

[0132] “DIPEA” refers to N,N-diisopropylethylamine.

[0133] “NBS” refers to N-bromosuccinimide.

[0134] “NIS” refers to N-iodosuccinimide.

[0135] “Cbz-Cl” refers to benzyl chloroformate.

[0136] “Pd.sub.2(dba).sub.3” refers to tris(dibenzylideneacetone)dipalladium.

[0137] “Dppf” refers to 1,1'-bisdiphenylphosphinoferrocene.

[0138] “HATU” refers to 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate.

[0139] “KHMDS” refers to potassium hexamethyldisilazide.

[0140] “LiHMDS” refers to lithium bis(trimethylsilyl)amide.

[0141] “MeLi” refers to methyl lithium.

[0142] “n-BuLi” refers to n-butyl lithium.

[0143] “NaBH(OAc).sub.3” refers to sodium triacetoxyborohydride.

[0144] Different expressions such as “X is selected from the group consisting of A, B or C”, “X is selected from the group consisting of A, B and C”, “X is A, B or C”, “X is A, B and C” and the like, express the same meaning, that is, X can be any one or more of A, B and C.

[0145] The hydrogen atom of the present invention can be substituted by its isotope deuterium. Any of the hydrogen atoms in the compounds of the examples of the present invention can also be substituted by deuterium atom.

[0146] “Optional” or “optionally” means that the event or circumstance described subsequently can, but need not, occur, and such a description includes the situation in which the event or circumstance does or does not occur. For example, “the heterocyclyl optionally substituted by an alkyl” means that an alkyl group can be, but need not be, present, and such a description includes the situation of the heterocyclyl being substituted by an alkyl and the heterocyclyl being not substituted by an alkyl.

[0147] “Substituted” refers to one or more hydrogen atoms in a group, preferably up to 5, and more preferably 1 to 3 hydrogen atoms, independently substituted by a corresponding number of substituents. It goes without saying that the substituents only exist in their possible chemical position. The person skilled in the art is able to determine whether the substitution is possible or impossible by experiments or theory without excessive efforts. For example, the combination of amino or hydroxy having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable.

[0148] A “pharmaceutical composition” refers to a mixture of one or more of the compounds according to the present invention or physiologically/pharmaceutically acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient so as to exert biological activity.

[0149] In general, the compound of formula (IX-A) or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount by any acceptable administration mode of an agent with similar use. The therapeutically effective amount of the compound of the present disclosure may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single dose or multiple doses. Suitable dose level can be about 0.1 to about 250 mg/kg per day, about 0.5 to about 100 mg/kg per day. Suitable dose level can be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range, the dose can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. When administered orally, the composition may be provided in the form of a tablet containing about 1.0 to about 1000 mg of the active ingredient, particularly about 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7.5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient, and preferably 0.1, 0.2, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7.5, 10, 15 and 20 mg of the active ingredient. The actual amount of the compound of the present disclosure, i.e., the active ingredient, depends on many factors, such as the severity of the disease to be treated, the age and relative health condition of the patient, the efficacy of the compound used, the route and form of administration and the like.

[0150] A “pharmaceutically acceptable salt” refers to a salt of the compound of the present invention, which is safe and effective in mammals and has the desired biological activity.

DETAILED DESCRIPTION OF THE INVENTION

[0151] The present invention will be further described with reference to the following examples, but the examples should not be considered as limiting the scope of the present invention.

Examples

[0152] The structures of the compounds of the present invention were identified by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). NMR shifts (8) are given in parts per million (ppm). NMR was determined by a Bruker AVANCE-400 machine. The solvents for determination were deuterated-dimethyl sulfoxide (DMSO-d.sub.6), deuterated-methanol (CD.sub.3OD) and deuterated-chloroform (CDCl.sub.3), and the internal standard was tetramethylsilane (TMS).

[0153] Liquid chromatography-mass spectrometry (LC-MS) was determined on an Agilent 1200 Infinity Series mass spectrometer. High performance liquid chromatography (HPLC) was determined on an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm chromatographic column), and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm chromatographic column).

[0154] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used as the thin-layer silica gel chromatography (TLC) plate. The dimension of the silica gel plate used in TLC was 0.15 mm to 0.2 mm, and the dimension of the silica gel plate used in product purification was 0.4 mm to 0.5 mm. Yantai Huanghai 200 to 300 mesh silica gel was generally used as a carrier for column chromatography.

[0155] The raw materials used in the examples of the present invention are known and commercially available, or can be synthesized by adopting or according to known methods in the art.

[0156] Unless otherwise stated, all reactions of the present invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, the solvent was dry, and the reaction temperature was in degrees celsius.

Example 1

[0157] 1-Benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea

##STR00132##

[0158] Step 1: 1-Benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea

##STR00133##

[0159] Trans(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexan-1-amine (60 mg, 0.162 mmol) and triethylamine (50 mg, 0.49 mmol) were added to DCM (3 mL). CDI (29 mg, 0.178 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. Benzylamine (36 mg, 0.324 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and purified by preparative chromatography to obtain 1-benzyl-3-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)cyclohexyl)urea as a white solid (10 mg, yield: 12%).

[0160] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.36 - 7.27 (m, 5H), 7.18 - 7.04 (m, 2H), 6.97 (d, J = 6.9 Hz, 1H), 4.58 (s, 1H), 4.37 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 7.5 Hz, 1H), 3.48 (s, 1H), 3.11-2.79 (m, 8H), 2.00 (s, 2H), 1.79-1.64 (m, 4H), 1.33 - 1.00 (m, 9H). MS m/z (ESI): 503.2 [M+H].sup.+.

Example 2

[0161] 3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

##STR00134##

[0162] Step 1: Tert-butyl (3-oxocyclobutyl)carbamate

##STR00135##

[0163] 3-Oxocyclobutane-1-carboxylic acid (1.5 g, 13.2 mmol), triethylamine (2.0 mL, 14.5 mmol) and toluene (30 mL) were added to a 100 mL eggplant-shaped flask successively. Diphenylphosphoryl azide (4.0 g, 14.5 mmol) was slowly added at -5° C. to 0° C. The reaction solution was stirred at 0° C. for 16 hours. The reaction solution was washed with saturated aqueous sodium bicarbonate solution (30 mLx1) and saturated aqueous sodium chloride solution (30 mLx1) at 0° C., and the organic phase was dried over anhydrous sodium sulfate. Tert-butanol (7.5 mL, 74.8 mmol) was added to the organic phase, and the reaction solution was heated to 100° C. and stirred for 16 hours. The reaction solution was concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 5/1) to obtain tert-butyl (3-oxocyclobutyl)carbamate (500 mg, yield: 20.5%).

[0164] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.86 (s, 1H), 4.27 (s, 1H), 3.50 - 3.33 (m, 2H), 3.11 - 2.97 (m, 2H), 1.46 (s, 9H).

[0165] Step 2: Methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutylidene)acetate

##STR00136##

[0166] Tert-butyl (3-oxocyclobutyl)carbamate (450 mg, 2.43 mmol) and toluene (20 mL) were added to a 50 mL eggplant-shaped flask successively, followed by the slow addition of methyl (triphenylphosphoranylidene)acetate (1.22 g, 3.64 mmol). The reaction solution was refluxed under a nitrogen atmosphere for 16 hours, cooled, and concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 6/1) to obtain methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutylidene)acetate (450 mg, yield: 76.8%).

[0167] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.76 - 5.66 (m, 1H), 4.80 (br, 1H), 4.24 (s, 1H), 3.69 (s, 3H), 3.63 - 3.49 (m, 1H), 3.27 - 3.10 (m, 1H), 3.00 - 2.86 (m, 1H), 2.82 - 2.64 (m, 1H), 1.45 (s, 9H).

[0168] Step 3: Methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)acetate

##STR00137##

[0169] Methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutylidene)acetate (450 mg, 1.9 mmol) and methanol (10 mL) were added to a 50 mL eggplant-shaped flask successively. Pd/C (45 mg, containing 10% palladium and 50% water) were added slowly under a nitrogen atmosphere. The reaction solution was stirred under a hydrogen atmosphere (1 atm) for 5 hours, filtered, and concentrated to dryness by rotary evaporation to remove the solvent and obtain the crude product methyl 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)acetate (450 mg), which was used directly in the next step.

[0170] MS m/z (ESI):244.2 [M+H].sup.+.

[0171] Step 4: Tert-butyl (3-(2-hydroxyethyl)cyclobutyl)carbamate

##STR00138##

[0172] Methyl 2(3–((tert-butoxycabronyl)amino)cyclobutyl)acetate (450 mg, 1.9 mmol) and anhydrous tetrahydrofuran (10 mL) were added to a 50 mL eggplant-shaped flask successively. Lithium aluminum tetrahydride (210 mg, 5.6 mmol) was added slowly at 0° C. under a nitrogen atmosphere. The reaction solution was stirred at 0° C. for 2 hours, and the reaction was quenched by saturated aqueous sodium bicarbonate solution. The reaction solution was dried over anhydrous sodium sulfate directly, and stirred for 15 minutes. The organic phase was filtered, and concentrated to dryness by rotary evaporation to obtain the crude product tert-butyl (3–2–hydroxyethyl)cyclobutyl)carbamate (450 mg), which was used directly in the next step. MS m/z (ESI):216.2 [M+H].sup.+. Step 5: 2–(3–((Tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4–methylbenzenesulfonate

##STR00139##

[0173] Tert-butyl (3-(2-hydroxyethyl)cyclobutyl)carbamate (450 mg, 2.1 mmol), triethylamine (634 mg, 6.3 mmol) and dichloromethane (10 mL) were added to a 50 mL eggplant-shaped flask successively, followed by the slow addition of 4-tosyl chloride (438 mg, 2.3 mmol). The reaction solution was stirred at room temperature overnight, followed by the addition of dichloromethane (20 mL), and washed with water (30 mLx1). The organic phase was dried and concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 5/1) to obtain 2-(3-((tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate (710 mg, yield: 84%).

[0174] MS m/z (ESI):370.2 [M+H].sup.+.

[0175] Step 6: Tert-butyl (3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)carbamate

##STR00140##

[0176] 2-((Tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate (350 mg, 0.95 mmol), potassium carbonate (392 mg, 2.84 mmol) and acetonitrile (10 mL) were added to a 50 mL eggplant-shaped flask successively, followed by the slow addition of 1-(2,3-dichlorophenyl)piperazine (219 mg, 0.95 mmol). The reaction solution was refluxed overnight. The reaction solution was cooled, followed by the addition of dichloromethane (20 mL), and washed with water (30 mLx3). The organic phase was dried and concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (dichloromethane/methanol: 50/1) to obtain tert-butyl (3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)carbamate (310 mg, yield: 76%).

[0177] MS m/z (ESI):428.2 [M+H].sup.+.

