BENZOTHIOPHENE DERIVATIVE REGULATOR, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

A nitrogen-containing ring derivative regulator, a preparation method therefor and use thereof. In particular, the present invention relates to a compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and use thereof as a G protein-coupled receptor regulator in the treatment or prevention of central nervous system diseases and/or mental diseases.

##STR00001##

Claims

1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ##STR00169## wherein: is selected from the group consisting of a single bond and a double bond; M is selected from the group consisting of N and CR.sub.aa; ring A is selected from the group consisting of aryl and heteroaryl; R.sub.1 is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —P(O)R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb and —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb; R.sub.2 is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —P(O)R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb and —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb; or, two R.sub.2 on the same or different carbon atoms are bonded to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, which is optionally further substituted by one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, ester group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NHR.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd and —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.3 is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S(O)(═NR.sub.aa)R.sub.bb, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —P(O)R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb and —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb; or, two R.sub.3 on the same or different carbon atoms are bonded to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, which is optionally further substituted by one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, ester group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NHR.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd and —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.4 and R.sub.5 are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —C(O)(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1OR.sub.aa, —C(O)NR.sub.aa(CH.sub.2).sub.n1R.sub.bb, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O)(═NR.sub.aa)R.sub.bb, —P(O)R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb and —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, amino, hydroxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, ester group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NHR.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd and —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; or, R.sub.4 and R.sub.5 are bonded to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, which is optionally further substituted by one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, ester group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NH.sub.1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd and —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.aa, R.sub.bb, R.sub.cc and R.sub.dd are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; or, R.sub.aa and R.sub.bb are bonded to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, which is optionally further substituted by one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thioxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; m is 0, 1 or 2; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; z is 0, 1, 2, 3 or 4; m1 is 0, 1 or 2; and n1 is 0, 1, 2, 3, 4 or 5.

2. The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is selected from the group consisting of C.sub.6-10 aryl and 5 to 10 membered heteroaryl, and preferably phenyl, 5 to 6 membered monocyclic heteroaryl, benzo-5 to 6 membered heteroaryl and benzo-3 to 6 membered heterocyclyl.

3. The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein ##STR00170## selected from the group consisting of ##STR00171## ##STR00172##

4. The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.4 is selected from the group consisting of hydrogen and methyl; R.sub.5 is selected from the group consisting of —R.sub.aa, —C(O)(CH.sub.2).sub.n1R.sub.aa, —C(O)NR.sub.aa(CH.sub.2).sub.n1R.sub.bb and —S(O).sub.2R.sub.aa; or, R.sub.4 and R.sub.5 are bonded to form a 3 to 8 membered heterocyclyl or 5 to 14 membered heteroaryl, wherein the 3 to 8 membered heterocyclyl or 5 to 14 membered heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of C.sub.1-6 alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C.sub.3-8 alkoxy, C.sub.3-8 haloalkoxy, C.sub.3-8 hydroxyalkyl, —C(O)R.sub.cc and —C(O)NR.sub.ccR.sub.dd; wherein the heterocyclyl or heteroaryl is selected from the group consisting of heterocyclyl containing 1 to 2 nitrogen, oxygen or sulfur atoms and heteroaryl containing 1 to 2 nitrogen, oxygen or sulfur atoms; R.sub.aa and R.sub.bb are each independently selected from the group consisting of hydrogen, amino, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, 3 to 6 membered heterocyclyl, phenyl and 5 to 6 membered heteroaryl, wherein the amino, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, C.sub.3-6 cycloalkyl, 3 to 6 membered heterocyclyl, phenyl and 5 to 6 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, C.sub.3-6 cycloalkyl, 3 to 6 membered heterocyclyl, phenyl and 5 to 6 membered heteroaryl; R.sub.cc and R.sub.dd 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.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 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.6-14 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; and n1 is 0, 1, 2 or 3.

5. The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is further shown as formula (IV-A): ##STR00173## wherein: R.sub.2 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.3-6 cycloalkyl; or, two R.sub.2 on the same or different carbon atoms are bonded to form a C.sub.3-8 cycloalkyl or 3 to 8 membered heterocyclyl, wherein the C.sub.3-8 cycloalkyl or 3 to 8 membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of deuterium, C.sub.1-6 alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C.sub.3-8 alkoxy, C.sub.3-8 haloalkoxy and C.sub.3-8 hydroxyalkyl; R.sub.3 is selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, hydroxy, cyano, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; R.sub.4 is selected from the group consisting of hydrogen and C.sub.1-6 alkyl; R.sub.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 aryl, 5 to 14 membered heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —C(O)R.sub.aa, —C(O)NR.sub.aaR.sub.bb, —C(O)(CH.sub.2).sub.n1R.sub.aa, —C(O)NR.sub.aa(CH.sub.2).sub.n1R.sub.bb, —S(O).sub.2R.sub.aa, —(CH.sub.2).sub.n1S(O)(═NR.sub.aa)R.sub.bb, —S(O).sub.m1NR.sub.aaR.sub.bb and —C(O)OR.sub.aa, wherein the C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of cyano, halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; or, R.sub.4 and R.sub.5 are bonded to form a 3 to 8 membered heterocyclyl or 5 to 14 membered heteroaryl, which is optionally further substituted by one or more substituents selected from the group consisting of C.sub.1-6 alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C.sub.3-8 alkoxy, C.sub.3-8 haloalkoxy, C.sub.3-8 hydroxyalkyl, —C(O)R.sub.cc and —C(O)NR.sub.ccR.sub.dd; R.sub.aa and R.sub.bb 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.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 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.6-14 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, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 aryl and 5 to 14 membered heteroaryl; or, R.sub.aa and R.sub.bb together with the adjacent nitrogen atom are bonded to form a 4 to 10 membered heterocyclyl, which is 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, C.sub.1-6 alkoxy and C.sub.1-6 hydroxyalkyl; R.sub.cc and R.sub.dd 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.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 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.6-14 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; m is 1 or 2; and n1 is 0, 1, 2 or 3; wherein the compound of formula (IV-A) does not comprise compounds ##STR00174##

6. The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 5, wherein the compound is further shown as formula (IX-B): ##STR00175## R.sub.2 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.3-6 cycloalkyl; R.sub.3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy and C.sub.1-6 haloalkoxy; R.sub.4 is selected from the group consisting of hydrogen and C.sub.1-6 alkyl; R.sub.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 aryl, 5 to 14 membered heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —C(O)R.sub.aa, —C(O)NR.sub.aaR.sub.bb, —C(O)(CH.sub.2).sub.n1R.sub.aa, —C(O)NR.sub.aa(CH.sub.2).sub.n1R.sub.bb, —S(O).sub.2R.sub.aa, —(CH.sub.2).sub.n1S(O)(═NR.sub.aa)R.sub.bb, —S(O).sub.m1NR.sub.aaR.sub.bb and —C(O)OR.sub.aa, wherein the C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of cyano, halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; or, R.sub.4 and R.sub.5 are bonded to form a 3 to 8 membered heterocyclyl or 5 to 10 membered heteroaryl, which is optionally further substituted by one or more substituents selected from the group consisting of C.sub.1-6 alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C.sub.3-8 alkoxy, C.sub.3-8 haloalkoxy and C.sub.3-8 hydroxyalkyl; R.sub.aa and R.sub.bb 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.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 aryl and 5 to 10 membered heteroaryl containing 1 to 2 heteroatom selected from the group consisting of N, O and S, which 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, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 aryl and 5 to 14 membered heteroaryl; or, R.sub.aa and R.sub.bb together with the adjacent nitrogen atom are bonded to form a 4 to 6 membered heterocyclyl, which is 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, C.sub.1-6 alkoxy and C.sub.1-6 hydroxyalkyl.

7. The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 5, wherein R.sub.2 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl and C.sub.3-6 cycloalkyl; R.sub.3 is selected from the group consisting of hydrogen, halogen and C.sub.1-3 alkyl; R.sub.4 is selected from the group consisting of hydrogen and C.sub.1-3 alkyl; R.sub.5 is selected from the group consisting of —(CH.sub.2).sub.n1R.sub.aa, —C(O)R.sub.aa, —C(O)NR.sub.aaR.sub.bb, —S(O).sub.2R.sub.aa and —S(O).sub.m1NR.sub.aaR.sub.bb; R.sub.aa and R.sub.bb are each independently selected from the group consisting of hydrogen, amino, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, C.sub.3-6 cycloalkyl and 5 to 6 membered heteroaryl containing 1 to 2 heteroatom selected from the group consisting of N, O and S, which are each optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy and C.sub.3-6 cycloalkyl; or, R.sub.aa and R.sub.bb together with the adjacent nitrogen atom are bonded to form a 4 to 6 membered nitrogen-containing heterocyclyl, which is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl and C.sub.1-3 alkoxy.

8. The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 5, wherein R.sub.2 is selected from the group consisting of hydrogen, cyano, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, trifluoromethyl and cyclopropyl; R.sub.3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl and ethyl; R.sub.4 is selected from the group consisting of hydrogen and methyl; R.sub.5 is selected from the group consisting of —R.sub.aa, —C(O)R.sub.aa and —C(O)NR.sub.aaR.sub.bb; R.sub.aa and R.sub.bb are each independently selected from the group consisting of hydrogen, C.sub.1-3 alkyl, C.sub.1-3 fluoroalkyl, C.sub.1-3 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, furyl, oxazolyl and isoxazolyl, which are each optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C.sub.1-3 alkyl and C.sub.1-3 alkoxy; or, R.sub.aa and R.sub.bb together with the adjacent nitrogen atom are bonded to form an azetidinyl, pyrrolidinyl or piperidinyl, which is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl and C.sub.1-3 alkoxy.

9. The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein ##STR00176## is selected from the group consisting of: ##STR00177##

10. The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.1 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy and C.sub.3-6 cycloalkyl; R.sub.2 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.3-6 cycloalkyl; or, two R.sub.2 on the same or different carbon atoms are bonded to form a C.sub.3-8 cycloalkyl or 3 to 8 membered heterocyclyl, wherein the C.sub.3-8 cycloalkyl or 3 to 8 membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium atom, C.sub.1-6 alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C.sub.3-8 alkoxy, C.sub.3-8 haloalkoxy and C.sub.3-8 hydroxyalkyl; R.sub.3 is selected from the group consisting of hydrogen atom, halogen, hydroxy, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; or, two R.sub.3 on the same or different carbon atoms are bonded to form a C.sub.3-8 cycloalkyl or 3 to 8 membered heterocyclyl, wherein the C.sub.3-8 cycloalkyl or 3 to 8 membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, C.sub.1-6 alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C.sub.3-8 alkoxy, C.sub.3-8 haloalkoxy and C.sub.3-8 hydroxyalkyl; R.sub.4 is selected from the group consisting of hydrogen and C.sub.1-6 alkyl; R.sub.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 aryl, 5 to 14 membered heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —C(O)R.sub.aa, —C(O)NR.sub.aaR.sub.bb, —C(O)NR.sub.aa(CH.sub.2).sub.n1R.sub.bb, —S(O).sub.2R.sub.aa, —(CH.sub.2).sub.n1S(O)(═NR.sub.aa)R.sub.bb, —S(O).sub.m1NR.sub.aaR.sub.bb and —C(O)OR.sub.aa, wherein the C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; or, R.sub.4 and R.sub.5 are bonded to form a heterocyclyl, wherein the heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of hydrogen, C.sub.1-6 alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C.sub.3-8 alkoxy, C.sub.3-8 haloalkoxy and C.sub.3-8 hydroxyalkyl; R.sub.aa 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.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 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.6-14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.1-6 alkoxy; R.sub.bb 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.3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C.sub.6-14 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.6-14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of hydrogen atom, halogen, hydroxy, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.1-6 alkoxy; or, R.sub.aa and R.sub.bb are bonded to form a heterocyclyl, wherein the heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of hydrogen atom, C.sub.1-6 alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C.sub.3-8 alkoxy, C.sub.3-8 haloalkoxy and C.sub.3-8 hydroxyalkyl.