[0178] Step 7: 3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride

##STR00141##

[0179] Tert-butyl (3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)carbamate (310 mg, 0.72 mmol) and ethyl acetate (2 mL) were added to a 25 mL eggplant-shaped flask successively, followed by the addition of hydrochloric acid in ethyl acetate (10 mL, 4M) at 0° C. The reaction solution was stirred at room temperature for 1 hour, and concentrated to dryness by rotary evaporation to remove the solvent and obtain the crude product 3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride (310 mg), which was used directly in the next step.

[0180] MS m/z (ESI):328.1 [M+H].sup.+.

[0181] Step 8: 3 -(3 -(2-(4-(2,3 -Dichlorophenyl)piperazin-1 -yl)ethyl)cyclobutyl)-1,1 -dimethylurea

##STR00142##

[0182] 3-(4-(2,3-Dichlorophenyl)piperazin- 1-yl)ethyl)cyclobutan-1-amine hydrochloride (50 mg, 0.11 mmol), triethylamine (69 mg, 0.69 mmol) and dichloromethane (2 mL) were added to a 10 mL reaction flask successively, followed by the addition of dimethylcarbamoyl chloride (18.4 mg, 0.17 mmol) under stirring. The reaction solution was stirred at room temperature for 12 hours, and concentrated to dryness by rotary evaporation to remove the solvent and obtain the crude product. The crude product was purified by preparative HPLC to obtain 3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea (11 mg, yield: 24%).

[0183] .sup.1H NMR (400 MHz, CDCl.sub.3) 8 7.23 - 7.10 (m, 2H), 7.08 - 6.91 (m, 1H), 4.61 -3.93 (m, 2H), 3.56 - 3.02 (m, 4H), 3.03 - 2.64 (m, 8H), 2.65 - 2.31 (m, 3H), 2.31- 1.21 (m, 7H).

[0184] MS m/z (ESI): 399.2[M+H]+.

Example 2A

[0185] 3-(Trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

##STR00143##

[0186] Step 1: Trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (intermediate 2-1) and cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (intermediate 2-2)

##STR00144##

##STR00145##

##STR00146##

[0187] 3-(4-(2,3-Dichlorophenyl)piperazin- 1-yl)ethyl)cyclobutan- 1-amine hydrochloride was resolved to obtain trans-3-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine 1) and cis-3-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine 2).

TABLE-US-00001 Chiral preparation conditions Instrument SFC-200 (Thar, Waters) Column type AD 20*250 mm, 10 .Math.m (Daicel) Column pressure 100 bar Mobile phase CO2/ Methanol (0.2% Methanol Ammonia) = 70/30 Flow rate 130 g/min Detection wavelength UV 254 nm Column temperature 35° C.

Intermediate 2-1: t.SUB.R.=1.285 min

[0188] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.18 - 7.12 (m, 2H), 6.99 - 6.93 (m, 1H), 3.63 - 3.53 (m, 1H), 3.16 - 3.02 (m, 4H), 2.74 - 2.54 (m, 4H), 2.39 - 2.30 (m, 2H), 2.26 - 2.13 (m, 1H), 2.06 - 1.99 (m, 2H), 1.99 - 1.93 (m, 2H), 1.91 - 1.84 (m, 2H), 1.72 -1.64 (m, 2H).

[0189] MS m/z (ESI):328.1 [M+H].sup.+.

Intermediate 2-2: t.SUB.R.=0.882 min

[0190] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.18 - 7.11 (m, 2H), 7.00 - 6.93 (m, 1H), 3.33 - 3.22 (m, 1H), 3.13 - 3.00 (m, 4H), 2.71 - 2.56 (m, 4H), 2.51 - 2.43 (m, 2H), 2.37 - 2.30 (m, 2H), 2.07 - 1.97 (m, 2H), 1.89 - 1.75 (m, 1H), 1.67 - 1.58 (m, 2H), 1.39 -1.28 (m, 2H).

[0191] MS m/z (ESI):328.1 [M+H].sup.+.

[0192] Step 2: 3-(Trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

##STR00147##

[0193] In accordance with the reaction conditions of Step 8 of Example 2, the intermediate 2-1 was used as the starting material, accordingly, 3-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea was obtained.

[0194] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.23 - 7.07 (m, 2H), 7.07 - 6.91 (m, 1H), 4.49 (d, J = 7.1 Hz, 1H), 4.44 - 4.28 (m, 1H), 3.53 - 3.03 (m, 5H), 2.90 (s, 6H), 2.82 -2.61 (m, 3H), 2.51 - 2.35 (m, 2H), 2.27 - 2.10 (m, 3H), 2.08 - 1.95 (m, 2H), 1.88 - 1.72 (m, 2H).

[0195] MS m/z (ESI): 399.1[M+H].sup.+.

Example 2B

[0196] 3-(Cis(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea

##STR00148##

##STR00149##

[0197] In accordance with the reaction conditions of Step 8 of Example 2, the intermediate 2-2 was used as the starting material, accordingly, 3-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1,1-dimethylurea was obtained.

[0198] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.20 - 7.12 (m, 2H), 6.97 (dd, J = 6.7, 2.8 Hz, 1H), 4.41 (d, J = 7.5 Hz, 1H), 4.21 - 4.08 (m, 1H), 3.21 - 3.04 (m, 4H), 2.89 (s, 6H), 2.81 - 2.59 (m, 4H), 2.53 (dd, J = 9.6, 7.0 Hz, 2H), 2.45 - 2.32 (m, 2H), 1.99 -1.88 (m, 1H), 1.70 - 1.65 (m, 2H), 1.47 - 1.39 (m, 2H).

[0199] MS m/z (ESI): 399.1[M+H].sup.+.

Example 3

[0200] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)propionamide

##STR00150##

[0201] Step 1: N-(3-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)propionamide

##STR00151##

[0202] 3-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride (50 mg, 0.11 mmol), diisopropylethylamine (88 mg, 0.69 mmol) and dichloromethane (10 mL) were added to a 10 mL reaction flask successively, followed by the addition of propionyl chloride (12.7 mg, 0.14 mmol) under stirring. The reaction solution was stirred at room temperature for 12 hours, and washed with water. The organic phase was dried, and concentrated to dryness by rotary evaporation to remove the solvent and obtain the crude product. The crude product was purified by preparative HPLC to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)propionamide (18 mg, yield: 41%).

[0203] MS m/z (ESI): 384.2[M+H].sup.+.

Example 4

[0204] 1-Cyclopropyl-3 -(3 -(2-(4-(2,3 -dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)urea

##STR00152##

##STR00153##

[0205] 3-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride (33 mg, 0.09 mmol), triethylamine (46 mg, 0.45 mmol) and N’N-carbonyldiimidazole (22 mg, 0.16 mmol) were dissolved in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 2 hours, and the raw materials disappeared. Cyclopropylamine (10 mg, 0.18 mmol) was added, and the reaction solution was stirred at 35° C. for 48 hours. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by preparative HPLC to obtain 1-cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)urea (12 mg, yield: 32.2%).

[0206] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.20 - 7.12 (m, 2H), 6.97 (dd, J = 7.0, 2.4 Hz, 1H), 5.08 (dd, J = 28.8, 7.3 Hz, 1H), 4.64 (s, 1H), 4.43 - 4.09 (m, 1H), 3.14 (s, 4H), 2.73 (s, 4H), 2.56 (ddd, J= 16.2, 7.4, 2.8 Hz, 2H), 2.43 (s, 3H), 2.05 (dddd, J= 33.4, 24.1, 16.7, 8.5 Hz, 4H), 1.83 - 1.68 (m, 2H), 1.48 (dt, J= 9.6, 6.0 Hz, 2H), 0.76 (q, J= 6.3 Hz, 2H), 0.61 - 0.53 (m, 2H).

[0207] MS m/z (ESI): 411.2[M+H].sup.+.

Example 5

[0208] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1H-indole-2-carboxa mide

##STR00154##

##STR00155##

[0209] 3-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 1H-indole-2-carboxylic acid (30 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol) and diisopropylethylamine (58 mg, 0.45 mmol). The reaction solution was stirred at room temperature overnight, and concentrated to dryness by rotary evaporation. The resulting crude product was purified by high performance liquid chromatography to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1H-indole-2-carboxam ide.

[0210] MS m/z (ESI): 471.2 [M+H].sup.+.

Example 6

[0211] 3 -(3 -(4-(Benzo [b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1 -dimethylurea

##STR00156##

[0212] Step 1: Tert-butyl (3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-l-yl)ethyl)cyclobutyl)carbamate

##STR00157##

[0213] 2-((Tert-butoxycarbonyl)amino)cyclobutyl)ethyl 4-methylbenzenesulfonate (200 mg, 0.54 mmol), potassium carbonate (224 mg, 1.62 mmol) and acetonitrile (10 mL) were added to a 50 mL eggplant-shaped flask successively, followed by the slow addition of 1-(benzo[b]thiophen-4-yl)piperazine (118 mg, 0.54 mmol). The reaction solution was refluxed overnight. The reaction solution was cooled, followed by the addition of dichloromethane (20 mL), and washed with water (30 mLx3). The organic phase was dried and concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (dichloromethane/methanol: 50/1) to obtain tert-butyl (3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)carbamate (120 mg, yield: 53%).

[0214] MS m/z (ESI):416.2 [M+H].sup.+.

[0215] Step 2: 3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride

##STR00158##

[0216] Tert-butyl (3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)carbamate (120 mg, 0.29 mmol) and ethyl acetate (1 mL) were added to a 25 mL eggplant-shaped flask successively, followed by the addition of hydrochloric acid in ethyl acetate (6 mL, 4M) at 0° C. The reaction solution was stirred at room temperature for 1 hour, and concentrated to dryness by rotary evaporation to remove the solvent and obtain the crude hydrochloride (110 mg), which was used directly in the next step.

[0217] MS m/z (ESI):316.1 [M+H].sup.+.

[0218] Step 3: 3 -(3 -(2-(4-(Benzo [b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1, 1-dimethylurea

##STR00159##

[0219] 3 -(4-(Benzo [b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride (50 mg, 0.12 mmol), triethylamine (71 mg, 0.70 mmol) and dichloromethane (2 mL) were added to a 10 mL reaction flask successively, followed by the addition of dimethylcarbamoyl chloride (19 mg, 0.18 mmol) under stirring. The reaction solution was stirred at room temperature for 12 hours, and concentrated to dryness by rotary evaporation to remove the solvent and obtain the crude product. The crude product was purified by preparative HPLC to obtain 3 -(3 -(2-(4-(benzo [b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1,1 -dimethylurea (17 mg, yield: 37%).

[0220] MS m/z (ESI):387.2 [M+H].sup.+.