11. The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is further shown as formula (XII): ##STR00178## wherein: ring B is selected from the group consisting of C.sub.3-8 cycloalkyl, 3 to 8 membered heterocyclyl and 5 to 10 membered heteroaryl; and preferably selected from the group consisting of cyclopropyl, azetidinyl, pyrrolidonyl, furyl, oxazolyl and isoxazolyl; R.sub.2 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.3-6 cycloalkyl; and preferably selected from the group consisting of hydrogen and C.sub.1-6 haloalkyl; and more preferably selected from the group consisting of hydrogen and trifluoromethyl; R.sub.4 is selected from the group consisting of hydrogen and C.sub.1-6 alkyl; and preferably selected from the group consisting of hydrogen and methyl; R.sub.6 is selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, hydroxy, cyano, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; and preferably selected from the group consisting of hydrogen and halogen; and more preferably selected from the group consisting of hydrogen and fluorine; R.sub.17 is selected from the group consisting of hydrogen, halogen, amino, hydroxy, cyano, 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.6-14 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.6-10 aryl and 5 to 10 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, cyano, oxo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and C.sub.1-6 alkoxy; preferably selected from the group consisting of hydrogen, amino, halogen, amino, hydroxy, cyano, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl and C.sub.1-3 alkoxy; and more preferably selected from the group consisting of hydrogen, fluorine, chlorine, hydroxy, cyano, methyl and methoxy; and v is an integer from 0 to 5, and preferably 0, 1, 2 or 3.

12. The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein the specific structure of the compound is as follows: ##STR00179## ##STR00180## ##STR00181## ##STR00182## ##STR00183## ##STR00184## ##STR00185##

13. A method for preparing the compound of formula (IX-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 6, comprising the following steps of, ##STR00186## deprotecting a compound of formula (IX-B3) to obtain a compound of formula (IX-B1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof; reacting the compound of formula (IX-B1) with an acyl chloride, amine, carboxylic acid or sulfonyl chloride of formula (II-2) to obtain the compound of formula (VIII), the stereoisomer thereof or the pharmaceutically acceptable salt thereof; the compound of formula (II-2) represents R.sub.5X, R.sub.5OH or R.sub.5NH.sub.2; X is a halogen; Pg is a hydrogen or amino protecting group selected from the group consisting of allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, fluorenylmethyloxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, t-butoxycarbonyl, benzyl and p-methoxyphenyl, and preferably t-butoxycarbonyl.

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

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

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

Description

DETAILED DESCRIPTION OF THE INVENTION

[0172] 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

[0173] 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 (δ) are given in parts per million (ppm). NMR is determined by a Bruker AVANCE-400 instrument. The solvents for determination are deuterated-dimethyl sulfoxide (DMSO-d.sub.6), deuterated-methanol (CD.sub.3OD) and deuterated-chloroform (CDCl.sub.3), and the internal standard is tetramethylsilane (TMS).

[0174] Liquid chromatography-mass spectrometry (LC-MS) is determined on an Agilent 1200 Infinity Series mass spectrometer. High performance liquid chromatography (HPLC) is determined on an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column), and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0175] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is used as the thin-layer silica gel chromatography (TLC) plate. The dimension of the silica gel plate used in TLC is 0.15 mm to 0.2 mm, and the dimension of the silica gel plate used in product purification is 0.4 mm to 0.5 mm. Yantai Huanghai 200 to 300 mesh silica gel is generally used as a carrier for column chromatography.

[0176] The raw materials used in the examples of the present invention are known and commercially available, or can be synthesized by or according to known methods in the art.

[0177] Unless otherwise stated, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere. The solvent is dry, and the reaction temperature is in degrees celcius.

Example 1

N-(Trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide

[0178] ##STR00027##

Step 1: Tert-butyl (trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate

[0179] ##STR00028##

[0180] 1-(2,3-Dichlorophenyl)piperazine (460 mg, 2 mmol) was dissolved in 10 mL of acetonitrile in a 100 mL round-bottom flask. 2-(Trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl 4-methylbenzenesulfonate (794 mg, 2 mmol) and potassium carbonate (834 mg, 6 mmol) were added to the reaction system. The reaction solution was stirred at 80° C. for 12 hours. After completion of the reaction, the reaction system was cooled to room temperature, quenched with water, and extracted with ethyl acetate (10 mL*3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluted with petroleum ether/ethyl acetate=1/1) to obtain tert-butyl (trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (550 mg, white solid, yield: 60.5%).

[0181] MS m/z (ESI): 456.2 [M+H].sup.+.

Step 2: Trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexan-1-amine

[0182] ##STR00029##

[0183] Tert-buty (trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (550 mg, 1.2 mmol) was dissolved in 5 mL of dichloromethane in a 100 mL round-bottom flask, followed by the addition of a solution of hydrochloric acid in ethyl acetate (4 M, 1 mL, 4 mmol). The reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the reaction system was concentrated, quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (10 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness by rotary evaporation to obtain trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexan-1-amine (400 mg, white solid, yield: 91.3%).

[0184] MS m/z (ESI): 356.1 [M+H].sup.+.

Step 3: N-(Trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide

[0185] ##STR00030##

[0186] Trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexan-1-amine (80 mg, 0.22 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (67 mg, 0.66 mmol), N,N′-carbonyldiimidazole (43 mg, 0.27 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 3,3-Difluoroazetidine hydrochloride (42 mg, 0.34 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed with water three times (2 mL*3). The organic phase was concentrated and purified by prep-HPLC to obtain the product N-(trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide (69 mg, white solid, yield: 64.6%).

[0187] MS m/z (ESI): 475.1 [M+H].sup.+.

[0188] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.19-7.11 (m, 2H), 7.00-6.94 (m, 1H), 4.24 (t, J=12.1 Hz, 4H), 3.98 (d, J=8.1 Hz, 1H), 3.63-3.50 (m, 1H), 3.24-3.03 (m, 4H), 2.85-2.61 (m, 4H), 2.56-2.43 (m, 2H), 2.08-1.95 (m, 2H), 1.84-1.75 (m, 2H), 1.56-1.43 (m, 2H), 1.28-1.22 (m, 1H), 1.16-1.01 (m, 4H).

Example 2

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoro azetidine-1-carboxamide

[0189] ##STR00031##

Step 1: Tert-butyl (trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)carbamate

[0190] ##STR00032##

[0191] 1-(Benzo[b]thiophen-4-yl)piperazine (440 mg, 2 mmol) was dissolved in 10 mL of acetonitrile in a 100 mL round-bottom flask. 2-(Trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl 4-methylbenzenesulfonate (794 mg, 2 mmol) and potassium carbonate (834 mg, 6 mmol) were added to the reaction system. The reaction solution was stirred at 80° C. for 12 hours. After completion of the reaction, the reaction system was cooled to room temperature, quenched with water, and extracted with ethyl acetate (10 mL*3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluted with petroleum ether/ethyl acetate=1/1) to obtain tert-butyl (trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (500 mg, white solid, yield: 55.9%).

[0192] MS m/z (ESI): 444.2 [M+H].sup.+.

[0193] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J=8.0 Hz, 1H), 7.41-7.37 (m, 1H), 7.30-7.25 (m, 2H), 6.90 (d, J=7.6 Hz, 1H), 4.44-4.24 (m, 1H), 3.46-3.31 (m, 1H), 3.29-3.19 (m, 4H), 2.95-2.63 (m, 4H), 2.61-2.42 (m, 2H), 2.09-1.94 (m, 2H), 1.87-1.72 (m, 2H), 1.58-1.49 (m, 2H), 1.44 (s, 9H), 1.30-1.20 (m, 1H), 1.16-0.98 (m, 4H).

Step 2: Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine

[0194] ##STR00033##

[0195] Tert-butyl (trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (500 mg, 1.13 mmol) was dissolved in 5 mL of dichloromethane in a 100 mL round-bottom flask, followed by the addition of a solution of hydrochloric acid in ethyl acetate (4 M, 1 mL, 4 mmol). The reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the reaction system was concentrated, quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (10 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness by rotary evaporation to obtain trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (350 mg, white solid, yield: 90.4%).

[0196] MS m/z (ESI): 344.2 [M+H].sup.+.

Step 3: N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoro azetidine-1-carboxamide

[0197] ##STR00034##

[0198] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (50 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (45 mg, 0.45 mmol), N,N′-carbonyldiimidazole (28 mg, 0.17 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 3,3-Difluoroazetidine hydrochloride (28 mg, 0.22 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed with water three times (2 mL*3). The organic phase was concentrated and purified by prep-HPLC to obtain the product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide (22 mg, white solid, yield: 32.1%).

[0199] MS m/z (ESI): 463.2 [M+H].sup.+.

[0200] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J=8.0 Hz, 1H), 7.45-7.36 (m, 2H), 7.31-7.26 (m, 1H), 6.91 (d, J=7.6 Hz, 1H), 4.24 (t, J=12.1 Hz, 4H), 3.99 (d, J=8.1 Hz, 1H), 3.64-3.51 (m, 1H), 3.37-3.14 (m, 4H), 2.94-2.67 (m, 4H), 2.64-2.51 (m, 2H), 2.08-1.96 (m, 2H), 1.89-1.76 (m, 2H), 1.59-1.48 (m, 2H), 1.29-1.23 (m, 1H), 1.19-1.04 (m, 4H).

Example 3

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-hydroxy-3-methylazetidine-1-carboxamide

[0201] ##STR00035##

[0202] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (50 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (45 mg, 0.45 mmol), N,N′-carbonyldiimidazole (28 mg, 0.17 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 3-Methylazetidin-3-ol hydrochloride (27 mg, 0.22 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed with water three times (2 mL*3). The organic phase was concentrated and purified by prep-HPLC to obtain the product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-hydroxy-3-methylazetidine-1-carboxamide (23.5 mg, white solid, yield: 35.3%).

[0203] MS m/z (ESI): 457.3 [M+H].sup.+.

[0204] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J=8.0 Hz, 1H), 7.44-7.35 (m, 2H), 7.32-7.26 (m, 1H), 6.90 (d, J=7.6 Hz, 1H), 3.93-3.76 (m, 5H), 3.63-3.49 (m, 1H), 3.32-3.13 (m, 4H), 3.00-2.87 (m, 1H), 2.83-2.64 (m, 4H), 2.57-2.44 (m, 2H), 2.05-1.93 (m, 3H), 1.87-1.73 (m, 2H), 1.53 (s, 3H), 1.52-1.43 (m, 2H), 1.16-1.00 (m, 4H).

Example 4

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-methoxy-3-methylazetidine-1-carboxamide

[0205] ##STR00036##

[0206] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (50 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (45 mg, 0.45 mmol), N,N′-carbonyldiimidazole (28 mg, 0.17 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 3-Methoxy-3-methylazetidine hydrochloride (30 mg, 0.22 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed with water three times (2 mL*3). The organic phase was concentrated and purified by prep-HPLC to obtain the product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-methoxy-3-methylazetidine-1-carboxamide (22 mg, white solid, yield: 32.1%).

[0207] MS m/z (ESI): 471.2 [M+H].sup.+.

[0208] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J=8.0 Hz, 1H), 7.44-7.35 (m, 2H), 7.29-7.23 (m, 1H), 6.90 (d, J=7.4 Hz, 1H), 3.88 (dd, J=11.6, 8.0 Hz, 3H), 3.65 (d, J=8.0 Hz, 2H), 3.61-3.51 (m, 1H), 3.33-3.13 (m, 7H), 2.86-2.63 (m, 4H), 2.55-2.42 (m, 2H), 2.07-1.94 (m, 2H), 1.85-1.75 (m, 2H), 1.56-1.42 (m, 5H), 1.30-1.19 (m, 1H), 1.19-0.99 (m, 4H).

Example 5

3-(Trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea

[0209] ##STR00037##

Step 1: Tert-butyl bis(fluoromethyl)carbamate

[0210] ##STR00038##

[0211] Tert-butyl carbamate (500 mg, 4.3 mmol) was dissolved in 10 mL DMF. NaH (427 mg, 10.7 mmol) was added at 0° C., and the reaction solution was stirred at 0° C. for 0.5 hour. Fluoroiodomethane (1.7 g, 3.8 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water, and extracted with ethyl acetate (20 mL*3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluted with petroleum ether/ethyl acetate=10/1) to obtain tert-butyl bis(fluoromethyl)carbamate (150 mg, colorless liquid, yield: 19%).

Step 2: Bis(fluoromethyl)amine hydrochloride

[0212] ##STR00039##

[0213] Tert-butyl bis(fluoromethyl)carbamate (150 mg) was dissolved in a solution of hydrochloric acid in ethyl acetate (4 M, 2 mL), and stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation to obtain the crude product bis(fluoromethyl)amine hydrochloride (97 mg, 99%).

Step 3: 3-(Trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea

[0214] ##STR00040##

[0215] The product 3-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea was obtained according to Example 1.

[0216] MS m/z (ESI): 452.2 [M+H].sup.+.