Example 7

[0221] N-(2-(4-(2,3-Dichlorophenyl)-1,4-diazepan-l-yl)ethyl)cyclobutyl)furan-2-carboxami de

##STR00160##

[0222] The process was the same as in Example 2.

[0223] MS m/z (ESI): 436.2[M+H].sup.+.

Example 8

[0224] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-5-methylfuran-2-carbo xamide

##STR00161##

[0225] In accordance with Step 8 of Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-5-methylfuran-2-carbo xamide (23 mg, white solid, yield: 28.3%) was obtained.

[0226] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.21 - 7.12 (m, 2H), 7.01 - 6.96 (m, 2H), 6.39 (dd, J = 34.1, 8.0 Hz, 1H), 6.11 - 6.06 (m, 1H), 4.52 (dq, J = 84.5, 8.0 Hz, 1H), 3.23 - 3.05 (m, 4H), 2.76 (s, 4H), 2.59 (td, J = 7.4, 6.8, 2.2 Hz, 1H), 2.48 - 2.46 (m, 1H), 2.35 (s, 3H), 2.24 - 2.13 (m, 2H), 2.04 - 1.97 (m, 1H), 1.84 - 1.75 (m, 2H), 1.62 (qd, J = 9.1, 2.8 Hz, 2H).

[0227] MS m/z (ESI): 436.1 [M+H].sup.+.

Example 9

[0228] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methoxyacetamide

##STR00162##

[0229] In accordance with Step 8 of Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methoxyacetamide (29 mg, white solid, yield: 33%) was obtained.

[0230] .sup.1H NMR (400 MHz, Chloroform-d) 8 7.19 - 7.12 (m, 2H), 6.97 (dd, J = 7.0, 2.5 Hz, 1H), 6.63 (dd, J = 42.2, 8.2 Hz, 1H), 4.42 (dq, J = 87.5, 7.9 Hz, 1H), 3.86 (d, J = 4.7 Hz, 2H), 3.42 (d, J = 2.5 Hz, 3H), 3.22 - 3.06 (m, 4H), 2.81 - 2.61 (m, 4H), 2.58 -2.52 (m, 1H), 2.45 - 2.32 (m, 2H), 2.21 - 2.03 (m, 2H), 2.02 - 1.91 (m, 1H), 1.79 - 1.73 (m, 1H), 1.70 - 1.67 (m, 1H), 1.57 - 1.49 (m, 1H).

[0231] MS m/z (ESI): 400.1 [M+H].sup.+.

Example 10

[0232] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)nicotinamide

##STR00163##

[0233] In accordance with Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)nicotinamide (25 mg, white solid, yield: 29%) was obtained.

[0234] The compound of Example 10 can also be obtained in accordance with the synthesis method of Example 5.

[0235] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.97 (d, J = 2.2 Hz, 1H), 8.72 (dd, J = 4.8, 1.8 Hz, 1H), 8.12 (dq, J = 8.0, 2.0 Hz, 1H), 7.44 - 7.34 (m, 1H), 7.19 - 7.12 (m, 2H), 6.97 (dt, J = 7.0, 2.7 Hz, 1H), 6.41 (dd, J = 14.4, 7.5 Hz, 1H), 4.85 - 4.34 (m, 1H), 3.12 (t, J= 5.0 Hz, 4H), 2.78 - 2.66 (m, 4H), 2.46 - 2.39 (m, 2H), 2.27 - 2.16 (m, 2H), 2.13 - 2.02 (m, 1H), 1.87 - 1.79 (m, 1H), 1.79 - 1.57 (m, 3H).

[0236] MS m/z (ESI): 433.1 [M+H].sup.+.

Example 11

[0237] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpr opanamide

##STR00164##

[0238] In accordance with Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-hydroxy-2-methylpr opanamide (32 mg, white solid, yield: 30%) was obtained.

[0239] The compound of Example 11 can also be obtained in accordance with the synthesis method of Example 5.

[0240] MS m/z (ESI): 414.1 [M+H].sup.+.

Example 12

[0241] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxyazetidine-1-carboxamide

##STR00165##

[0242] In accordance with Example 4, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methoxyazetidine-1-carboxamide (22 mg, white solid, yield: 23%) was obtained.

[0243] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.18 - 7.12 (m, 2H), 6.96 (dd, J = 7.1, 2.6 Hz, 1H), 4.41 - 4.22 (m, 1H), 4.21 - 4.15 (m, 2H), 4.11 - 4.06 (m, 2H), 3.85 - 3.78 (m, 2H), 3.29 (s, 3H), 3.16 - 3.08 (m, 4H), 2.69 (s, 4H), 2.55 - 2.49 (m, 1H), 2.42 - 2.35 (m, 2H), 2.11 (ddd, J = 11.5, 7.3, 2.9 Hz, 1H), 2.04 - 1.85 (m, 2H), 1.71 (dq, J = 32.8, 7.8 Hz, 2H), 1.44 (td, J= 9.2, 2.9 Hz, 1H).

[0244] MS m/z (ESI): 441.1 [M+H].sup.+.

Example 13

[0245] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropan e-1-carboxamide

##STR00166##

[0246] 3-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 1-hydroxycyclopropane-1-carboxylic acid (18 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol) and diisopropylethylamine (58 mg, 0.45 mmol). The reaction solution was stirred at room temperature overnight, and concentrated to dryness by rotary evaporation. The resulting crude product was purified by high performance liquid chromatography to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopropan e-1-carboxamide (13 mg, white solid, yield: 21%).

[0247] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.20 - 7.12 (m, 2H), 7.07 (dd, J = 28.3, 8.0 Hz, 1H), 6.96 (dd, J = 7.1, 2.5 Hz, 1H), 4.38 (dq, J = 87.6, 7.9 Hz, 1H), 3.20 - 3.05 (m, 4H), 2.72 (s, 4H), 2.56 (dd, J = 8.9, 2.9 Hz, 1H), 2.41 (dd, J = 9.5, 6.3 Hz, 2H), 2.25 (d, J = 8.4 Hz, 1H), 2.19 - 2.06 (m, 2H), 1.99 (dd, J = 14.2, 6.4 Hz, 1H), 1.82 - 1.69 (m, 2H), 1.55 (dd, J = 9.1, 2.9 Hz, 1H), 1.35 - 1.30 (m, 2H), 1.01 (q, J = 4.6 Hz, 2H).

[0248] MS m/z (ESI): 412.1 [M+H].sup.+.

Example 13A

[0249] N-(Trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclo propane-1-carboxamide

##STR00167##

[0250] In accordance with the reaction conditions of Example 13, the intermediate 2-1 was used as the starting material, accordingly, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclop ropane-1-carboxamide was obtained.

[0251] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.20 - 7.13 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.97 (dd, J = 7.0, 2.6 Hz, 1H), 4.56 - 4.44 (m, 1H), 3.22 - 3.07 (m, 4H), 2.86 -2.66 (m, 4H), 2.50 - 2.41 (m, 2H), 2.32 - 2.24 (m, 1H), 2.20 - 2.05 (m, 5H), 1.84 - 1.76 (m, 2H), 1.38 - 1.32 (m, 2H), 1.06 - 1.00 (m, 2H).

[0252] MS m/z (ESI): 412.1 [M+H].sup.+.

Example 13B

[0253] N-(Cis(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopro pane-1-carboxamide

##STR00168##

##STR00169##

[0254] In accordance with the reaction conditions of Example 13, the intermediate 2-2 was used as the starting material, accordingly, N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-hydroxycyclopro pane-1-carboxamide (13B) was obtained.

[0255] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.24 - 7.15 (m, 2H), 7.09 (d, J = 7.8 Hz, 1H), 7.02 - 6.98 (m, 1H), 4.36 - 4.25 (m, 1H), 3.33 (s, 4H), 3.18 - 2.95 (m, 3H), 2.73 -2.65 (m, 2H), 2.63 - 2.54 (m, 2H), 2.05 - 1.89 (m, 4H), 1.71 - 1.59 (m, 3H), 1.36 - 1.30 (m, 2H), 1.06 - 1.00 (m, 2H).

[0256] MS m/z (ESI): 412.1 [M+H].sup.+.

Example 14

[0257] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamid e

##STR00170##

##STR00171##

[0258] 3-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of thiazole-2-carboxylic acid (23 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol) and diisopropylethylamine (58 mg, 0.45 mmol). The reaction solution was stirred at room temperature overnight, and concentrated to dryness by rotary evaporation. The resulting crude product was purified by high performance liquid chromatography to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carboxamide (21 mg, white solid, yield: 32%).

[0259] .sup.1H NMR (400 MHz, Chloroform-d) 8 7.86 (dd, J = 3.1, 1.5 Hz, 1H), 7.57 (d, J = 3.1 Hz, 1H), 7.40 (dd, J = 42.4, 8.2 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.01 - 6.93 (m, 1H), 4.73 - 4.28 (m, 1H), 3.18 - 3.03 (m, 4H), 2.78 - 2.54 (m, 6H), 2.44 - 2.35 (m, 2H), 2.24 - 2.19 (m, 1H), 2.10 - 1.98 (m, 1H), 1.81- 1.75 (m, 1H), 1.71 - 1.65 (m, 2H).

[0260] MS m/z (ESI): 439.1 [M+H].sup.+.

Example 14A

[0261] N-(Trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carbox amide

##STR00172##

##STR00173##

[0262] In accordance with the reaction conditions of Example 14, the intermediate 2-1 was used as the starting material, accordingly, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)thiazole-2-carbox amide (21 mg, white solid, yield: 32%) was obtained.

[0263] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J= 3.1 Hz, 1H), 7.57 (d, J= 3.1 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.21 - 7.13 (m, 2H), 7.00 - 6.95 (m, 1H), 4.74 - 4.59 (m, 1H), 3.18 - 3.02 (m, 4H), 2.79 - 2.58 (m, 4H), 2.47 - 2.38 (m, 2H), 2.35 - 2.27 (m, 1H), 2.25 - 2.18 (m, 4H), 1.87 - 1.77 (m, 2H).

[0264] MS m/z (ESI): 439.1 [M+H].sup.+.

Example 15

[0265] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-hydroxy-3-methylbu tanamide

##STR00174##

[0266] In accordance with Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-hydroxy-3-methylbu tanamide (21 mg, white solid, yield: 20%) was obtained.

[0267] The compound of Example 15 can also be obtained in accordance with the synthesis method of Example 5.

[0268] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.21 - 7.13 (m, 2H), 6.96 (dd, J = 7.0, 2.7 Hz, 1H), 6.08 (dd, J= 21.6, 7.5 Hz, 1H), 4.51 - 4.19 (m, 2H), 3.10 (d, J= 6.2 Hz, 4H), 2.76 - 2.62 (m, 4H), 2.56 (ddd, J = 8.9, 5.9, 2.7 Hz, 1H), 2.42 - 2.36 (m, 2H), 2.29 (d, J = 6.4 Hz, 2H), 2.05 - 1.96 (m, 3H), 1.72 (dq, J= 28.0, 7.6 Hz, 2H), 1.51 (td, J= 9.1, 2.8 Hz, 1H), 1.27 (d, J= 2.2 Hz, 6H).

[0269] MS m/z (ESI): 428.1 [M+H].sup.+.

Example 16

[0270] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-(5-methyloxazol-2-y 1)acetamide

##STR00175##

[0271] In accordance with Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-(5-methyloxazol-2-y 1)acetamide (15 mg, white solid, yield: 16%) was obtained.

[0272] The compound of Example 16 can also be obtained in accordance with the synthesis method of Example 5.

[0273] MS m/z (ESI): 451.1 [M+H].sup.+.

Example 17

[0274] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methylisoxazol-5 -yl)acetamide

##STR00176##

[0275] In accordance with Example 2, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-(3-methylisoxazol-5-yl)acetamide (26 mg, white solid, yield: 28%) was obtained.

[0276] The compound of Example 17 can also be obtained in accordance with the synthesis method of Example 5.

[0277] MS m/z (ESI): 451.1 [M+H].sup.+.

Example 18

[0278] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropanesulfonami de

##STR00177##

##STR00178##

[0279] 3-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine hydrochloride (40 mg, 0.11 mmol), triethylamine (44 mg, 0.44 mmol) and cyclopropanesulfonyl chloride (31 mg, 0.22 mmol) were dissolved in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 12 hours, and concentrated to dryness by rotary evaporation to remove the solvent. The resulting crude product was purified by preparative HPLC to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropanesulfonami de (15 mg, yield: 31.6%).

[0280] .sup.1H NMR (400 MHz, CDCl.sub.3) 8 7.20 - 7.10 (m, 2H), 7.00 - 6.92 (m, 1H), 4.75 -4.60 (m, 1H), 4.14 - 3.73 (m, 1H), 3.09 (s, 4H), 2.67 (s, 4H), 2.62 - 2.49 (m, 2H), 2.42 - 2.29 (m, 3H), 2.25 - 1.89 (m, 5H), 1.79 - 1.54 (m, 4H), 1.16 (d, J = 4.8 Hz, 2H), 0.99 (q, J = 6.8 Hz, 2H).

[0281] MS m/z (ESI): 432.0 [M+H].sup.+.

Example 19

[0282] 3-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1-ethyl-1-methylure a

##STR00179##

[0283] In accordance with Example 6, 1-(benzo[b]thiophen-4-yl)piperazine was used as the starting material, accordingly, 3-(3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclobutyl)-1-ethyl-1-methylure a was obtained.

[0284] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 3.7 Hz, 2H), 7.31 - 7.26 (m, 1H), 6.90 (d, J = 7.6 Hz, 1H), 4.54 - 4.09 (m, 2H), 3.41 - 3.15 (m, 6H), 2.85 (d, J = 4.0 Hz, 3H), 2.82 - 2.63 (m, 4H), 2.59 - 2.51 (m, 1H), 2.48 - 2.35 (m, 2H), 2.28 - 2.07 (m, 1H), 2.07 - 1.87 (m, 2H), 1.85 - 1.62 (m, 2H), 1.53 - 1.40 (m, 1H), 1.22 - 1.02 (m, 3H).

[0285] MS m/z (ESI): 401.2 [M+H].sup.+.

Example 20

[0286] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide

##STR00180##

[0287] In accordance with Step 1 of Example 3, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide (white solid, yield: 26%) was obtained.

[0288] The compound of Example 20 can also be obtained by the following method:

##STR00181##

[0289] 3-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutan-1-amine (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature, followed by the addition of oxazole-2-carboxylic acid (20 mg, 0.18 mmol), HATU (86 mg, 0.23 mmol) and diisopropylethylamine (58 mg, 0.45 mmol). The reaction solution was stirred at room temperature overnight, and concentrated to dryness by rotary evaporation. The resulting crude product was purified by high performance liquid chromatography to obtain N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxamide (13 mg, white solid, yield: 21%).

[0290] .sup.1H NMR (400 MHz, Chloroform-d) 8 7.79 (d, J = 1.9 Hz, 1H), 7.24 - 7.14 (m, 4H), 6.98 (m, 2.0 Hz, 1H), 4.68 - 4.59 (m, 0.3H), 4.48 - 4.38 (m, 0.7H), 3.26 - 3.15 (m, 4H), 2.98 - 2.81 (m, 4H), 2.64 - 2.56 (m, 2H), 2.22 (t, J= 7.0 Hz, 2H), 2.07 - 1.99 (m, 1H), 1.89 - 1.80 (m, 2H), 1.75 - 1.67 (m, 2H).

[0291] MS m/z (ESI): 423.1M+H].sup.+.

Example 20A and Example 20B

[0292] N-(Trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carbox amide (20A)

[0293] N-(Cis(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxa mide (20B)

##STR00182##

##STR00183##

[0294] The compound of Example 20 was resolved to obtain N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carbox amide (20A) and N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)oxazole-2-carboxam ide (20B), the mass ratio of 20A to 20B was about 1:2.

TABLE-US-00002 Chiral preparation conditions Instrument SFC-80 (Thar, Waters) Column type AD 20*250 mm, 10 um (Daicel) Column pressure 100 bar Mobile phase CO.sub.2/ EtOH(1%Methanol Ammonia) = 50/50 Flow rate 80 g/min Detection wavelength UV 214 nm Column temperature 35° C.

Example 20A: t.SUB.R.= 2.473 min

[0295] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.24 - 7.20 (m, 2H), 7.17 -7.11 (m, 2H), 6.97 (dd, J= 6.4, 3.1 Hz, 1H), 4.69 - 4.58 (m, 1H), 3.16 - 3.02 (m, 4H), 2.76 - 2.58 (m, 4H), 2.41 - 2.36 (m, 2H), 2.36 - 2.28 (m, 1H), 2.24 - 2.17 (m, 4H), 1.82 - 1.73 (m, 2H).

[0296] MS m/z (ESI): 423.1M+H].sup.+.

Example 20B: t.SUB.R.= 1.782 min

[0297] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.22 (s, 1H), 7.19 - 7.10 (m, 3H), 6.97 (dd, J= 7.0, 2.5 Hz, 1H), 4.49 - 4.37 (m, 1H), 3.28 - 3.03 (m, 4H), 2.84 -2.67 (m, 4H), 2.67 - 2.54 (m, 2H), 2.53 - 2.35 (m, 2H), 2.15 - 2.02 (m, 1H), 1.75 - 1.63 (m, 4H).

[0298] MS m/z (ESI): 423.1M+H].sup.+.

Example 21

[0299] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazole-5-c arboxamide

##STR00184##

[0300] In accordance with Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazole-5-c arboxamide was obtained.

[0301] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.23 - 7.09 (m, 2H), 7.05 -6.91 (m, 1H), 6.75 - 6.51 (m, 1H), 4.70 - 4.33 (m, 1H), 3.41 - 3.00 (m, 4H), 2.90 - 2.54 (m, 4H), 2.54 - 2.40 (m, 2H), 2.34 (s, 3H), 2.26 - 2.02 (m, 3H), 1.91 - 1.58 (m, 4H).

[0302] MS m/z (ESI): 437.1[M+H].sup.+.

Example 21A

[0303] N-(Trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazo le-5-carboxamide

##STR00185##

##STR00186##

[0304] In accordance with the reaction conditions of Example 5, the intermediate 2-1 was used as the starting material, accordingly, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazol e-5-carboxamide (21A) (21 mg, white solid, yield: 25%) was obtained.

[0305] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.22 - 7.09 (m, 2H), 7.02 -6.90 (m, 1H), 6.71 (d, J = 7.5 Hz, 1H), 4.69 - 4.54 (m, 1H), 3.30 - 3.00 (m, 4H), 2.86 -2.58 (m, 4H), 2.53 - 2.39 (m, 2H), 2.34 (s, 3H), 2.33 - 2.27 (m, 1H), 2.26 - 2.12 (m, 4H), 1.91 - 1.72 (m, 2H).

[0306] MS m/z (ESI): 437.1[M+H].sup.+.

Example 21B

[0307] N-(Cis(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazole -5-carboxamide

##STR00187##

[0308] In accordance with the reaction conditions of Example 5, the intermediate 2-2 was used as the starting material, accordingly, N-(cis-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-4-methylisoxazole-5-carboxamide (21B) was obtained.

[0309] MS m/z (ESI): 437.1[M+H].sup.+.

Example 22

[0310] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methylisoxazole-5-c arboxamide

##STR00188##

[0311] In accordance with Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-3-methylisoxazole-5-c arboxamide (21 mg, white solid, yield: 32%) was obtained.

[0312] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.21 - 7.11 (m, 2H), 7.02 - 6.93 (m, 1H), 6.77 - 6.57 (m, 2H), 4.69 - 4.33 (m, 1H), 3.30 - 3.01 (m, 4H), 2.89 - 2.56 (m, 5H), 2.49 - 2.38 (m, 2H), 2.36 (s, 3H), 2.27 - 2.15 (m, 1H), 2.10 - 1.99 (m, 1H), 1.87 - 1.57 (m, 4H).

[0313] MS m/z (ESI): 437.0 [M+H].sup.+.

Example 23

[0314] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-5-carboxami de

##STR00189##

[0315] In accordance with Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-5-carboxamid e (14 mg, white solid, yield: 22%) was obtained.

[0316] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 1.6 Hz, 1H), 7.21 - 7.11 (m, 2H), 7.06 - 6.87 (m, 2H), 6.84 - 6.77 (m, 1H), 4.70 - 4.34 (m, 1H), 3.24 - 3.01 (m, 4H), 2.76 - 2.57 (m, 5H), 2.46 - 2.35 (m, 2H), 2.34 - 2.14 (m, 2H), 2.11 - 1.99 (m, 1H), 1.83 - 1.59 (m, 3H).

[0317] MS m/z (ESI): 423.0 [M+H].sup.+.

Example 23A

[0318] N-(Trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-5-carb oxamide

##STR00190##

##STR00191##

[0319] In accordance with the reaction conditions of Example 5, the intermediate 2-1 was used as the starting material, accordingly, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-5-carbo xamide (23A) (white solid) was obtained.

[0320] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.34 (d, J = 1.8 Hz, 1H), 7.22 - 7.11 (m, 2H), 6.98 (dd, J = 6.7, 2.9 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 4.70 - 4.57 (m, 1H), 3.28 - 3.02 (m, 4H), 2.86 - 2.56 (m, 4H), 2.50 - 2.39 (m, 2H), 2.39 - 2.30 (m, 1H), 2.28 - 2.14 (m, 4H), 1.88 - 1.76 (m, 2H).