Example 6

3-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-(fluoromethyl)-1-methylurea

[0217] ##STR00041##

Step 1: Tert-butyl (fluoromethyl)(methyl)carbamate

[0218] ##STR00042##

[0219] Tert-butyl methylcarbamate (500 mg, 3.8 mmol) was dissolved in 10 mL DMF. NaH (228 mg, 5.7 mmol) was added at 0° C., and the reaction solution was stirred at 0° C. for 0.5 hour. Fluoroiodomethane (610 mg, 3.8 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water, and extracted with ethyl acetate (20 mL*3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluted with petroleum ether/ethyl acetate=10/1) to obtain tert-butyl (fluoromethyl)(methyl)carbamate (50 mg, colorless liquid, yield: 8.1%).

Step 2: 1-Fluoro-N-methylmethanamine hydrochloride

[0220] ##STR00043##

[0221] Tert-butyl (fluoromethyl)(methyl)carbamate (50 mg) was dissolved in a solution of hydrochloric acid in ethyl acetate (4 M, 2 mL), and stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation to obtain the crude product 1-fluoro-N-methylmethanamine hydrochloride (30 mg, 99%).

Step 3: 3-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-(fluoromethyl)-1-methylurea

[0222] ##STR00044##

[0223] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (50 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (45 mg, 0.45 mmol), N,N′-carbonyldiimidazole (28 mg, 0.17 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 1-Fluoro-N-methylmethanamine hydrochloride (30 mg, 0.3 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed with water three times (2 mL*3). The organic phase was concentrated and purified by prep-HPLC to obtain the product 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-(fluoromethyl)-1-methylurea (12 mg, white solid, yield: 18.5%).

[0224] MS m/z (ESI): 433.2 [M+H].sup.+.

Example 7

3-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea

[0225] ##STR00045##

Step 1: Tert-butyl bis(fluoromethyl)carbamate

[0226] ##STR00046##

[0227] Tert-butyl carbamate (500 mg, 4.3 mmol) was dissolved in 10 mL DMF. NaH (427 mg, 10.7 mmol) was added at 0° C., and the reaction solution was stirred at 0° C. for 0.5 hour. Fluoroiodomethane (1.7 g, 3.8 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water, and extracted with ethyl acetate (20 mL*3). The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluted with petroleum ether/ethyl acetate=10/1) to obtain tert-butyl bis(fluoromethyl)carbamate (150 mg, colorless liquid, yield: 19%).

Step 2: Bis(fluoromethyl)amine hydrochloride

[0228] ##STR00047##

[0229] Tert-butyl bis(fluoromethyl)carbamate (150 mg) was dissolved in a solution of hydrochloric acid in ethyl acetate (4 M, 2 mL), and stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation to obtain the crude product bis(fluoromethyl)amine hydrochloride (97 mg, 99%).

Step 3: 3-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea

[0230] ##STR00048##

[0231] 3-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis(fluoromethyl)urea was obtained according to Example 5.

[0232] MS m/z (ESI): 451.2 [M+H].sup.+.

Example 8

3-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methyl-1-(trifluoromethyl)urea

[0233] ##STR00049##

Step 1: Tert-butyl methyl(trifluoromethyl)carbamate

[0234] ##STR00050##

[0235] Tert-butyl methylcarbamate (500 mg, 3.8 mmol) was dissolved in 10 mL DMF. NaH (228 mg, 5.7 mmol) was added at 0° C., and the reaction solution was stirred at 0° C. for 0.5 hour. Trifluoroiodomethane (2.98 g, 3.8 mmol, 25% in DMF) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water, and extracted with ethyl acetate (10 mL*3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluted with petroleum ether/ethyl acetate=10/1) to obtain tert-butyl methyl(trifluoromethyl)carbamate (40 mg, colorless liquid, yield: 5.3%).

Step 2: 1,1,1-Trifluoro-N-methylmethanamine hydrochloride

[0236] ##STR00051##

[0237] Tert-butyl methyl(trifluoromethyl)carbamate (40 mg) was dissolved in a solution of hydrochloric acid in ethyl acetate (4 M, 2 mL), and stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation to obtain the crude product 1,1,1-trifluoro-N-methylmethanamine hydrochloride (25 mg, 99%).

Step 3: 3-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methyl-1-(trifluoromethyl)urea

[0238] ##STR00052##

[0239] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (50 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (45 mg, 0.45 mmol), N,N′-carbonyldiimidazole (28 mg, 0.17 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. 1,1,1-Trifluoro-N-methylmethanamine hydrochloride (25 mg, 0.18 mmol) was added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed with water three times (2 mL*3). The organic phase was concentrated and purified by prep-HPLC to obtain the product 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methyl-1-(t rifluoromethyl)urea (8 mg, white solid, yield: 11.3%).

[0240] MS m/z (ESI): 469.2 [M+H].sup.+.

Example 8

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)dimethylsulfonamide

[0241] ##STR00053##

[0242] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine and triethylamine were dissolved in dichloromethane. Dimethylsulfamoyl chloride was added dropwise, and the reaction solution was stirred at room temperature for 16 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and purified by preparative chromatography to obtain N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)dimethylsulfonamide as a white solid.

[0243] Same as Example 10, MS m/z (ESI): 451.2 [M+H].sup.+.

Example 10

N-(Trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)dimethylsulfonamide

[0244] ##STR00054##

Step 1: N-(Trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)dimethylsulfonamide

[0245] ##STR00055##

[0246] Trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexane-1-amine (60 mg, 0.17 mmol) and triethylamine (52 mg, 0.51 mmol) were dissolved in dichloromethane (3 mL). Dimethylsulfamoyl chloride (49 mg, 0.34 mmol) was added dropwise, 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 N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)dimethylsulfonamide as a white solid (33 mg, yield: 43%).

[0247] MS m/z (ESI): 452.2 [M+H].sup.+.

[0248] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.90 (d, J=8.2 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.47 (t, J=7.4 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 3.97 (d, J=8.0 Hz, 1H), 3.59 (s, 4H), 3.19-3.09 (m, 1H), 2.79 (s, 6H), 2.69 (s, 4H), 2.52-2.39 (m, 2H), 2.10-2.01 (m, 2H), 1.82 (d, J=12.3 Hz, 2H), 1.50-1.44 (m, 2H), 1.34-0.97 (m, 4H).

Example 11

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)pyridine-3-sulfonamide

[0249] ##STR00056##

[0250] N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)pyridine-3-sulfonamide was obtained according to Example 10.

[0251] MS m/z (ESI): 485.2 [M+H].sup.+.

Example 12

3-(Cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea

[0252] ##STR00057##

Step 1: Preparation of tert-butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate

[0253] ##STR00058##

[0254] Tert-butyl (4-oxocyclohexyl)carbamate (18.0 g, 84.40 mmol) was dissolved in anhydrous THF (400 mL). Allylmagnesium bromide (254 mL, 254 mmol, 1M in THF) was slowly added dropwise at −70° C. After completion of the addition, the reaction solution was stirred for 1 hour. Water (100 mL) was slowly added dropwise to the reaction solution to quench the reaction, which was then extracted with ethyl acetate (500 mL*2). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate=55/45) to obtain tert-butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate (5.4 g, yield: 25%). MS m/z (ESI): 256.2[M+H].sup.+.

Step 2: Preparation of tert-butyl (trans-4-hydroxy-4-(2-oxoethyl)cyclohexyl)carbamate

[0255] ##STR00059##

[0256] Tert-butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate (5.4 g, 21.15 mmol) was dissolved in THF (100 mL), followed by the addition of water (100 mL). K.sub.2OsO.sub.4.2 H.sub.2O (779 mg, 2.11 mmol) and NaIO.sub.4 (18.09 g, 84.59 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at room temperature overnight. Saturated aqueous Na.sub.2S.sub.2O.sub.4 solution (50 mL) was added to the reaction solution, followed by the addition of ethyl acetate (400 mL) and stirring for 5 minutes. The organic phase was collected, dried and concentrated to obtain tert-butyl (trans-4-hydroxy-4-(2-oxoethyl)cyclohexyl)carbamate (4.8 g, yield: 88%). MS m/z (ESI): 258.1[M+H].sup.+.

Step 3: Preparation of tert-butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate

[0257] ##STR00060##

[0258] Tert-butyl (trans-4-hydroxy-4-(2-oxoethyl)cyclohexyl)carbamate (4.8 g, 18.65 mmol) was dissolved in anhydrous THF (100 mL), and NaBH.sub.4 (1.41 g, 37.31 mmol) was added in batches. After completion of the addition, the reaction solution was stirred at room temperature for 2 hours. Water (50 mL) was slowly added to the reaction solution to quench the reaction, followed by extracting with ethyl acetate (200 mL*2). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (ethyl acetate/MeOH=95/5) to obtain tert-butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate (3.2 g, yield: 66%).

[0259] MS m/z (ESI): 260.2[M+H].sup.+.

Step 4: Preparation of 2-(trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate

[0260] ##STR00061##

[0261] Tert-butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate (3.2 g, 12.34 mmol) was dissolved in anhydrous dichloromethane (50 mL), followed by the addition of DMAP (151 mg, 1.23 mmol) and DIPEA (3.19 g, 24.68 mmol). The reaction solution was cooled to 0° C., to which TsCl (2.82 g, 14.81 mmol) was added. The reaction solution was warmed up to 30° C., and stirred overnight. The reaction solution was partitioned between water (50 mL) and dichloromethane (100 mL). The organic phase was dried and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/2) to obtain 2-(trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate (2.0 g, yield: 39%).

[0262] MS m/z (ESI): 414.1[M+H].sup.+.

Step 5: Preparation of 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate and 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate

[0263] ##STR00062##

[0264] 2-(Trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate (2 g, 4.84 mmol) was dissolved in anhydrous dichloromethane (50 mL), and DAST (4.68 g, 29.02 mmol) was slowly added dropwise at −70° C. After completion of the addition, the reaction solution was stirred at −70° C. for 2 hours. Water (10 mL) was slowly added dropwise to quench the reaction, and saturated NaHCO.sub.3 solution (10 mL) was added to adjust the pH to weakly alkali. The mixed solution was extracted with dichloromethane (100 mL). The organic phase was dried and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate=3/2) to obtain 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate (630 mg, yield: 31%) and 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate (600 mg, yield: 31%).

[0265] 2-(Cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate:

[0266] MS m/z (ESI): 416.1[M+H].sup.+.

[0267] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.79 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.39 (s, 1H), 4.21-4.12 (m, 2H), 3.45-3.30 (m, 1H), 2.45 (s, 3H), 2.06-1.75 (m, 7H), 1.52-1.46 (m, 1H), 1.44 (s, 9H), 1.41-1.31 (m, 2H).

[0268] 2-(4-((Tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate:

[0269] MS m/z (ESI): 396.1[M+H].sup.+.

[0270] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78 (d, J=8.2 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 5.32 (s, 1H), 4.49 (s, 1H), 4.13-4.00 (m, 2H), 3.75-3.61 (m, 1H), 2.45 (s, 3H), 2.30-2.27 (m, 2H), 1.99-1.94 (m, 1H), 1.85-1.76 (m, 2H), 1.70-1.64 (m, 1H), 1.56-1.50 (m, 1H), 1.45 (s, 9H).

Step 6: Preparation of tert-butyl (cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate

[0271] ##STR00063##

[0272] 2-(Cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate (390 mg, 0.94 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of 1-(2,3-dichlorophenyl)piperazine (260 mg, 1.13 mmol) and potassium carbonate (389 mg, 2.82 mmol). The reaction solution was stirred at 90° C. overnight. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/9) to obtain tert-butyl (cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate (210 mg, yield: 47%).

[0273] MS m/z (ESI): 474.2[M+H].sup.+.

Step 7: Preparation of cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine

[0274] ##STR00064##

[0275] Tert-butyl (cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate (210 mg, 0.442 mmol) was dissolved in 25% TFA/dichloromethane (10 mL). The reaction solution was stirred at room temperature for 2 hours, and concentrated to dryness to obtain cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine (210 mg, as a TFA salt). MS m/z (ESI): 374.2[M+H].sup.+.

Step 8: Preparation of 3-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea

[0276] ##STR00065##

[0277] Cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine (210 mg, as a TFA salt, about 0.147 mmol) was dissolved in anhydrous dichloromethane (5 mL), followed by the addition of DIPEA (0.1 mL) and dimethylcarbamic chloride (one drop). The reaction solution was stirred at room temperature overnight. Water (5 mL) was added to the reaction solution, which was then extracted with dichloromethane (10 mL). The organic phase was dried and concentrated to dryness by rotary evaporation. The resulting crude product was purified by prep-HPLC to obtain 3-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimeth ylurea (21.1 mg, yield: 32%).

[0278] MS m/z (ESI): 445.2[M+H].sup.+.

[0279] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.20-7.12 (m, 2H), 6.97 (dd, J=7.1, 2.3 Hz, 1H), 4.18 (d, J=7.7 Hz, 1H), 3.75-3.60 (m, 1H), 3.27-3.03 (m, 4H), 2.89 (s, 6H), 2.86-2.51 (m, 6H), 2.04-1.81 (m, 6H), 1.64-1.53 (m, 1H), 1.52-1.40 (m, 3H).

Example 13

N-(Cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1H-indole-2-carboxamide

[0280] ##STR00066##

Step 1: Preparation of N-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1H-indole-2-carboxamide

[0281] ##STR00067##

[0282] Cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine (100 mg, as a TFA salt, about 0.21 mmol) was dissolved in anhydrous DMF (3 mL), and 1H-indole-2-carboxylic acid (52 mg, 0.32 mmol), HATU (160 mg, 0.42 mmol) and DIEA (0.2 mL) were added respectively. The reaction solution was stirred at room temperature overnight. The reaction solution was filtered and purified by prep-HPLC to obtain N-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1H-indole-2-carboxamide (25 mg, yield: 23%).

[0283] MS m/z (ESI): 517.2[M+H].sup.+.

[0284] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.52 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.35-7.24 (m, 2H), 7.22-7.10 (m, 3H), 7.02 (t, J=7.4 Hz, 1H), 3.95-3.79 (m, 1H), 3.08-2.92 (m, 4H), 2.67-2.51 (m, 6H), 1.99-1.87 (m, 2H), 1.86-1.51 (m, 8H).

Example 14

N-(Cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide

[0285] ##STR00068##

Step 1: Preparation of N-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide

[0286] ##STR00069##

[0287] N-(Cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide (off-white solid, yield: 36%) was obtained according to Step 1 of Example 13 with cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine and furan-2-carboxylic acid as the starting materials.

[0288] MS m/z (ESI): 468.2[M+H].sup.+.

[0289] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.19 (d, J=8.1 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H), 7.63 (d, J=5.6 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.44 (d, J=5.6 Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 7.10 (d, J=3.5 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.60 (dd, J=3.5, 1.7 Hz, 1H), 3.83-3.72 (m, 1H), 3.55-3.38 (m, 4H), 2.98-2.55 (m, 6H), 2.06-1.92 (m, 2H), 1.92-1.72 (m, 4H), 1.72-1.62 (m, 4H), 1.58-1.48 (m, 1H).

Example 15

3-(Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea

[0290] ##STR00070##

Step 1: Preparation of tert-butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate

[0291] ##STR00071##

[0292] Tert-butyl (4-oxocyclohexyl)carbamate (18.0 g, 84.40 mmol) was dissolved in anhydrous THF (400 mL). Allylmagnesium bromide (254 mL, 254 mmol, 1M in THF) was slowly added dropwise at −70° C. After completion of the addition, the reaction solution was stirred for 1 hour. Water (100 mL) was slowly added dropwise to the reaction solution to quench the reaction, which was then extracted with ethyl acetate (500 mL*2). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate=55/45) to obtain tert-butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate (5.4 g, yield: 25%). MS m/z (ESI): 256.2[M+H].sup.+.

Step 2: Preparation of tert-butyl (trans-4-hydroxy-4-(2-oxoethyl)cyclohexyl)carbamate

[0293] ##STR00072##

[0294] Tert-butyl (trans-4-allyl-4-hydroxycyclohexyl)carbamate (5.4 g, 21.15 mmol) was dissolved in THF (100 mL), followed by the addition of water (100 mL). K.sub.2OsO.sub.4.2 H.sub.2O (779 mg, 2.11 mmol) and NaIO.sub.4 (18.09 g, 84.59 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at room temperature overnight. Saturated aqueous Na.sub.2S.sub.2O.sub.4 solution (50 mL) was added to the reaction solution, followed by the addition of ethyl acetate (400 mL) and stirring for 5 minutes. The organic phase was collected, dried and concentrated to obtain tert-butyl (trans-4-hydroxy-4-(2-oxoethyl)cyclohexyl)carbamate (4.8 g, yield: 88%). MS m/z (ESI): 258.1[M+H].sup.+.

Step 3: Preparation of tert-butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate

[0295] ##STR00073##

[0296] Tert-butyl trans-4-hydroxy-4-2-oxoethyl)cyclohexyl)carbamate (4.8 g, 18.65 mmol) was dissolved in anhydrous THF (100 mL), and NaBH.sub.4 (1.41 g, 37.31 mmol) was added in batches. After completion of the addition, the reaction solution was stirred at room temperature for 2 hours. Water (50 mL) was slowly added to the reaction solution to quench the reaction, which was then extracted with ethyl acetate (200 mL*2). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (ethyl acetate/MeOH=95/5) to obtain tert-butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate (3.2 g, yield: 66%).

[0297] MS m/z (ESI): 260.2[M+H].sup.+.

Step 4: Preparation of 2-(trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate

[0298] ##STR00074##

[0299] Tert-butyl (trans-4-hydroxy-4-(2-hydroxyethyl)cyclohexyl)carbamate (3.2 g, 12.34 mmol) was dissolved in anhydrous dichloromethane (50 mL), followed by the addition of DMAP (151 mg, 1.23 mmol) and DIPEA (3.19 g, 24.68 mmol). The reaction solution was cooled to 0° C., to which TsCl (2.82 g, 14.81 mmol) was added. The reaction solution was warmed up to 30° C., and stirred overnight. The reaction solution was partitioned between water (50 mL) and dichloromethane (100 mL). The organic phase was dried and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/2) to obtain 2-(trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate (2.0 g, yield: 39%).

[0300] MS m/z (ESI): 414.1[M+H].sup.+.

Step 5: Preparation of 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate and 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate

[0301] ##STR00075##

[0302] 2-(Trans-4-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)ethyl 4-methylbenzenesulfonate (2 g, 4.84 mmol) was dissolved in anhydrous dichloromethane (50 mL), and DAST (4.68 g, 29.02 mmol) was slowly added dropwise at −70° C. After completion of the addition, the reaction solution was stirred at −70° C. for 2 hours. Water (10 mL) was slowly added dropwise to quench the reaction, and saturated NaHCO.sub.3 solution (10 mL) was added to adjust the pH to weakly alkali. The mixed solution was extracted with dichloromethane (100 mL). The organic phase was dried and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate=3/2) to obtain 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate (630 mg, yield: 31%) and 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate (600 mg, yield: 31%).

[0303] 2-(Cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate:

[0304] MS m/z (ESI): 416.1[M+H].sup.+.

[0305] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.79 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.39 (s, 1H), 4.21-4.12 (m, 2H), 3.45-3.30 (m, 1H), 2.45 (s, 3H), 2.06-1.75 (m, 7H), 1.52-1.46 (m, 1H), 1.44 (s, 9H), 1.41-1.31 (m, 2H).

[0306] 2-(4-((Tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate:

[0307] MS m/z (ESI): 396.1[M+H].sup.+.

[0308] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78 (d, J=8.2 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 5.32 (s, 1H), 4.49 (s, 1H), 4.13-4.00 (m, 2H), 3.75-3.61 (m, 1H), 2.45 (s, 3H), 2.30-2.27 (m, 2H), 1.99-1.94 (m, 1H), 1.85-1.76 (m, 2H), 1.70-1.64 (m, 1H), 1.56-1.50 (m, 1H), 1.45 (s, 9H).

Step 6: Preparation of tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate

[0309] ##STR00076##

[0310] 2-(Cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate was dissolved in acetonitrile (20 mL), followed by the addition of 1-(benzo[b]thiophen-4-yl)piperazine and potassium carbonate (389 mg, 2.82 mmol). The reaction solution was stirred at 90° C. overnight. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/9) to obtain tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate (180 mg, yield: 70%).

[0311] MS m/z (ESI): 462.2[M+H].sup.+.

Step 7: Preparation of cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine

[0312] ##STR00077##

[0313] Tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate was dissolved in 25% TFA/dichloromethane (10 mL). The reaction solution was stirred at room temperature for 2 hours, and concentrated to dryness to obtain cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine (180 mg, as a TFA salt).

[0314] MS m/z (ESI): 362.1[M+H].sup.+.

Step 8: Preparation of 3-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea

[0315] ##STR00078##

[0316] Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-am me was dissolved in anhydrous dichloromethane, followed by the addition of DIPEA and dimethylcarbamic chloride. The reaction solution was stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with dichloromethane. The organic phase was dried and concentrated to dryness by rotary evaporation. The resulting crude product was purified by prep-HPLC to obtain 3-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea (18.0 mg, yield: 32%).

[0317] MS m/z (ESI): 433.2[M+H].sup.+.

[0318] .sup.1H NMR (400 MHz, DMSO) δ 7.69 (d, J=5.5 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.40 (d, J=5.5 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 5.96 (d, J=7.9 Hz, 1H), 3.52-3.38 (m, 1H), 3.16-2.98 (m, 4H), 2.76 (s, 6H), 2.70-2.56 (m, 4H), 2.49-2.44 (m, 2H), 1.94-1.72 (m, 4H), 1.67-1.60 (m, 2H), 1.60-1.43 (m, 4H).

Example 16

1-(Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-3-ethylurea

[0319] ##STR00079##

Step 1: Preparation of 1-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-3-ethyl urea

[0320] ##STR00080##

[0321] Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-am me and triethylamine were dissolved in anhydrous dichloromethane. Isocyanatoethane was added dropwise, and the reaction solution was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and purified by preparative chromatography to obtain 1-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-3-ethyl urea (37.2 mg, yield: 66%).

[0322] MS m/z (ESI): 433.2[M+H].sup.+.

[0323] .sup.1H NMR (400 MHz, DMSO) δ 7.69 (d, J=5.5 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.40 (d, J=5.5 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 6.94-6.87 (m, 1H), 5.74 (d, J=7.9 Hz, 1H), 5.62 (t, J=5.5 Hz, 1H), 3.44-3.34 (m, 1H), 3.14-3.03 (m, 4H), 3.03-2.94 (m, 2H), 2.71-2.55 (m, 4H), 2.46 (s, 2H), 1.88-1.73 (m, 4H), 1.71-1.61 (m, 2H), 1.61-1.43 (m, 2H), 1.40-1.26 (m, 2H), 0.97 (t, J=7.2 Hz, 3H).

Example 17

N-(Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)pyrrolidine-1-carboxamide

[0324] ##STR00081##

[0325] N-(Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)pyrrolidine-1-carboxamide was obtained according to Step 3 of Example 8 with cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine and pyrrole hydrochloride as the starting materials.

[0326] MS m/z (ESI): 459.2[M+H].sup.+.

Example 18

1-(Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-3-cyclopropylurea

[0327] ##STR00082##

##STR00083##

[0328] 1-(Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-3-cyclopropylurea was obtained according to Step 3 of Example 8 with cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine and cyclopropanamine hydrochloride as the starting materials.

[0329] MS m/z (ESI): 445.2[M+H].sup.+.

Example 19

3-(4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethyl urea

[0330] ##STR00084##

Step 1: Preparation of ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate

[0331] ##STR00085##

[0332] Ethyl (1r,4r)-4-aminocyclohexane-1-carboxylate (5 g, 29 mmol) was dissolved in toluene (200 mL). Triethylamine (8.8 g, 88 mmol) and isobenzofuran-1,3-dione (5.2 g, 35 mmol) were added, and the reaction solution was stirred at 140° C. for 8 hours. The reaction solution was cooled to room temperature, and concentrated to dryness by rotary evaporation. Water (50 mL) was added, and the solution was stirred for half an hour. Solids were precipitated and filtered. The solids were collected, and concentrated to dryness by rotary evaporation to obtain ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate (3 g).

[0333] MS m/z (ESI): 302.2 [M+H].sup.+.

Step 2: Preparation of ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate

[0334] ##STR00086##

[0335] Ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate (3 g, 10 mmol) was dissolved in tetrahydrofuran (50 mL), and cooled to −78° C. Lithium diisopropylamide (11 mL, 11 mmol) was added, and the reaction solution was stirred at −78° C. for half an hour. Iodomethane (1.7 g, 12 mmol) was added, and the reaction solution was slowly warmed up to room temperature and stirred overnight. Aqueous solution of ammonium chloride (50 mL) was added, and the solution was stirred for half an hour. The aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate (3.0 g, yield: 100%, crude).