[0321] MS m/z (ESI): 423.2 [M+H].sup.+.

Example 24

[0322] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole-5-car boxamide

##STR00192##

[0323] In accordance with Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole-5-car boxamide was obtained.

[0324] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.55 (s, 1H), 7.16 (dd, J= 7.2, 4.3 Hz, 2H), 6.96 (dd, J= 6.6, 2.8 Hz, 1H), 6.28 (d, J= 7.7 Hz, 1H), 4.47 - 4.32 (m, 1H), 3.09 (s, 4H), 2.68 - 2.58 (m, 7H), 2.41 - 2.33 (m, 2H), 2.18 (td, J= 20.3, 12.2 Hz, 2H), 2.02 (dd, J= 15.7, 8.3 Hz, 1H), 1.78 (dd, J= 15.3, 7.6 Hz, 1H), 1.71 - 1.55 (m, 3H).

[0325] MS m/z (ESI):437.1 [M+H].sup.+.

Example 25

[0326] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-3-carboxami de

##STR00193##

[0327] In accordance with Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-3-carboxamid e was obtained.

[0328] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.33 (d, J= 1.7 Hz, 1H), 7.19 - 7.14 (m, 2H), 7.02 -6.93 (m, 1H), 6.91 (d, J = 1.6 Hz, 1H), 4.48-4.64 (m, 1H), 3.29-3.11 (m, 4H), 2.79 -2.60 (m, 4H), 2.45 - 2.39 (m, 2H), 2.26-2.22 (m, 2H), 2.05-2.01(m, 1H), 1.76-1.60 (m, 4H).

[0329] MS m/z (ESI):423.1 [M+H].sup.+.

Example 25A

[0330] N-(Trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-3-carb oxamide

##STR00194##

##STR00195##

[0331] In accordance with the reaction conditions of Example 5, the intermediate 2-1 was used as the starting material, accordingly, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)isoxazole-3-carbo xamide was obtained.

[0332] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.46 (d, J= 1.4 Hz, 1H), 7.22-7.17(m, 2H), 7.00 (d, J= 6.8 Hz, 2H), 6.81 (d, J= 1.4 Hz, 1H), 4.64 (dd, J= 15.1, 7.5 Hz, 1H), 3.29 (s, 4H), 2.79-2.77 (m, 4H), 2.36 (s, 2H), 2.24 (d, J= 7.0 Hz, 2H), 2.01 (s, 1H), 1.60 (s, 4H).

[0333] MS m/z (ESI):423.1 [M+H].sup.+.

Example 26

[0334] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole-4-car boxamide

##STR00196##

[0335] In accordance with Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole-4-car boxamide (white solid) was obtained.

[0336] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J = 1.6 Hz, 1H), 7.17 - 7.13 (m, 2H), 7.05 - 6.90 (m, 2H), 4.66 - 4.36 (m, 1H), 3.19 - 3.05 (m, 4H), 2.74 - 2.63 (m, 3H), 2.64 - 2.53 (m, 2H), 2.50 - 2.46 (m, 3H), 2.42 - 2.34 (m, 2H), 2.21 - 2.13 (m, 1H), 2.08 - 1.94 (m, 1H), 1.68 - 1.60 (m, 4H).

[0337] MS m/z (ESI): 437.1M+H].sup.+.

Example 26A

[0338] N-(Trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole -4-carboxamide

##STR00197##

##STR00198##

[0339] In accordance with the reaction conditions of Example 5, the intermediate 2-1 was used as the starting material, accordingly, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-2-methyloxazole -4-carboxamide was obtained.

[0340] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.20 - 7.11 (m, 2H), 7.05 -6.92 (m, 2H), 4.67 - 4.54 (m, 1H), 3.19 - 3.06 (m, 4H), 2.76 - 2.63 (m, 4H), 2.48 (s, 3H), 2.44 - 2.41 (m, 2H), 2.21 - 2.11 (m, 5H), 1.84 - 1.75 (m, 2H).

[0341] MS m/z (ESI): 437.1M+H].sup.+.

Example 27

[0342] N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxami de

##STR00199##

[0343] In accordance with Step 1 of Example 5, N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carboxamid e (35 mg, white solid) was obtained.

[0344] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.96 (dd, J= 4.2, 1.7 Hz, 1H), 8.76 (d, J = 8.7 Hz, 1H), 8.25 - 8.16 (m, 1H), 7.75 - 7.67 (m, 2H), 7.51 - 7.45 (m, 1H), 7.16 (dd, J = 7.0, 2.0 Hz, 2H), 7.03 - 6.95 (m, 1H), 6.29 - 6.15 (m, 1H), 4.84 - 4.52 (m, 1H), 3.23 - 3.05 (m, 4H), 2.80 - 2.67 (m, 4H), 2.52 - 2.41 (m, 2H), 2.35 - 2.04 (m, 3H), 1.70 -1.57 (m, 4H).

[0345] MS m/z (ESI): 483.1M+H].sup.+.

Example 27A

[0346] N-(Trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carb oxamide

##STR00200##

##STR00201##

[0347] In accordance with the reaction conditions of Example 5, the intermediate 2-1 was used as the starting material, accordingly, N-(trans-3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)quinoline-5-carbo xamide was obtained.

[0348] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.96 (dd, J = 4.3, 1.7 Hz, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.25 - 8.14 (m, 1H), 7.69 (d, J = 5.0 Hz, 2H), 7.47 (dd, J = 8.6, 4.2 Hz, 1H), 7.19 - 7.14 (m, 2H), 6.98 (dd, J = 7.2, 2.4 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 4.84 -4.71 (m, 1H), 3.22 - 3.14 (m, 4H), 2.94 - 2.88 (m, 1H), 2.86 - 2.74 (m, 4H), 2.56 - 2.50 (m, 2H), 2.32 - 2.26 (m, 2H), 2.25 - 2.18 (m, 2H), 1.93 - 1.84 (m, 2H).

[0349] MS m/z (ESI): 483.1M+H].sup.+.

Example 28

[0350] 1-Cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-methy lurea

##STR00202##

[0351] In accordance with Step 1 of Example 1, 1-cyclopropyl-3-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)-1-methyl urea (43 mg, white solid, yield: 33%) was obtained.

[0352] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.22 - 7.11 (m, 2H), 7.03 - 6.92 (m, 1H), 5.32 (dd, J = 36.5, 7.6 Hz, 1H), 4.45 - 4.10 (m, 1H), 3.25 - 3.02 (m, 4H), 2.88 (d, J = 1.7 Hz, 3H), 2.82 - 2.57 (m, 4H), 2.57 - 2.51 (m, 1H), 2.47 - 2.32 (m, 3H), 2.24 - 2.10 (m, 1H), 2.08 - 1.90 (m, 1H),2.06 - 1.75 (m, 2H), 1.50 - 1.39 (m, 1H), 0.88 - 0.78 (m, 2H), 0.75 - 0.67 (m, 2H).

[0353] MS m/z (ESI): 425.1 [M+H].sup.+.

Example 29

[0354] 1-Cyano-N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropane-1-carboxamide

##STR00203##

[0355] In accordance with Step 1 of Example 5, 1-cyano-N-(3-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclobutyl)cyclopropane-1-carboxamide (31 mg, white solid) was obtained.

[0356] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.19 - 7.12 (m, 2H), 7.00 - 6.94 (m, 1H), 6.56 - 6.36 (m, 1H), 4.54 - 4.17 (m, 1H), 3.21 - 3.02 (m, 4H), 2.79 - 2.60 (m, 4H), 2.57 - 2.53 (m, 1H), 2.43 - 2.36 (m, 2H), 2.18 - 2.12 (m, 1H), 2.06 - 1.95 (m, 1H), 1.68 -1.65 (m, 3H), 1.63 - 1.56 (m, 3H), 1.51- 1.45 (m, 2H).

[0357] MS m/z (ESI): 421.1M+H].sup.+.

Example 30

[0358] (R)-N-(2-(4-(2,3-Dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-2-hydro xy-2-methylpropanamide

##STR00204##

Step 1: Tert-butyl (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate

##STR00205##

[0359] In accordance with Step 1 of Example 2, 1-bromo-2,3-dichlorobenzene and tert-butyl (R)-3-methylpiperazine-1-carboxylate were used as the starting materials, accordingly, tert-butyl (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate (600 mg, yellow solid, yield: 32.6%) was obtained.

[0360] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.26 - 7.21 (m, 1H), 7.21 - 7.11 (m, 1H), 7.11 - 6.94 (m, 1H), 3.99 - 3.00 (m, 7H), 1.49 (s, 9H), 0.91 (d, J = 6.3 Hz, 3H).

[0361] MS m/z (ESI):345.1 [M+H].sup.+.

[0362] Step 2: (R)-1-(2,3-Dichlorophenyl)-2-methylpiperazine

##STR00206##

[0363] In accordance with Step 2 of Example 2, tert-butyl (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate was used as the starting material, accordingly, (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine (420 mg, yellow solid, yield: 98.8%) was obtained.

[0364] .sup.1H NMR (400 MHz, Methanol-d4) δ 7.36 - 7.29 (m, 1H), 7.27 - 7.16 (m, 2H), 3.60 - 3.44 (m, 1H), 3.42 - 3.27 (m, 2H), 3.21 - 3.13 (m, 2H), 3.02 - 2.81 (m, 2H), 0.88 (d, J = 6.3 Hz, 3H).

[0365] MS m/z (ESI):245.1 [M+H].sup.+.

[0366] Step 3: (R)-3-(2-(4-(2,3-Dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutan-1-amine

##STR00207##

[0367] In accordance with Steps 6 and 7 of Example 2, (R)-3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutan-1-amine (280 mg) was obtained.

[0368] MS m/z (ESI): 342.1 [M+H].sup.+.

[0369] Step 4: (R)-N-(3-(2-(4-(2,3-Dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-2-hydro xy-2-methylpropanamide

##STR00208##

[0370] In accordance with Example 5, (R)-N-(3-(2-(4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclobutyl)-2-hydrox y-2-methylpropanamide (18 mg) was obtained.

[0371] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.25 - 7.20 (m, 1H), 7.16 (t, J= 7.9 Hz, 1H), 7.10 - 7.04 (m, 1H), 6.91 - 6.75 (m, 1H), 4.49 - 4.14 (m, 1H), 3.47 - 3.34 (m, 1H), 3.21 - 3.13 (m, 1H), 2.91 - 2.82 (m, 1H), 2.83 - 2.68 (m, 2H), 2.59 - 2.48 (m, 2H), 2.38 -2.31 (m, 2H), 2.24 - 2.12 (m, 2H), 2.11 - 1.93 (m, 2H), 1.82 - 1.73 (m, 1H), 1.70 - 1.65 (m, 1H), 1.56 - 1.46 (m, 2H), 1.44 (d, J= 2.4 Hz, 6H), 0.90 (d, J= 6.2 Hz, 3H).