Step 3: Preparation of 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione

[0336] ##STR00087##

[0337] Ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate (3 g, 9.5 mmol) was dissolved in tetrahydrofuran (30 mL), and cooled to 0° C. Lithium aluminum hydride (0.43 g, 11 mmol) was added, and the reaction solution was stirred at 0° C. for 2 hours. Aqueous solution of sodium hydroxide (3 M, 5 mL) was added to quench the reaction, followed by the addition of water (50 mL). The aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (2.6 g, yield: 100%, crude).

Step 4: Preparation of 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde

[0338] ##STR00088##

[0339] 2-(4-(Hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (2.6 g, 9.5 mmol) was dissolved in dichloromethane (30 mL). PCC (4.1 g, 19 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1˜1/1) to obtain 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde (1.5 g).

[0340] MS m/z (ESI): 272.2 [M+H].sup.+.

Step 5: Preparation of 2-(4-methyl-4-vinylcyclohexyl)isoindoline-1,3-dione

[0341] ##STR00089##

[0342] Methyltriphenylphosphonium bromide (2.9 g, 8.3 mmol) was dissolved in tetrahydrofuran (50 mL). The solution was purged with N.sub.2, and cooled to 0° C. Potassium tert-butoxide (1.1 g, 10 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was cooled to 0° C., followed by the addition of a solution of 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde (1.5 g, 5.5 mmol) in tetrahydrofuran (10 mL). The reaction solution was stirred at room temperature for 2 hours and then at 50° C. overnight. Water (100 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1˜1/1) to obtain 2-(4-methyl-4-vinylcyclohexyl)isoindoline-1,3-dione (1.2 g).

[0343] MS m/z (ESI): 270.2 [M+H].sup.+.

Step 6: Preparation of 2-(4-(2-hydroxyethyl)-4-methylcyclohexyl)isoindoline-1,3-dione

[0344] ##STR00090##

[0345] 2-(4-Methyl-4-vinylcyclohexyl)isoindoline-1,3-dione (1.2 g, 4.5 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The solution was cooled to 0° C., and BH.sub.3/THF (13.5 mL, 13.5 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC showed that the reaction was complete. The reaction solution was cooled to 0° C., 3M NaOH aqueous solution (4 mL) was slowly added, followed by the addition of water (3 mL). The reaction solution was stirred at room temperature for 2 hours, and TLC showed that the reaction was complete. Ethyl acetate (50 mL) was added, and the solution was washed with saturated aqueous solution of Na.sub.2S.sub.2O.sub.3 (30 mL) and water (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product (1.2 g, yield: 100%, crude), which was directly used in the next step.

[0346] MS m/z (ESI): 288.2 [M+H].sup.+.

Step 7: Preparation of 2-(4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate

[0347] ##STR00091##

[0348] 2-(4-(2-Hydroxyethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.2 g, 4.5 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (1.4 g, 13.4 mmol) and p-toluenesulfonyl chloride (1.0 g, 5.4 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1˜1/1) to obtain 2-(4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate (1.5 g).

[0349] MS m/z (ESI): 442.2 [M+H].sup.+.

Step 8: Preparation of 2-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1, 3-dione

[0350] ##STR00092##

[0351] 2-(4-(1,3-Dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate (1.5 g, 3.4 mmol), 1-(2,3-dichlorophenyl)piperazine (0.79 g, 3.4 mmol) and potassium carbonate (1.4 g, 10.2 mmol) were dissolved in acetonitrile (30 mL), and the reaction solution was stirred at 80° C. overnight. The reaction solution was filtered, and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1˜1/1) to obtain 2-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1, 3-dione (1.4 g).

[0352] MS m/z (ESI): 500.2 [M+H].sup.+.

Step 9: Preparation of 4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine

[0353] ##STR00093##

[0354] 2-(4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.4 g, 2.8 mmol) was dissolved in ethanol (50 mL). Hydrazine hydrate (0.35 mL, 7.0 mmol) was added, and the reaction solution was stirred at 80° C. overnight. The reaction solution was concentrated to dryness by rotary evaporation, followed by the addition of water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine (0.6 g).

[0355] MS m/z (ESI): 370.2 [M+H].sup.+.

Step 10: Preparation of 3-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethyl urea

[0356] ##STR00094##

[0357] 4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine (50 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (71 mg, 0.7 mmol) and dimethylcarbamic chloride (299 mg, 2.3 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high performance liquid chromatography to obtain 3-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethyl urea (10.0 mg).

[0358] MS m/z (ESI): 441.2 [M+H].sup.+.

Example 20

3-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethylurea

[0359] ##STR00095##

Step 1: Preparation of ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate

[0360] ##STR00096##

[0361] Ethyl (1r,4r)-4-aminocyclohexane-1-carboxylate (5 g, 29 mmol) was dissolved in toluene (200 mL). Triethylamine (8.8 g, 88 mmol) and isobenzofuran-1,3-dione (5.2 g, 35 mmol) were added, and the reaction solution was stirred at 140° C. for 8 hours. The reaction solution was cooled to room temperature, and concentrated to dryness by rotary evaporation. Water (50 mL) was added, and the solution was stirred for half an hour. Solids were precipitated, and the solution was filtered. The solids were collected, and concentrated to dryness by rotary evaporation to obtain ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate (3 g).

[0362] MS m/z (ESI): 302.2 [M+H].sup.+.

Step 2: Preparation of ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate

[0363] ##STR00097##

[0364] Ethyl (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylate (3 g, 10 mmol) was dissolved in tetrahydrofuran (50 mL), and cooled to −78° C. Lithium diisopropylamide (11 mL, 11 mmol) was added, and the reaction solution was stirred at −78° C. for half an hour. Iodomethane (1.7 g, 12 mmol) was added, and the reaction solution was slowly warmed up to room temperature and stirred overnight. Aqueous solution of ammonium chloride (50 mL) was added, and the solution was stirred for half an hour. The aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate (3.0 g, yield: 100%, crude).

Step 3: Preparation of 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione

[0365] ##STR00098##

[0366] Ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate (3 g, 9.5 mmol) was dissolved in tetrahydrofuran (30 mL), and cooled to 0° C. Lithium aluminum hydride (0.43 g, 11 mmol) was added, and the reaction solution was stirred at 0° C. for 2 hours. Aqueous solution of sodium hydroxide (3 M, 5 mL) was added to quench the reaction, followed by the addition of water (50 mL). The aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (2.6 g, yield: 100%, crude).

Step 4: Preparation of 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde

[0367] ##STR00099##

[0368] 2-(4-(Hydroxymethyl)-4-methylcyclohexyl)isoindoline-1,3-dione 2.6 g, 9.5 mmol) was dissolved in dichloromethane (30 mL). PCC (4.1 g, 19 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1˜1/1) to obtain 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde (1.5 g).

[0369] MS m/z (ESI): 272.2 [M+H].sup.+.

Step 5: Preparation of 2-(4-methyl-4-vinylcyclohexyl)isoindoline-1,3-dione

[0370] ##STR00100##

[0371] Methyltriphenylphosphonium bromide (2.9 g, 8.3 mmol) was dissolved in tetrahydrofuran (50 mL). The solution was purged with N.sub.2, and cooled to 0° C. Potassium tert-butoxide (1.1 g, 10 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was cooled to 0° C., followed by the addition of a solution of 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde (1.5 g, 5.5 mmol) in tetrahydrofuran (10 mL). The reaction solution was stirred at room temperature for 2 hours and then at 50° C. overnight. Water (100 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1˜1/1) to obtain 2-(4-methyl-4-vinylcyclohexyl)isoindoline-1,3-dione (1.2 g).

[0372] MS m/z (ESI): 270.2 [M+H].sup.+.

Step 6: Preparation of 2-(4-(2-hydroxyethyl)-4-methylcyclohexyl)isoindoline-1,3-dione

[0373] ##STR00101##

[0374] 2-(4-Methyl-4-vinylcyclohexyl)isoindoline-1,3-dione (1.2 g, 4.5 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The solution was cooled to 0° C., and BH.sub.3/THF (13.5 mL, 13.5 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC showed that the reaction was complete. The reaction solution was cooled to 0° C., aqueous solution of NaOH (3M, 4 mL) was slowly added, followed by the addition of water (3 mL). The reaction solution was stirred at room temperature for 2 hours, and TLC showed that the reaction was complete. Ethyl acetate (50 mL) was added, and the solution was washed with saturated aqueous solution of Na.sub.2S.sub.2O.sub.3 (30 mL) and water (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product (1.2 g, yield: 100%, crude), which was directly used in the next step.

[0375] MS m/z (ESI): 288.2 [M+H].sup.+.

Step 7: Preparation of 2-(4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate

[0376] ##STR00102##

[0377] 2-(4-(2-Hydroxyethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.2 g, 4.5 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (1.4 g, 13.4 mmol) and p-toluenesulfonyl chloride (1.0 g, 5.4 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1˜1/1) to obtain 2-(4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate (1.5 g).

[0378] MS m/z (ESI): 442.2 [M+H].sup.+.

Step 8: Preparation of 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1,3-dione

[0379] ##STR00103##

[0380] 2-(4-(1,3-Dioxoisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate (1.5 g, 3.4 mmol), 1-(benzo[b]thiophen-4-yl)piperazine (0.79 g, 3.4 mmol) and potassium carbonate (1.4 g, 10.2 mmol) were dissolved in acetonitrile (30 mL), and the reaction solution was stirred at 80° C. overnight. The reaction solution was filtered, and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1˜1/1) to obtain 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.4 g).

[0381] MS m/z (ESI): 500.2 [M+H].sup.+.

Step 9: 3-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine

[0382] ##STR00104##

[0383] 3-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindoline-1,3-dione (1.4 g, 2.8 mmol) was dissolved in ethanol (50 mL). Hydrazine hydrate (0.35 mL, 7.0 mmol) was added, and the reaction solution was stirred at 80° C. overnight. The reaction solution was concentrated to dryness by rotary evaporation, followed by the addition of water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine (0.6 g).

[0384] MS m/z (ESI): 370.2 [M+H].sup.+.

Step 10: 3-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethylurea

[0385] ##STR00105##

[0386] 3-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexan-1-amine (50 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (71 mg, 0.7 mmol) and dimethylcarbamic chloride (299 mg, 2.3 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high performance liquid chromatography by referring to Example 19 to obtain 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)-1,1-dimethylurea (20.0 mg).

[0387] MS m/z (ESI): 429.2 [M+H].sup.+.

Example 21

3-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-1,1-dimethylurea

[0388] ##STR00106##

Step 1: Preparation of tert-butyl (4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)carbamate

[0389] ##STR00107##

[0390] Tert-butyl (4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)carbamate (400 mg, yield: 72%) was obtained according to Step 6 of Example 12 with 2-(4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate and 1-(benzo[b]thiophen-4-yl)piperazine as the starting materials.

[0391] MS m/z (ESI): 442.2[M+H].sup.+.

Step 2: Preparation of 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-amine

[0392] ##STR00108##

[0393] 4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-amine (280 mg, yield: 91%) was obtained by referring to Step 7 of Example 12 with tert-butyl (4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)carbamate as the starting material.

[0394] MS m/z (ESI): 342.1[M+H].sup.+.

Step 3: Preparation of 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-1,1-dimethylurea

[0395] ##STR00109##

[0396] 3-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-1,1-dimethylurea was obtained according to Step 8 of Example 12 with 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-amine as the starting material.

[0397] MS m/z (ESI): 413.2[M+H].sup.+.

Example 22

1-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-3-propylurea

[0398] ##STR00110##

Step 1: Preparation of 1-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-3-propylurea

[0399] ##STR00111##

[0400] 1-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-yl)-3-propylurea was obtained according to Step 8 of Example 12 or Example 16 with 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohex-3-en-1-amine and isocyanatopropane as the starting materials.

[0401] MS m/z (ESI): 427.2[M+H].sup.+.

Example 23

3-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)-1,1-dimethylurea

[0402] ##STR00112##

[0403] 3-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)-1,1-dimethylurea was obtained according to Step 8 of Example 12 with 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexane-1-amine and dimethylcarbamic chloride as the starting materials.

[0404] MS m/z (ESI): [M+H].sup.+. 433.2

Example 24

1-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)-3-ethylurea

[0405] ##STR00113##

[0406] 1-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)-3-eth ylurea was obtained according to Step 8 of Example 12 or Example 16 with 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexane-1-amine and isocyanatoethane as the starting materials.