[0372] MS m/z (ESI): 428.1 [M+H].sup.+.

BIOLOGICAL ASSAY AND EVALUATION

[0373] The present invention is further described below in combination with the following test examples, which are not intended to limit the scope of the present invention.

I. Radioligand-Receptor Binding Assay

Test Example 1. Determination of the Binding Ability of the Compounds of the Present Invention to Dopamine D3 Receptor

[0374] 1. Experimental objective:

[0375] The objective of this test example is to determine the affinity of the compounds for dopamine D3 receptor.

[0376] 2.1 Experimental instruments:

[0377] Vortex mixer (IKA; MS3 basic) [0378] Electric heating constant temperature incubator (Shanghai Yiheng Scientific Instruments Co., Ltd; DHP-9032) [0379] Microplate shaker (VWR; 12620-928) [0380] TopCount (PerkinElmer; NTX) [0381] Universal Harvester (PerkinElmer; UNIFILTER-96).

[0382] 2.2 Experimental reagents and consumables:

[0383] [.sup.3H]-methylspiperone (PerkinElmer; NET856250UC) [0384] Human Dopamine D3 Receptor membrane (PerkinElmer; ES-173-M400UA) [0385] GR 103691 (Sigma; 162408-66-4) [0386] ULTIMA GOLD (Perkin Elmer; 77-16061) [0387] 96 round deep well plate 1.1 mL (Perkin Elmer; P-DW-11-C) [0388] UNIFILTER-96 GF/B filter plate (PerkinElmer; 6005174) [0389] Polyethyleneimine [0390] branched (Sigma; 408727) [0391] Centrifuge tubes (BD, 352096; 352070) [0392] Loading slot (JET BIOFIL; LTT001050) [0393] Tray (JET BIOFIL; LTT001050) [0394] Pipette tips (Axygen; T-300-R-S, T-200-Y-R-S, T-1000-B-R-S) [0395] Magnesium chloride (Sigma, 7786-30-3) [0396] Tris-base (Sigma, 77-86-1)

[0397] 3. Experimental method:

[0398] 0.5 to 5 .Math.L of the test compounds (0.005 nM to 100 nM, 10 concentrations in total) and 100 .Math.L of buffer were added to a 96-well assay plate. 0.5 .Math.L of cell membrane and 300 .Math.L of buffer were added to each well. [.sup.3H]-methylspiperone was added to the buffer, and the plate was incubated at 27° C. for 30 min. The UNIFILTER-96 GF/B filter plate pre-incubated with 0.5% PEI for 1 h was washed twice with the buffer (1 mL/well). The cell membrane suspension was added to the UNIFILTER-96 GF/B filter plate, washed 4 times, and incubated at 55° C. for 10 min. 40 .Math.L of ULTIMA GOLD was added to each well, and liquid scintillation counting was carried out.

[0399] 4. Experimental data processing method:

[0400] The CPM (Counts per minute) values were determined by TopCount. The percent inhibition rate of [.sup.3H]-methylspiperone binding was calculated from the values of the High control (DMSO control) experimental group and Low control (100 nM positive compound) experimental group {% inhibition rate = (CPM.sub.sample-CPM.sub.low .sub.control) / (CPM.sub.high control-CPM.sub.low .sub.control) × 100}. The 10 concentrations of the compound were from 100 nM to 0.005 nM after 3-fold dilution of the reaction system. The percent inhibition rate and ten-point concentration data were fitted to the parametric nonlinear logistic equation by using GraphPad prism to calculate the IC.sub.50 values of the compound.

[0401] 5. Experimental results:

[0402] The binding activity of the compounds of the present invention to D3 was determined by the above assay, and the resulting IC.sub.50 values are shown in Table 1.

TABLE-US-00003 IC.sub.50 of the binding activity of the compounds of the present invention to D3 Example No. D3 Binding IC.sub.50 (nM) Cariprazine 0.89 7 0.79 11A 0.95 13A 0.75 13B 4.37 14A 0.44 18 0.62 19 1.13 20A 0.37 20B 2.54 21A 1.36 22A 0.34 23A 0.31 24A 0.33 25A 0.30 26A 0.42 27A 0.40 28 1.99 30 2.78

[0403] 6. Experimental conclusion:

[0404] The compounds of the present invention have good affinity for dopamine receptor D3.

Test Example 2. Determination of the Binding Ability of the Compounds of the Present Invention to 5-Ht2a Receptor

[0405] 1. Experimental objective:

[0406] The objective of this test example is to determine the affinity of the compounds for 5-HT2A receptor.

[0407] 2.1 Experimental instruments: [0408] Vortex mixer (IKA; MS3 basic) [0409] Electric heating constant temperature incubator (Shanghai Yiheng Scientific Instruments Co., Ltd; DHP-9032) [0410] Microplate shaker (VWR; 12620-928) [0411] TopCount (PerkinElmer; NTX) [0412] Universal Harvester (PerkinElmer; UNIFILTER-96).

[0413] 2.2 Experimental reagents and consumables: [0414] [.sup.3H]-Ketanserin (PerkinElmer NET791) [0415] Human Dopamine 5-HT2A Receptor membrane (PerkinElmer) [0416] GR 103691 (Sigma; 162408-66-4) [0417] ULTIMA GOLD (Perkin Elmer; 77-16061) [0418] 96 round deep well plate 1.1 mL (Perkin Elmer; P-DW-11-C) [0419] UNIFILTER-96 GF/B filter plate (PerkinElmer; 6005174) [0420] Polyethyleneimine, branched (Sigma; 408727) [0421] Centrifuge tubes (BD, 352096; 352070) [0422] Loading slot (JET BIOFIL; LTT001050) [0423] Tray (JET BIOFIL; LTT001050) [0424] Pipette tips (Axygen; T-300-R-S, T-200-Y-R-S, T-1000-B-R-S) [0425] Magnesium chloride (Sigma, 7786-30-3) [0426] Tris-base (Sigma, 77-86-1)

[0427] 3. Experimental method:

[0428] 0.5 to 5 .Math.L of the test compounds (0.005 nM to 100 nM, 10 concentrations in total) and 100 .Math.L of buffer were added to a 96-well assay plate. 0.5 .Math.L of cell membrane and 300 .Math.L of buffer were added to each well. [.sup.3H]-Ketanserin was added to the buffer, and the plate was incubated at 27° C. for 30 min. The UNIFILTER-96 GF/B filter plate pre-incubated with 0.5% PEI for 1 h was washed twice with the buffer (1 mL/well). The cell membrane suspension was added to the UNIFILTER-96 GF/B filter plate, washed 4 times, and incubated at 55° C. for 10 min. 40 .Math.L of ULTIMA GOLD was added to each well, and liquid scintillation counting was carried out.

[0429] 4. Experimental data processing method:

[0430] The CPM (Counts per minute) values were determined by TopCount. The percent inhibition rate of [.sup.3H]-Ketanserin binding was calculated from the values of the High control (DMSO control) experimental group and Low control (100 nM positive compound) experimental group {% inhibition rate = (CPM.sub.sample-CPM.sub.low .sub.control) / (CPM.sub.high control-CPM.sub.low .sub.control) × 100}. The 10 concentrations of the compound were from 100 nM to 0.005 nM after 3-fold dilution of the reaction system. The percent inhibition rate and ten-point concentration data were fitted to the parametric nonlinear logistic equation by using GraphPad prism to calculate the IC.sub.50 values of the compound.

[0431] 5. Experimental results:

[0432] The binding activity of the compounds of the present invention to 5-HT2A was determined by the above assay, and the resulting IC.sub.50 values are shown in Table 2.

TABLE-US-00004 IC.sub.50 of the binding ability of the compounds of the present invention to 5-HT2A Example No. 5HT-2A Binding IC.sub.50 (nM) Cariprazine 191.28 7 6.35 11A 41.5 13A 5.77 13B 48.45 14A 0.79 18 43.97 19 6.39 20A 4.19 20B 8.73 21A 1.81 22A 1.35 23A 0.98 24A 1.80 25A 1.92 26A 1.37 27A 1.89 28 19.08 30 9.63

[0433] 6. Experimental conclusion:

[0434] The above data show that the compounds of the present invention have good affinity for 5-HT2A.

II. Cell Function Assay

Test Example 1. Determination of the Effect of the Compounds of the Present Invention on Camp Content in Cells Stably Expressing D3 Receptors

[0435] 1. Experimental objective:

[0436] To determine the activation effect of the compounds on D3 receptor.

[0437] 2.1 Experimental instruments: [0438] 384-well assay plate (Perkin Elmer; 6007680) [0439] 96-well conical btm PP Plt nature RNASE/Dnase-free plate (ThermoFisher; 249944) [0440] Pipette (Axygen) [0441] EnVision (Perkin Elmer).

[0442] 2.2 Experimental reagents: [0443] Fetal Bovine Serum (Gibco, 10999141) [0444] Ham’s F-12K (Kaighn’s) Medium (Hyclone; SH30526.01) [0445] Penicillin-Streptomycin, Liquid (Gibco; 15140122) [0446] G418 (invitrogen; 0131-027) [0447] Forskolin (Selleck, S2449) [0448] BSA stabilizer (Perkin Elmer; CR84-100) [0449] cAMP kit (Cisbio; 62AM4PEC) [0450] IBMX (Sigma; I5879) [0451] HEPES (Gibco; 15630080).

[0452] 3. Experimental method: [0453] 1. Preparation of the buffer: 1* HBSS + 20 mM HEPES + 0.1% BSA + 500 .Math.M IBMX. [0454] Complete medium: Ham’s F12K + 10% fetal bovine serum +1* penicillin-streptomycin + 400 .Math.g/mL G418. [0455] 2. CHO-D3 cells were cultured in the complete medium at 37° C., 5% CO.sub.2. After TrypLE digestion, the cells were resuspended in the experimental buffer, and seeded into a 384-well cell culture plate at a seeding density of 8000 cells per well. [0456] 3. The experimental buffer (1*HBSS, 0.1% BSA, 20 mM HEPES and 500 .Math.M IBMX) was prepared. The compound was diluted with the buffer. 2.5 .Math.L of the compound solution was added to each well, and the plate was incubated at 37° C. for 10 minutes. The forskolin was diluted to 8 .Math.M (8*) with the experimental buffer. 2.5 .Math.L of the diluted 8* forskolin was added, and the plate was incubated at 37° C. for 30 minutes. cAMP-d2 and Anti-cAMP-Eu.sup.3+ were thawed, and diluted by 20-fold with the lysis buffer. 10 .Math.L of cAMP-d2 was added to the experimental well, followed by the addition of 10 .Math.L of Anti-cAMP-Eu.sup.3+. The reaction plate was centrifuged at 200 g for 30 s at room temperature, and left to stand at 25° C. for 1 h. Data was collected using Envision.

[0457] 4. Experimental data processing method: [0458] 1) Z′ factor = 1-3*(SDMax+SDMin)/(MeanMax-MeanMin); [0459] 2) CVMax = (SDMax/MeanMax)* 100%; [0460] 3) CVMin = (SDMin/MeanMin)* 100%; [0461] 4) S/B = Singal/Background; [0462] 5) EC.sub.50 of the compound was calculated using the GraphPad nonlinear fitting equation: [0463] Y=Bottom + (Top-Bottom)/(1+10^((LogEC.sub.50-X)*HillSlope)) [0464] X: log value of compound concentration; Y: Activation %

[0465] 5. Experimental results:

TABLE-US-00005 EC.sub.50 values of the compounds on cAMP content in cells stably expressing D3 receptors Example No. EC.sub.50 (nM) Cariprazine 1.7 8 3.5 9 2.2 10 1.2 11A 0.4 12 2.4 13 2.9 13A 0.6 14 2.8 14A 1.0 17 1.2 19 0.9 20 1.7 20A 0.6 20B 0.7 21 3.4 21A 1.1 22 1.2 22A 0.9 23 1.7 23A 0.7 24 0.7 24A 1.7 25 3.1 25A 1.1 26 3.9 26A 1.4 27 1.0 27A 1.6 28 1.0 29 3.3 30 0.4

[0466] 6. Experimental conclusion:

[0467] It can be seen from the data in the table that the compounds of the Examples of the present invention show good agonistic activity in the cAMP content effect assay in cells stably expressing D3 receptors.

Test Example 2. Determination of the Effect of the Compounds of the Present Invention on Calcium Ion Mobility in Cells Stably Expressing 5-Ht2a Receptors

[0468] 1. Experimental objective:

[0469] To determine the inhibitory effect of the compounds on 5-HT2A receptor.

[0470] 2. Experimental instruments and reagents:

[0471] 2.1 Experimental instruments: [0472] 384-well assay plate (Corning; 3712) [0473] Pipette (Axygen) [0474] FLIPR (Molecular Devices)

[0475] 2.2 Experimental reagents: [0476] DMEM (Invitrogen; 11965) [0477] Fetal bovine serum (Biowest; S1810-500) [0478] Dialysis serum (S-FBS-AU-065; Serana) [0479] Penicillin-Streptomycin (Biowest; L0022-100) [0480] Hygromycin B (CABIOCHEM, 400052) [0481] Matrigel (BD; 354230) [0482] DMSO (Sigma; D2650) [0483] HBSS (Invitrogen; 14065) [0484] HEPES (Invitrogen; 15630080) [0485] Probenecid (Sigma; P8761) [0486] BSA (renview; FA016) [0487] TrypLE (ThermoFisher; 12604021).

[0488] 3. Experimental method: [0489] 1) Preparation of the buffer: 1 × HBSS, 20 mM HEPES, 2.5 mM probenecid (probenecid was 400 mM stock in 1 M NaOH), 0.1% BSA. Probenecid and BSA were added fresh on the day of the experiment. Experimental buffers include dye buffer and compound dilution buffer. [0490] 2) Cell culture medium: Ham’s F-12K + 10% fetal bovine serum + 600 .Math.g/ml hygromycin B + 1* penicillin-streptomycin. Seeding medium: Ham’s F-12K + 10% dialysis serum. Assay buffer: 1 × HBSS + 20 mM HEPES. Cell line: Flp-In-CHO-5HT2A stable pool. [0491] 3) The cells were cultured in the complete medium at 37° C., 5% CO.sub.2 to 70%-90% confluency. The cells were digested with TrypLE trypsin, seeded to the 384-well assay plate at a density of 1 × 10.sup.4 cells/well, and incubated for 16 to 24 hours (at least overnight). [0492] 4) 20X Component A was thawed to room temperature, diluted to 2X working concentration (containing 5 mM Probenecid) with the assay buffer, and placed at room temperature for later use. [0493] 5) The cell culture plate was taken out and left to stand at room temperature for 10 min. FBS was diluted to a concentration of 0.03% with Apricot and the assay buffer, and 20 .Math.L of the solution was finally remained in the 3764 culture plate. 20 .Math.L of 2X Component A (containing 5mM Probenecid) was added to each experimental well, centrifuged at 200 g and RT for 3 to 5 sec, and incubated at 37° C. for 2 hr. [0494] 6) The medium was discarded, and 20 .Math.L of the dye was added. The plate was incubated at 37° C. in the dark for 60 min, and the calcium signal was determined. [0495] 7) The antagonist was prepared before the experiment: the working solution of the test compound (6X) was formulated with DMSO. The cell culture plate was taken out and left to stand at room temperature for 10 min. 6 × test compound was added to the 384-well assay plate (10 .Math.L/well), which was then incubated at room temperature in the dark for 35 min. The assay plate was transferred to the FLIPR. 10 .Math.L of diluted 5HT was added to each experimental well, followed by the addition of agonist compound at 6x concentration (5 .Math.L/well). The values were determined by the FLIPR and saved. The total assay volume was 30 .Math.L, including 20 .Math.L/well of the dye buffer, 5 .Math.L/well of the test compound at 5 × concentration and 5 .Math.L/well of the agonist compound at 6 × concentration.

[0496] 4. Experimental data processing method:

[0497] The calcium signal values were determined by FLIPR. The calculated output for each sampling time point in the experiment was the ratio of the 340/510 nm wavelength signals to 380/510 nm wavelength signals. The maximum minus minimum calculation was derived from the ratio signal curve. The percent inhibition rate and ten-point concentration data were fitted to the parametric nonlinear logistic equation by using GraphPad prism to calculate the IC.sub.50 values of the compound.

[0498] 5. Experimental results:

TABLE-US-00006 IC.sub.50 values of the compounds on calcium ion mobility in cells stably expressing 5-HT2A receptors Example No. IC.sub.50 (nM) Cariprazine 551.0 8 8.08 9 16.68 10 48.01 11A 38.98 12 22.08 13 13.05 13A 3.07 13B 38.95 14 6.44 14A 2.74 17 8.90 20 5.20 20A 2.21 20B 11.60 21 10.86 21A 11.73 22 13.35 22A 4.37 23 8.06 23A 3.14 24 5.78 24A 4.28 25 8.92 25A 20.79 26 6.40 26A 6.44 27 7.37 27A 7.67 28 11.59 29 33.54

[0499] 6. Experimental conclusion:

[0500] It can be seen from the data in the table that the compounds of the Examples of the present invention show good inhibitory activity in the calcium ion mobility assay in cells stably expressing 5-HT2A receptors.

III. Pharmacokinetic Assay in Balb/c Mice

[0501] 1. Study objective:

[0502] Balb/c mice were used as test animals. The pharmacokinetic behavior in mouse body (plasma and brain tissue) of the compounds of Examples of the present invention orally administrated at a dose of 5 mg/kg was studied.

[0503] 2. Experimental protocol:

[0504] 2.1 Test compounds:

[0505] Compounds of the Examples of the present invention, prepared by the applicant.

[0506] 2.2 Test animals:

[0507] Male Balb/c mice (12 mice per group), purchased from Shanghai Jiesijie Laboratory Animal Co., LTD, with Certificate No.: SCXK (Shanghai) 2013-0006 N0.311620400001794.

[0508] 2.3 Formulation of the preparation:

[0509] The test compound was dissolved in 0.5% CMC—Na (1% Tween80) by sonication to formulate a clear solution or homogeneous suspension.

[0510] 2.4 Administration:

[0511] After an overnight fast, male Balb/c mice (12 mice per group) were administered p.o. with the test compound at an administration dose of 5 mg/kg and an administration volume of 10 mL/kg.

[0512] 2.5 Sample collection:

[0513] 0.2 mL of blood was taken from the heart of the mouse before administration and at 1, 2, 4, 8 and 24 hours after administration, and the mice were sacrificed with CO.sub.2. The samples were stored in EDTA-K.sub.2 tubes, and centrifuged for 6 minutes at 4° C., 6000 rpm to separate the plasma. The plasma samples were stored at -80° C. Whole brain tissue was taken out, weighed, placed in a 2 mL centrifuge tube, and stored at -80° C.

[0514] 2.6 Sample process: [0515] 1) 160 .Math.L of acetonitrile was added to 40 .Math.L of the plasma sample for precipitation, and then the mixture was centrifuged for 5 to 20 minutes at 3500 × g. [0516] 2) 90 .Math.L of acetonitrile containing internal standard (100 ng/mL) was added to 30 .Math.L of the plasma and brain homogenate sample for precipitation, and then the mixture was centrifuged for 8 minutes at 13000 rpm. [0517] 3) 70 .Math.L of water was added to 70 .Math.L of the treated supernatant and mixed by vortex for 10 minutes. 20 .Math.L of the supernatant was taken to analyze the concentration of the test compound by LC/MS/MS. LC/MS/MS analytical instrument: AB Sciex API 4000 Qtrap.

[0518] 2.7 Liquid chromatography analysis: [0519] Liquid chromatography condition: Shimadzu LC-20AD pump [0520] Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1 mm, 3.5 .Math.m); Mobile phase: Eluent A was 0.1% formic acid in water, and Eluent B was acetonitrile [0521] Flow rate: 0.4 mL/min [0522] Elution time: 0-4.0 minutes, the eluent is as follows:

TABLE-US-00007 Time/minute Eluent A Eluent B 0.01 90% 10% 0.5 90% 10% 0.8 5% 95% 2.4 5% 95% 2.5 90% 10% 4.0 Stop

[0523] 3. Experimental results and analysis:

[0524] The main parameters of pharmacokinetics were calculated by WinNonlin 6.1. The results of pharmacokinetic test in mice are shown in the following Table 5:

TABLE-US-00008 Experimental results of pharmacokinetic assay in mice Example No. Pharmacokinetic test (5 mg/kg) Peak time Plasma concentration Area under curve Area under curve Half life Average residence time tmax (ng/mL) Cmax (ng/mL) AUC.sub.0-t (ng/mL×h) AUC.sub.0-∞ (ng/mL×h) t.sub.½ (h) MRT (h) 7 Plasma 1.0 49.7 239.5 297.3 3.25 5.1 7 Brain 1.0 161.9 1535.5 1653.4 NA NA 13 Plasma 0.5 864.7 2326.5 2462.4 1.9 2.8 13 Brain 1.0 464.0 1972.6 NA NA NA 13A Plasma 0.5 745.0 1423 1444.0 1.3 1.8 13A Brain 1.0 321.0 1081 NA NA NA 13B Plasma 0.5 961.0 2250 2325.0 1.6 2.3 13B Brain 1.0 361.0 900 NA NA NA 14 Plasma 0.5 254.0 503.0 540.9 2.1 2.8 14 Brain 1.0 569.3 2077.8 NA NA NA 14A Plasma 1.0 102.0 395 501.0 3.7 5.3 14A Brain 1.0 179.0 1346 NA NA NA 19 Plasma 0.5 368.7 1475.7 2001.3 3.4 5.7 19 Brain 1.0 338.7 2187.7 2305.1 NA NA 20 Plasma 0.5 391.0 1038.9 1227.3 2.8 3.9 20 Brain 1.0 1196.0 4830.1 4881.3 NA NA 20A Plasma 0.5 673.0 1844.0 1970.0 1.9 3.1 20A Brain 1.0 1763.0 8130.0 NA NA NA 20B Plasma 0.5 715.0 1624.0 1711.0 1.8 2.4 20B Brain 1.0 1871.0 5204.0 NA NA NA 25A Plasma 0.5 362 3049 12935 5.6 6.2 25A Brain 1.0 1535 11878 NA NA NA 27A Plasma 0.5 349.0 456 471.0 1.7 1.8 27A Brain 1.0 372.0 1236 NA NA NA

[0525] 4. Experimental conclusion:

[0526] It can be seen from the experimental results of pharmacokinetic assay in mice in the table that the compounds of the Examples of the present invention showed good pharmacokinetic properties, both the exposure AUC and maximum plasma concentration C.sub.max were good.