[0407] MS m/z (ESI): [M+H].sup.+ 433.2

Example 25

1-(4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-3-ethylurea

[0408] ##STR00114##

Step 1: Preparation of 1-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-3-ethylurea

[0409] ##STR00115##

[0410] 4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexan-1-amine (60 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL). Triethylamine (48.5 mg, 0.48 mmol) was added, and the reaction solution was stirred at room temperature for 5 minutes. Isocyanatoethane (17.3 mg, 0.24 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high performance liquid chromatography to obtain 1-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-3-ethylurea (11.9 mg, yield: 17%).

[0411] MS m/z (ESI): 441.2 [M+H].sup.+.

[0412] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.21-7.11 (m, 2H), 7.01-6.95 (m, 1H), 4.25-4.00 (m, 2H), 3.26-3.13 (m, 5H), 2.91-2.52 (m, 6H), 2.19-2.11 (m, 1H), 1.94-1.86 (m, 1H), 1.69-1.55 (m, 5H), 1.37-1.10 (m, 11H).

Example 26

N-(4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-5-fluoropyrimidin-2-amine

[0413] ##STR00116##

Step 1: Preparation of N-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-5-fluoropyrimidin-2-amine

[0414] ##STR00117##

[0415] 4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexan-1-amine (50 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (3 mL). Potassium carbonate (41 mg, 0.4 mmol) and 2-chloro-5-fluoropyrimidine (40 mg, 0.3 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high performance liquid chromatography to obtain N-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-5-fluoropyrimidin-2-amine.

[0416] MS m/z (ESI): 466.1 [M+H].sup.+.

Example 27

N-(4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1H-indole-2-carboxamide

[0417] ##STR00118##

Step 1: Preparation of N-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1H-indole-2-carboxamide

[0418] ##STR00119##

[0419] 4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexan-1-amine (50 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (3 mL). 1H-Indole-2-carboxylic acid (27 mg, 0.17 mmol), HATU (74 mg, 0.2 mmol) and diisopropylethylamine (39 mg, 0.3 mmol) were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high performance liquid chromatography to obtain N-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1H-indole-2-carboxamide.

[0420] MS m/z (ESI): 513.2 [M+H].sup.+.

Example 28

3-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1,1-dimethylurea

[0421] ##STR00120##

Step 1: Preparation of 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1,1-dimethylurea

[0422] ##STR00121##

[0423] 3-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexan)-1-amine was dissolved in N,N-dimethylformamide. Dimethylcarbamic acid, HATU and diisopropylethylamine were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high performance liquid chromatography by referring to Example 27 to obtain 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1,1-dimethylurea.

[0424] MS m/z (ESI): 429.2 [M+H].sup.+.

Example 29

1-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-3-ethylurea

[0425] ##STR00122##

[0426] 1-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-3-ethylurea was obtained according to Example 25.

[0427] MS m/z (ESI): 429.2 [M+H].sup.+.

Example 30

3-(Trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)-1, 1-dimethylurea

[0428] ##STR00123##

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

[0429] ##STR00124##

[0430] 1-Bromo-2,3-dichlorobenzene (1.35 g, 6 mmol), tert-butyl (R)-2-methylpiperazine-1-carboxylate (836 mg, 5 mmol), tris(dibenzylideneacetone)dipalladium (228 mg, 0.25 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (289 mg, 0.5 mmol) and sodium tert-butoxide (1.44 g, 15 mmol) were dissolved in 20 mL of toluene in a 50 mL round-bottom flask, and the reaction solution was purged with nitrogen. The reaction solution was stirred at 80° C. under a nitrogen atmosphere for 12 hours. After completion of the reaction, the reaction system was cooled to room temperature, quenched with water, and extracted with ethyl acetate (10 mL*3). The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluted with petroleum ether/ethyl acetate=4/1) to obtain tert-butyl (R)-4-(2,3-dichlorophenyl)-2-methylpiperazine-1-carboxylate (1.0 g, yellow solid, yield: 48.3%).

[0431] MS m/z (ESI): 345.1 [M+H].sup.+.

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

[0432] ##STR00125##

[0433] Tert-butyl (R)-4-(2,3-dichlorophenyl)-2-methylpiperazine-1-carboxylate (1 g, 2.89 mmol) was dissolved in 10 mL of dichloromethane in a 50 mL round-bottom flask, followed by the addition of trifluoroacetic acid (4 mL). The reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the reaction system was concentrated, quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (10 mL*3). The organic phase was dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated to dryness by rotary evaporation to obtain (R)-1-(2,3-dichlorophenyl)-3-methylpiperazine (600 mg, white solid, yield: 84.7%).

[0434] MS m/z (ESI): 245.1 [M+H].sup.+.

Step 3: Tert-butyl (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)carba mate

[0435] ##STR00126##

Tert-buty (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)carba mate (100 mg, yellow solid, yield: 26.0%) was obtained according to Step 1 of Example 2 with (R)-1-(2,3-dichlorophenyl)-3-methylpiperazine and 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl 4-methylbenzenesulfonate as the starting materials.

[0436] MS m/z (ESI): 470.1 [M+H].sup.+.

Step 4: Trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine

[0437] ##STR00127##

[0438] Trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine (75 mg, yellow solid, yield: 95.2%) was obtained according to Step 2 of Example 2 with tert-butyl (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)carba mate as the starting material.

[0439] MS m/z (ESI): 370.1 [M+H].sup.+.

Step 5: 3-(Trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)-1, 1-dimethylurea

[0440] ##STR00128##

[0441] Trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine (60 mg, 0.16 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (50 mg, 0.5 mmol) and dimethylcarbamic chloride (35 mg, 0.32 mmol) were added, and the reaction solution was reacted at room temperature for 12 hours. The reaction solution was washed with water three times (2 mL*3). The organic phase was concentrated and purified by prep-HPLC to obtain the product 3-(trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (8.3 mg, white solid, yield: 13.9%).

[0442] MS m/z (ESI): 441.2 [M+H].sup.+.

[0443] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.39-7.17 (m, 2H), 7.13-7.01 (m, 1H), 3.59-3.45 (m, 2H), 3.28-3.15 (m, 2H), 3.08-2.93 (m, 2H), 2.89 (s, 6H), 2.78-2.57 (m, 3H), 2.52-2.41 (m, 1H), 1.97-1.77 (m, 4H), 1.55-1.39 (m, 2H), 1.37-1.21 (m, 3H), 1.17 (d, J=6.0 Hz, 3H), 1.13-1.03 (m, 2H).

Example 31

3-(Trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-3-cyclopropylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0444] ##STR00129##

[0445] 3-(Trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-3-cyclopropylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea was obtained according to Example 30 with 4-bromobenzo[b]thiophene and tert-butyl (R)-3-cyclopropylpiperazine-1-carboxylate as the starting materials.

[0446] MS m/z (ESI): 455.2 [M+H]f.

Example 32

Preparation of 3-(trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-cyanopiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0447] ##STR00130##

[0448] 3-(Trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-cyanopiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea was obtained according to Example 30.

[0449] MS m/z (ESI): 440.2[M+H].sup.+.

Example 33

3-(Trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0450] ##STR00131##

[0451] The product 3-(trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea was obtained according to Example 30 with 4-bromobenzo[b]thiophene and tert-butyl (R)-3-methylpiperazine-1-carboxylate as the starting materials.

[0452] MS m/z (ESI): 429.2 [M+H].sup.+.

Example 34

3-(Trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0453] ##STR00132##

Step 1: 2-(Benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octane

[0454] ##STR00133##

[0455] 2-(Benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octane (290 mg, white solid, yield: 48%) was obtained according to Step 1 of Example 30 with 4-bromobenzo[b]thiophene and 2,5-diazabicyclo[4.2.0]octane as the starting materials.

[0456] MS m/z (ESI): 245.1 [M+H].sup.+.

Step 2: Tert-butyl (trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexyl)carbamate

[0457] ##STR00134##

[0458] Tert-butyl (trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexyl)carbamate (301 mg, white solid, yield: 54%) was obtained according to Step 3 of Example 30 with 2-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octane as the starting material.

[0459] MS m/z (ESI): 470.3 [M+H].sup.+.

Step 3: Trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexan-1-amine

[0460] ##STR00135##

[0461] Trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexan-1-amine triflate (299 mg, yield: 99%) was obtained according to Step 7 of Example 12 with tert-butyl (trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexyl)carbamate as the starting material.

[0462] MS m/z (ESI): 370.2 [M+H].sup.+.

Step 4: 3-(Trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclo hexyl)-1,1-dimethylurea

[0463] ##STR00136##

[0464] 3-(Trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl) cyclohexyl)-1,1-dimethylurea (23 mg, white solid, yield: 35%) was obtained according to Step 8 of Example 12 with trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)ethyl)cyclohexan-1-amine as the starting material.

[0465] MS m/z (ESI): 441.3 [M+H].sup.+.

Example 35

3-(Trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)-1, 1-dimethylurea

[0466] ##STR00137##

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

[0467] ##STR00138##

[0468] Tert-butyl (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate (600 mg, yellow solid, yield: 32.6%) was obtained according to Step 1 of Example 30 with 1-bromo-2,3-dichlorobenzene and tert-butyl (R)-3-methylpiperazine-1-carboxylate as the starting materials.

[0469] MS m/z (ESI): 345.1 [M+H].sup.+.

[0470] .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).

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

[0471] ##STR00139##

[0472] (R)-1-(2,3-Dichlorophenyl)-2-methylpiperazine (420 mg, yellow solid, yield: 98.8%) was obtained according to Step 2 of Example 30 with tert-butyl (R)-4-(2,3-dichlorophenyl)-3-methylpiperazine-1-carboxylate as the starting material.

[0473] MS m/z (ESI): 245.1 [M+H].sup.+.

[0474] 1H NMR (400 MHz, Methanol-d.sub.4) 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).

Step 3: Tert-butyl (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)carba mate

[0475] ##STR00140##

[0476] Tert-butyl (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)carba mate (100 mg, yellow solid, yield: 26.0%) was obtained according to Step 1 of Example 2 with (R)-1-(2,3-dichlorophenyl)-2-methylpiperazine and 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl 4-methylbenzenesulfonate as the starting materials.

[0477] MS m/z (ESI): 470.1 [M+H].sup.+.

Step 4: Trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine

[0478] ##STR00141##

[0479] Trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine (75 mg, yellow solid, yield: 95.2%) was obtained according to Step 2 of Example 2 with tert-butyl (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)carba mate as the starting material.

[0480] MS m/z (ESI): 370.1 [M+H].sup.+.

Step 5: 3-(Trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)-1, 1-dimethylurea

[0481] ##STR00142##

[0482] 3-(Trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (25 mg, white solid, yield: 35.0%) was obtained according to Step 5 of Example 30 with trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material.

[0483] MS m/z (ESI): 441.2 [M+H].sup.+.

[0484] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.38-7.15 (m, 3H), 3.56-3.44 (m, 1H), 3.36 (s, 2H), 3.12 (d, J=11.6 Hz, 1H), 2.93 (s, 1H), 2.87 (s, 6H), 2.77-2.67 (m, 1H), 2.52-2.34 (m, 3H), 2.17-2.02 (m, 1H), 1.96-1.75 (m, 4H), 1.57-1.42 (m, 2H), 1.37-1.21 (m, 3H), 1.15-0.99 (m, 2H), 0.87 (d, J=6.1 Hz, 3H).

Example 36

3-(Trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea

[0485] ##STR00143##

##STR00144##

[0486] 3-(Trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)eth yl)cyclohexyl)-1,1-dimethylurea was obtained according to Step 5 of Example 30 with trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclo hexan-1-amine as the starting material.

[0487] MS m/z (ESI): 483.2 [M+H].sup.+.

Example 37

N-(Trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclohexyl)oxazole-2-carboxamide

[0488] ##STR00145##

[0489] N-(Trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclohexyl)oxazole-2-carboxamide was obtained according to Step 5 of Example 30 with trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclo hexan-1-amine as the starting material.

[0490] MS m/z (ESI): 507.2 [M+H].sup.+.

Example 38

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide

[0491] ##STR00146##

[0492] N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide was obtained according to Steps 1 to 3 of Example 2 with 1-(benzo[b]thiophen-4-yl)-1,4-diazepane as the starting material.

[0493] MS m/z (ESI): 477.2 [M+H].sup.+.

Example 39

3-(Cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)-1, 1-dimethylurea

[0494] ##STR00147##

Step 1: Preparation of tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)carbamate

[0495] ##STR00148##

[0496] Tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)carba mate was obtained according to Step 6 of Example 12 with 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate and 1-(benzo[b]thiophen-4-yl)-1,4-diazepane as the starting materials.