IV. Stability Assay in Liver Microsome In Vitro

[0527] 1. Experimental objective:

[0528] To evaluate the metabolic stability of the compounds of the present invention in liver microsome in vitro.

[0529] 2. Experimental instruments:

TABLE-US-00009 2.1 Instruments Instrument Brand Model Vortex mixer IKA Vortex Thermostatic mixer SpecificAction Incubation-micro mixer Centrifuge Eppendorf Centrifuge 5804R Liquid chromatograph Shimadzu LC-30 AD Mass spectrometer AB Sciex API5500

TABLE-US-00010 2.2 Reagents Reagent Brand Article number 7-Hydroxycoumarin J&K Scientific 153384 DMSO Sigma 34869 PBS Gibco 10010-023 Human liver microsome BD H0610 SD rat liver microsome Corning 452501 CD-1 mouse liver microsome BD M1000 Dog liver microsome BD D1000 NADPH Bide BD11658 UDPGA Sigma U6751 Avermectin J&K Scientific 622045

[0530] 3. Experimental processes:

[0531] 3.1. Formulation of the working solution of the compound

[0532] Formulation of the working solution of the compound: 2 .Math.L of the stock solution of the compound was added to 998 .Math.L of phosphate buffer, and the final concentration was 20 .Math.M.

[0533] Formulation of the working solution of the control compound (7-hydroxycoumarin): The formulation was consistent with that of the compound.

[0534] 3.2. Formulation of the working solution of liver microsome

[0535] 78.1 .Math.L of 20 mg/mL microsome was diluted to 2.5 mL with 100 mM phosphatebuffer and mixed well, and the final concentration was 0.625 mg/mL.

[0536] 3.3. Formulation of NADPH and UDPGA

[0537] 33.3 mg of NADPH and 25.8 mg of UDPGA were weighed respectively, followed by the addition of 2 mL of 100 mM phosphate buffer. The final concentrations were 20 mM.

[0538] 3.4. Formulation of the channel-forming reagent (Alamethicin)

[0539] 1 mg of Alamethicin was weighed, to which 200 .Math.L of DMSO was added to obtain a 5 mg/mL solution. 10 .Math.L of this solution was added to 990 .Math.L of phosphate buffer (pH 7.4), and the final concentration was 50 .Math.g/mL.

[0540] 3.5. Formulation of the reaction stop solution

[0541] Stop solution: Cold acetonitrile containing 100 ng/mL labetalol hydrochloride and 400 ng/mL tolbutamide as internal standards, stored in a refrigerator at 2 to 8° C.

[0542] 3.6. Incubation procedure

[0543] 400 .Math.L of the formulated liver microsome, 25 .Math.L of the working solution of the compound (10 .Math.M) and 25 .Math.L of Alamethicin (50 .Math.g/mL) were added to a 96-well plate successively, which was then pre-incubated at 37° C. for 10 min. 50 .Math.L of the formulated NADPH/UDPGA was added to initiate the reaction, and the plate was incubated at 37° C. The total volume of the reaction system was 500 .Math.L. The final contents of the components are as follows:

TABLE-US-00011 Component Content Liver microsome 0.5 mg/mL Compound 1 .Math.M NADPH 2 mM UDPGA 2mM Alamethicin 2.5 .Math.g/mL Alamethicin 2.5 .Math.g/mL

[0544] 50 .Math.L of the sample was taken out at time points of 0 min, 5 min, 10 min, 20 min, 30 min and 60 min respectively, followed by the addition of 200 .Math.L of the cold stop solution containing the internal standards to stop the reaction in the samples. The resulting sample was centrifuged at 4000 g for 10 min, and the supernatant was collected for LC-MS/MS analysis.

[0545] 4. Experimental results:

TABLE-US-00012 Stability in liver microsome in vitro Species No. Half life (t.sub.½) min Intrinsic clearance rate (CL.sub.int) (.Math.L/min/mg protein) Remaining (%, 120 min) Human Cariprazine 77.2 18 34.4 Example 6 76.3 45.4 61.2 Example 13 93.3 37.2 63.0 Example 13A 138.8 10 53.3 Example 15 189.4 18.3 79.5 Example 20A 105.9 13.1 42.8 Example 25A 90.1 15.4 38.8 Rat Cariprazine 52.7 26.3 19.1 Example 20A 60 23.1 25.4 Example 25A 60.5 22.9 27.0 Dog Cariprazine 50.1 27.7 21.4 Example 20A 70.6 19.6 29.2 Example 25A 69.5 19.9 30.2

Note:

TABLE-US-00013 Type of clearance rate Intrinsic clearance rate (.Math.L/min/mg protein) Human Rat Dog Slow < 8.6 < 13.2 < 5.3 Rapid > 47.0 > 71.9 > 28.9

[0546] 5. Experimental conclusion:

[0547] The above data show that the compounds of the Examples of the present invention are moderately metabolized in human, rat and dog liver microsome in vitro.

V. Pharmacodynamic Model of Active Escape Experiment in Rats

[0548] 1. Experimental objective:

[0549] To evaluate the anti-schizophrenic effect of the compounds using the pharmacodynamic model of the active escape experiment in rats.

[0550] 2. Experimental instruments and reagents:

TABLE-US-00014 2.1 Instruments No. Instrument name Instrument model Source Manufacturer 1 Active and passive shuttle device MED-APA-D1R Imported Med Associates, Inc. 2 Thermostatic magnetic stirrer 85-2 Domestic Shanghai Sile Instrument Co., Ltd. 3 Vortex mixer H-101 Domestic Shanghai Kanghe Photoelectric Instrument Co., Ltd. 4 Ultrasonic cleaner KQ3200DE Domestic Kunshan Ultrasonic Instruments Co., Ltd

TABLE-US-00015 2.2 Reagents No. Name Purity Batch number Storage condition Manufacturer 1 CMC—Na 100% SLBV9664 RT Sigma 2 Tween 80 100% BCBV8843 RT Sigma

[0551] 2.3 Test compounds:

[0552] Compounds of the Examples of the present invention, prepared by the applicant.

TABLE-US-00016 3. Test animals Species Strain Age Gender Supplier Rats F344 6-8 weeks Male Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0553] 4. Formulation of the vehicle and compounds:

[0554] 4.1 Vehicle (0.5%CMC-Na+1%Tween80)

[0555] A certain mass (such as 1.0 g) of CMC—Na was weighed into a glass bottle, a certain volume (such as 200 mL) of purified water was added, and the resulting mixture was stirred to disperse evenly. 1% (v/v) Tween 80 was added according to the solution volume, and the resulting mixture was stirred overnight to obtain a homogeneous clear solution, which was stored at 2 to 8° C. for later use.

[0556] 4.2 Formulation of the compounds:

[0557] A prescription amount of the compound was weighed, followed by the addition of a prescription volume of 0.5% CMC-Na+1% Tween 80 solution. The compound solution was formulated before the administration, stored at 2 to 8° C., and used within 4 days.

[0558] The actual sample amount needs to be calculated during the formulation and administration of the compound solution. The calculation equation is as follows: the actual sample amount of the compound = theoretical weighing sample amount * purity / salt coefficient.

[0559] 5. Experimental operation:

[0560] After arriving at the experimental facility, the animals were acclimatized for one week before starting the experiment.

[0561] 5.1 Establishment of the pharmacodynamic model:

[0562] 5.1.1 The animal was put into the shuttle box and adapted for 5 seconds, followed by subjecting to 10 seconds of sound and light stimulation;

[0563] 5.1.2 If the animal avoided to the other side during the 10 seconds of sound and light stimulation, then no electric shock would be given, this would be recorded as avoids, and the single training ended;

[0564] 5.1.3 If the animal failed to move to the other side after the 10 seconds of sound and light stimulation, then an electric shock would be given, the current intensity was 0.6 mA, the duration was 10 seconds, if the animal avoided to the other side during the 10 seconds of electric shock, then the electric shock would stop, this would be recorded as escapes, and the single training ended;

[0565] 5.1.4 If the animal failed to avoid during the 10 seconds of electric shock, then the electric shock would stop, this would be recorded as escape failures, and the single training ended;

[0566] 5.1.5 Each animal was trained 30 times a day for a total of 6 days, and returned to the cage after the training.

[0567] 5.2 Baseline test and grouping

[0568] The day before the compound screening test, a baseline test was performed. The test process was the same as 5.1.1 to 5.1.3, and the number of the baseline test was 20. The animals whose number of avoids reached 16 (80%) were grouped according to the number of avoids, 10 animals per group. The first group was administered with the vehicle orally, and the other groups were administered with the corresponding test compounds according to the experimental design.

[0569] 5.3 Compound screening test

[0570] The compound was administered orally (5 mL/kg) one hour before the test;

[0571] The test process was the same as 5.1.1 to 5.1.4, and the number of the test was 20.

[0572] 6. Data process:

[0573] The following data was collected by the software for data analysis: [0574] Number of avoids of the animal; [0575] Number of escape failures of the animal; [0576] Escape latency of the animal; [0577] All measurement data were expressed as mean ± standard error (Mean ± SEM), and analyzed by Graphpad 6 statistical software. The difference was considered to be significant when p<0.05.

TABLE-US-00017 Experimental results Example No. CAR value Dose (mg/kg) Vehicle 91-98% - 20 30% 1 20A 18.5% 1 25A 18% 1

[0578] 8. Experimental conclusion:

[0579] It can be seen from the above data that the compounds of the Examples of the present invention show good effects in the pharmacodynamic model of the active escape experiment in rats, indicating that they have anti-schizophrenia effect.