[0497] MS m/z (ESI): 476.2[M+H].sup.+.

Step 2: Preparation of cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexan-1-amine

[0498] ##STR00149##

[0499] Cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexan-1-amine was obtained according to Step 7 of Example 12 with tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)carba mate as the starting material.

[0500] MS m/z (ESI): 376.2[M+H].sup.+.

Step 3: Preparation of 3-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea

[0501] ##STR00150##

[0502] 3-(Cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexyl)-1,1-dimethylurea was obtained according to Step 8 of Example 12 with cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazepan-1-yl)ethyl)-4-fluorocyclohexan-1-amine as the starting material.

[0503] MS m/z (ESI): 447.2[M+H].sup.+.

[0504] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.63 (d, J=5.6 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.44 (d, J=5.6 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 5.96 (d, J=7.9 Hz, 1H), 3.55-3.37 (m, 5H), 2.90-2.78 (m, 2H), 2.75 (s, 6H), 2.71-2.51 (m, 4H), 2.58 (s, 4H), 2.05-1.90 (m, 2H), 1.89-1.71 (m, 4H), 1.66-1.58 (m, 2H), 1.58-1.40 (m, 4H).

Example 40

N-(Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide

[0505] ##STR00151##

Step 1: Preparation of tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate

[0506] ##STR00152##

[0507] Tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate (180 mg, yield: 70%) was obtained according to Step 6 of Example 12 with 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate and 1-(benzo[b]thiophen-4-yl)piperazine as the starting materials.

[0508] MS m/z (ESI): 462.2[M+H].sup.+.

Step 2: Preparation of cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine

[0509] ##STR00153##

[0510] Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine (180 mg, as a TFA salt) was obtained according to Step 7 of Example 12 with tert-butyl (cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate as the starting material.

[0511] MS m/z (ESI): 362.2[M+H].sup.+.

Step 3: Preparation of N-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide

[0512] ##STR00154##

[0513] N-(Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)furan-2-carboxamide (33.3 mg, yield: 56%) was obtained according to Step 8 of Example 12 with cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexan-1-amine and furan-2-carbonyl chloride as the starting materials.

[0514] MS m/z (ESI): 456.2 [M+H].sup.+.

[0515] .sup.1H NMR (400 MHz, DMSO) δ 8.20 (d, J=8.1 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J=5.5 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.40 (d, J=5.5 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.11 (d, J=3.3 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.66-6.57 (m, 1H), 3.86-3.72 (m, 1H), 3.15-2.97 (m, 4H), 2.74-2.57 (m, 4H), 2.50-2.43 (m, 2H), 1.98-1.75 (m, 4H), 1.72-1.48 (m, 6H).

Example 41

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-hydroxy-2-methylpropanamide

[0516] ##STR00155##

[0517] N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-hydroxy-2-methylpropanamide was obtained according to Example 27 with trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine and 2-hydroxy-2-methylpropionic acid as the starting materials.

[0518] MS m/z (ESI): 430.2 [M+H].sup.+.

Example 42

[0519] N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-hydroxycyclopropane-1-carboxamide

##STR00156##

Step 1: N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-hydroxycyclopropane-1-carboxamide

[0520] ##STR00157##

[0521] Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine (100 mg, 0.291 mmol) was dissolved in anhydrous DMF (5 mL), and 1-hydroxycyclopropane-1-carboxylic acid (59 mg, 0.582 mmol), DIEA (301 mg, 2.328 mmol) and HATU (221 mg, 0.582 mmol) were added respectively. The reaction solution was stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic phase was dried and concentrated to dryness by rotary evaporation. The resulting crude product was purified by prep-HPLC to obtain N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-hydroxycyclopropane-1-carboxamide (38.4 mg, 31% yield).

[0522] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.69 (d, J=5.5 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.21 (s, 1H), 3.61-3.47 (m, 1H), 3.16-2.96 (m, 4H), 2.73-2.53 (m, 4H), 2.39 (t, J=7.5 Hz, 2H), 1.85-1.67 (m, 4H), 1.45-1.35 (m, 2H), 1.35-1.19 (m, 3H), 1.07-0.90 (m, 4H), 0.84-0.74 (m, 2H).

[0523] MS m/z (ESI): 428.2 [M+H].sup.+.

Example 43

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)oxazole-2-carboxamide

[0524] ##STR00158##

[0525] N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)oxazole-2-carboxamide was obtained according to Example 27 with trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine and oxazole-2-carboxylic acid as the starting materials.

[0526] MS m/z (ESI): 439.2 [M+H].sup.+.

[0527] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.05 (s, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.51 (d, J=5.6 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H), 7.33 (s, 1H), 7.27 (t, J=7.8 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 3.90-3.75 (m, 1H), 3.25-3.05 (m, 4H), 2.89-2.65 (m, 4H), 2.59-2.45 (m, 2H), 2.07-1.94 (m, 2H), 1.94-1.84 (m, 2H), 1.55-1.29 (m, 6H), 1.23-1.08 (m, 1H).

Example 44

2-((Trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)amino)pyrimidine-5-carbonitrile

[0528] ##STR00159##

Step 1: Trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine

[0529] ##STR00160##

[0530] Trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine was obtained according to Steps 1 to 3 of Example 35 with 4-bromobenzo[b]thiophene as the starting material.

[0531] MS m/z (ESI): 358.2[M+H].sup.+.

Step 2: (R)-4-(2-(4-(Benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine

[0532] ##STR00161##

[0533] Trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexan-1-amine was dissolved in N,N-dimethylformamide. Potassium carbonate and 2-chloropyrimidine-5-carbonitrile were added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation, and the resulting crude product was purified by high performance liquid chromatography according to Example 26 to obtain 2-((trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl) amino)pyrimidine-5-carbonitrile.

[0534] MS m/z (ESI): 461.2 [M+H].sup.+.

[0535] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.62 (s, 1H), 8.43 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.40 (dd, J=11.2, 5.5 Hz, 2H), 7.29-7.26 (m, 1H), 6.89 (d, J=7.6 Hz, 1H), 5.59 (d, J=8.0 Hz, 1H), 3.86-3.83 (m, 1H), 3.37-3.30 (m, 2H), 3.06-3.04 (m, 2H), 2.88-2.80 (m, 3H), 2.65 (s, 1H), 2.48 (s, 1H), 2.11 (d, J=11.1 Hz, 2H), 1.88 (s, 2H), 1.51 (d, J=6.4 Hz, 2H), 1.30-1.13 (m, 8H).

Example 45

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)furan-2-carboxamide

[0536] ##STR00162##

[0537] The product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)furan-2-carboxamide was obtained according to Example 27 with trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material.

[0538] MS m/z (ESI): 438.2 [M+H].sup.+.

[0539] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.64 (dd, J=1.8, 0.8 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.51 (d, J=5.5 Hz, 1H), 7.42 (dd, J=5.6, 0.8 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.09 (dd, J=3.5, 0.8 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.56 (dd, J=3.5, 1.8 Hz, 1H), 3.89-3.74 (m, 1H), 3.26-3.08 (m, 4H), 2.90-2.67 (m, 4H), 2.61-2.49 (m, 2H), 2.02-1.81 (m, 4H), 1.58-1.48 (m, 2H), 1.47-1.26 (m, 4H), 1.23-1.06 (m, 2H).

Example 46

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methylfuran-2-carboxamide

[0540] ##STR00163##

[0541] The product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-methylfuran-2-carboxamide was obtained according to Example 27 with trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material.

[0542] MS m/z (ESI): 452.2 [M+H].sup.+.

[0543] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.62-7.47 (m, 2H), 7.42 (dd, J=5.6, 0.8 Hz, 1H), 7.27 (t, J=7.9 Hz, 1H), 7.06-6.88 (m, 2H), 6.17 (dd, J=3.3, 1.1 Hz, 1H), 3.91-3.70 (m, 1H), 3.26-3.07 (m, 4H), 2.90-2.65 (m, 4H), 2.62-2.47 (m, 2H), 2.36 (s, 3H), 2.00-1.79 (m, 4H), 1.67-1.49 (m, 2H), 1.47-1.25 (m, 4H), 1.23-1.05 (m, 2H).

Example 47

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-methoxyacetamide

[0544] ##STR00164##

[0545] N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-2-meth oxyacetamide (21 mg) was obtained according to Step 8 of Example 12.

[0546] MS m/z (ESI): 416.2 [M+H].sup.+.

[0547] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J=8.0 Hz, 1H), 7.33-7.24 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 6.34 (d, J=8.6 Hz, 1H), 3.87 (s, 2H), 3.83-3.72 (m, 1H), 3.41 (s, 3H), 3.35-3.18 (m, 4H), 2.91-2.67 (m, 4H), 2.66-2.51 (m, 2H), 2.00 (d, J=10.9 Hz, 2H), 1.82 (d, J=11.8 Hz, 2H), 1.61-1.50 (m, 2H), 1.35-1.23 (m, 2H), 1.20-1.12 (m, 3H).

Example 48

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-hydroxy-3-methylbutanamide

[0548] ##STR00165##

[0549] The product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-3-hydroxy-3-methylbutanamide was obtained according to Example 27 with trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material.

[0550] MS m/z (ESI): 444.2 [M+H].sup.+.

[0551] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.55 (d, J=8.1 Hz, 1H), 7.50 (d, J=5.6 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H), 7.26 (t, J=7.9 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 3.71-3.54 (m, 1H), 3.24-3.06 (m, 4H), 2.86-2.64 (m, 4H), 2.57-2.46 (m, 2H), 2.30 (s, 2H), 1.99-1.80 (m, 4H), 1.55-1.45 (m, 2H), 1.39-1.18 (m, 10H), 1.17-1.03 (m, 2H).

Example 49

N-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-fluoropyrimidin-2-amine

[0552] ##STR00166##

[0553] The product N-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-5-fluoropyrimidin-2-amine was obtained according to Example 26 with trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material.

[0554] MS m/z (ESI): 440.2 [M+H].sup.+.

[0555] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.19 (s, 2H), 7.59-7.48 (m, 2H), 7.42 (d, J=5.6 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 3.70-3.60 (m, 1H), 3.23-3.15 (m, 4H), 2.84-2.70 (m, 4H), 2.59-2.50 (m, 2H), 2.22-2.16 (m, 1H), 2.10-1.98 (m, 3H), 1.91-1.82 (m, 2H), 1.65-1.49 (m, 3H), 1.21-1.10 (m, 2H).

Example 50

3-(Trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methoxy-1-methylurea

[0556] ##STR00167##

[0557] The product 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1-methoxy-1-methylurea was obtained according to Step 3 of Example 1 with trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexan-1-amine as the starting material.

[0558] MS m/z (ESI): 431.2 [M+H].sup.+.

[0559] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.62-7.48 (m, 2H), 7.42 (dd, J=5.6, 0.8 Hz, 1H), 7.26 (t, J=7.9 Hz, 1H), 6.93 (dd, J=7.7, 0.8 Hz, 1H), 3.63 (s, 3H), 3.57-3.41 (m, 1H), 3.26-3.10 (m, 4H), 3.03 (s, 3H), 2.86-2.65 (m, 4H), 2.60-2.46 (m, 2H), 1.97-1.80 (m, 4H), 1.56-1.42 (m, 2H), 1.40-1.25 (m, 4H), 1.20-1.02 (m, 2H).

Example 51

N-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)furan-2-carboxamide

[0560] ##STR00168##

[0561] N-(4-(2-(4-(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)furan-2-carboxamide was obtained according to Step 1 of Example 14 with 4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexane-1-amine and furan-2-carboxylic acid as the starting materials.

[0562] MS m/z (ESI): 456.2 [M+H].sup.+.

[0563] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.56 (d, J=8.0 Hz, 1H), 7.46-7.42 (m, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.14-7.09 (m, 1H), 6.91 (d, J=7.6 Hz, 1H), 6.65-6.54 (m, 1H), 6.50 (d, J=5.1 Hz, 1H), 6.33-6.16 (m, 1H), 4.93-4.73 (m, 1H), 4.38-3.96 (m, 1H), 3.24 (s, 4H), 2.78 (s, 4H), 2.13-1.95 (m, 2H), 1.88-1.83 (m, 2H), 1.75-1.54 (m, 4H), 1.34-1.12 (m, 3H).

Biological Assay and Evaluation

[0564] The present invention is further illustrated 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

[0565] 1. Experimental Objective:

[0566] The objective of this test example is to determine the affinity of the compounds for dopamine D3 receptor.

[0567] 2. Experimental Instruments and Reagents:

[0568] 2.1 Experimental Instruments:

[0569] Vortex mixer (IKA; MS3 basic);

[0570] Electric heating constant temperature incubator (Shanghai Yiheng Scientific Instruments Co., Ltd; DHP-9032);

[0571] Microplate shaker (VWR; 12620-928);

[0572] TopCount (PerkinElmer; NTX);

[0573] Universal Harvester (PerkinElmer; UNIFILTER-96).

[0574] 2.2 Experimental Reagents and Materials:

[0575] [.sup.3H]-methylspiperone (PerkinElmer; NET856250UC);

[0576] Human Dopamine D3 Receptor membrane (PerkinElmer; ES-173-M400UA);

[0577] GR 103691 (Sigma; 162408-66-4);

[0578] ULTIMA GOLD (Perkin Elmer; 77-16061);

[0579] 96 round deep well plate 1.1 mL (Perkin Elmer; P-DW-11-C);

[0580] UNIFILTER-96 GF/B filter plate (PerkinElmer; 6005174);

[0581] Polyethyleneimine, branched (Sigma; 408727);

[0582] Centrifuge tubes (BD, 352096; 352070);

[0583] Loading slot (JET BIOFIL; LTT001050);

[0584] Pipette tips (Axygen; T-300-R-S, T-200-Y-R-S, T-1000-B-R-S);

[0585] Magnesium chloride (Sigma, 7786-30-3);

[0586] Tris-base (Sigma, 77-86-1);

[0587] HCl (Beijing Xingling Precision Chemical Technology CO., LTD).

[0588] 3. Experimental Method:

[0589] Assay buffer: 50 mM Tris-HCl pH 7.4, 10 mM MgCl.sub.2; wash solution: 50 mM Tris-HCl pH 7.4, stored at 4° C.; 0.5% PEI solution: 0.5 g PEI dissolve in 100 mL ddH.sub.2O, 4° C. storage of spare.

[0590] 5 μL of the test compounds (0.005 nM to 100 nM, 10 concentrations in total) and 100 μL of buffer were added to a 96-well assay plate. 1 μL of cell membrane and 300 μL of buffer were added to each well, and the plate was shaken at 600 rpm for 5 min. A mixed solution of 100 μL of buffer and [.sup.3H]-methylspiperone (the final concentration was 0.5 nM) was added to each well. The plate was shaken at 600 rpm for 5 min, and 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 μL of ULTIMA GOLD was added to each well, and liquid scintillation counting was carried out.

[0591] 4. Processing Method of the Experimental Data:

[0592] 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 control)/(CPM.sub.high control−CPM.sub.low 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.

[0593] 5. Experimental Results:

[0594] 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-00001 TABLE 1 IC.sub.50 of the binding activity of the compounds of the present invention to D3 D3 binding activity Example No. IC.sub.50 (nM) Cariprazine 0.89 2 0.76 3 1.59 4 1.52 15 4.25 16 0.57 23 2.69 40 0.83 41 1.03 42 0.20 43 0.43 44 1.58 45 0.12 46 0.60 47 0.47 48 0.36 49 2.43 50 1.29 51 0.76

[0595] 6. Experimental Conclusion:

[0596] 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

[0597] 1. Experimental Objective:

[0598] The objective of this test example is to determine the affinity of the compounds for 5-HT2A receptor.

[0599] 2. Experimental Instruments and Reagents:

[0600] 2.1 Experimental Instruments:

[0601] Vortex mixer (IKA; MS3 basic);

[0602] Electric heating constant temperature incubator (Shanghai Yiheng Scientific Instruments Co., Ltd; DHP-9032);

[0603] Microplate shaker (VWR; 12620-928);

[0604] TopCount (PerkinElmer; NTX);

[0605] Universal Harvester (PerkinElmer; UNIFILTER-96).

[0606] 2.2 Experimental reagents and materials:

[0607] [.sup.3H]-Ketanserin (PerkinElmer NET791);

[0608] Human Dopamine 5-HT2A Receptor membrane (PerkinElmer);

[0609] ULTIMA GOLD (Perkin Elmer; 77-16061);

[0610] 96 round deep well plate 1.1 mL (Perkin Elmer; P-DW-11-C);

[0611] UNIFILTER-96 GF/B filter plate (PerkinElmer; 6005174);

[0612] Polyethyleneimine, branched (Sigma; 408727);

[0613] Centrifuge tubes (BD, 352096; 352070);

[0614] Loading slot (JET BIOFIL; LTT001050);

[0615] Pipette tips (Axygen; T-300-R-S, T-200-Y-R-S, T-1000-B-R-S);

[0616] Calcium chloride (Sigma);

[0617] Tris-base (Sigma, 77-86-1);

[0618] HCl (Beijing Xingling Precision Chemical Technology CO., LTD);

[0619] L-Ascorbic acid (Tianjin Guangfu).

[0620] 3. Experimental Method:

[0621] Assay buffer: 50 mM Tris-HCl pH 7.4, 4 mM CaCl.sub.2); wash solution: 50 mM Tris-HCl pH 7.4, stored at 4° C.; 0.5% PEI solution: 0.5 g PEI dissolve in 100 mL ddH.sub.2O, 4° C. storage of spare.

[0622] 5 μL of the test compounds (0.005 nM to 100 nM, 10 concentrations in total) and 100 μL of buffer were added to a 96-well assay plate. 1.5 μL of cell membrane and 300 L of buffer were added to each well. The plate was shaken at 600 rpm for 5 min. A mixed solution of 100 μL of buffer and [.sup.3H]-Ketanserin (the final concentration was 2 nM) was added to each well. The plate was shaken at 600 rpm for 5 min, and 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 μL of ULTIMA GOLD was added to each well, and liquid scintillation counting was carried out.

[0623] 4. Experimental Data Processing Method:

[0624] 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 control)/(CPM.sub.high control−CPM.sub.low 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.

[0625] 5. Experimental Results:

[0626] 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-00002 TABLE 2 IC.sub.50 of the binding activity of the compounds of the present invention to 5-HT2A 5HT-2A binding activity Example No. IC.sub.50 (nM) Cariprazine 191.28 2 3.4 4 0.26 16 2.07 23 6.45 40 0.43 41 0.43 42 0.26 43 0.37 44 2.59 45 0.63 46 0.91 47 0.96 48 0.83 49 0.34 50 2.16 51 0.90

[0627] 6. Experimental conclusion:

[0628] 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

[0629] 1. Experimental Objective:

[0630] To determine the activation effect of the compounds on D3 receptor.

[0631] 2. Experimental Instruments and Reagents:

[0632] 2.1 Experimental Instruments:

[0633] 384-well assay plate (Perkin Elmer; 6007680);

[0634] 96-well conical btm PP Plt nature RNASE/Dnase-free plate (ThermoFisher; 249944);

[0635] EnVision (Perkin Elmer).

[0636] 2.2 Experimental Reagents:

[0637] Fetal Bovine Serum (Gibco, 10999141);

[0638] Ham's F-12K (Kaighn's) Medium (Hyclone; SH30526.01);

[0639] Penicillin-Streptomycin, Liquid (Gibco; 15140122);

[0640] G418 (invitrogen; 0131-027);

[0641] Forskolin (Selleck, S2449);

[0642] BSA stabilizer (Perkin Elmer; CR84-100);

[0643] cAMP kit (Cisbio; 62AM4PEC);

[0644] IBMX (Sigma; I5879);

[0645] HEPES (Gibco; 15630080);

[0646] HBSS (Gibco; 14025076);

[0647] TrypLE (ThermoFisher; 12604021).

[0648] 3. Experimental Method:

[0649] 1. Preparation of the buffer: 1*HBSS+20 mM HEPES+0.1% BSA+500 μM IBMX.

[0650] Complete medium: Ham's F12K+10% fetal bovine serum+1* penicillin-streptomycin+400 μg/mL G418.

[0651] 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.

[0652] 3. The experimental buffer (1*HBSS, 0.1% BSA, 20 mM HEPES and 500 μM IBMX) was prepared. The compound was diluted with the buffer. 2.5 μL 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 μM (8*) with the experimental buffer. 2.5 μL of the diluted 8* forskolin was added, and the plate was incubated at 37° C. for 30 minutes. cAMP-d2 and Anti-cAMP-Eu3+ were thawed, and diluted by 20-fold with the lysis buffer. 10 μL of cAMP-d2 was added to the experimental well, followed by the addition of 10 μL of Anti-cAMP-Eu3+. 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.

[0653] 4. Processing method of the experimental data:

[0654] 1) Z′ factor=1−3*(SDMax+SDMin)/(MeanMax−MeanMin);

[0655] 2) CVMax=(SDMax/MeanMax)*100%;

[0656] 3) CVMin=(SDMin/MeanMin)*100%;

[0657] 4) S/B=Singal/Background;

[0658] 5) EC.sub.50 of the compound was calculated using the GraphPad nonlinear fitting equation:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log EC.sub.50−X)*HillSlope))

[0659] X: log value of compound concentration; Y: Activation %

[0660] 5. Experimental Results:

TABLE-US-00003 TABLE 3 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 42 1.1 43 0.1

[0661] 6. Experimental Conclusion:

[0662] 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 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

[0663] 1. Experimental Objective:

[0664] To determine the inhibitory effect of the compounds on 5-HT2A receptor.

[0665] 2. Experimental Instruments and Reagents:

[0666] 2.1 Experimental Instruments:

[0667] 384-well assay plate (Corning; 3712);

[0668] Pipette (Axygen);

[0669] FLIPR (Molecular Devices).

[0670] 2.2 Experimental Reagents:

[0671] DMEM (Invitrogen; 11965);

[0672] Fetal bovine serum (Biowest; S1810-500);

[0673] Dialysis serum (S-FBS-AU-065; Serana);

[0674] Penicillin-Streptomycin (Biowest; L0022-100);

[0675] Hygromycin B (CABIOCHEM, 400052);

[0676] Matrigel (BD; 354230);

[0677] DMSO (Sigma; D2650);

[0678] HBSS (Invitrogen; 14065);

[0679] HEPES (Invitrogen; 15630080);

[0680] Probenecid (Sigma; P8761);

[0681] BSA (renview; FA016);

[0682] TrypLE (ThermoFisher; 12604021).

[0683] 3. Experimental Method:

[0684] 1) Preparation of the buffer: 1×HBSS, 20 mM HEPES, 2.5 mM probenecid (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.

[0685] 2) Cell culture medium: Ham's F-12K+10% fetal bovine serum+600 μg/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.

[0686] 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).

[0687] 4) 20× Component A was thawed to room temperature, diluted to 2× working concentration (containing 5 mM Probenecid) with the assay buffer, and placed at room temperature for later use.

[0688] 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 μL of the solution was finally remained in the 3764 culture plate. 20 μL of 2× Component A (containing 5 mM Probenecid) was added to each assay well, centrifuged at 200 g at RT for 3 to 5 sec, and incubated at 37° C. for 2 hr. 6) The medium was discarded, and 20 μL of the dye was added. The plate was incubated at 37° C. in the dark for 60 min, and the calcium signal was determined.

[0689] 7) The antagonist was obtained before the experiment: the working solution of the test compound (6×) 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 μL/well), which was then incubated at room temperature in the dark for 35 min.

[0690] 8) 5HT was diluted to 6 nM (6×) with the assay buffer. 50 μL of the solution was transferred to a 384-well plate (Corning, 3657), and placed at room temperature for later use. The assay plate was transferred to the FLIPR, followed by the addition of agonist compound at 6× concentration (5 μL/well). 10 μL of diluted 5HT was added to each experimental well using FLIPR, and the values were determined and saved. The total assay volume was 30 μL, including 20 μL/well of the dye buffer, 5 μL/well of the test compound at 5× concentration and 5 μL/well of the agonist compound at 6× concentration.

[0691] 4. Processing Method of the Experimental Data:

[0692] The calcium signal values were determined by FLIPR. The ratio of the 340/510 nm wavelength signals to 380/510 nm wavelength signals was used as the calculated results for each sampling time point in the experiment. The calculation of maximum minus minimum 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.

[0693] 5. Experimental results:

TABLE-US-00004 TABLE 4 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 40 3.16 42 3.42

[0694] 6. Experimental Conclusion:

[0695] 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

[0696] 1. Study Objective:

[0697] Balb/c mice were used as test animals. The pharmacokinetic behavior of the compounds of Examples of the present invention was studied in mouse body (plasma and brain tissue) by orally administration at a dose of 5 mg/kg.

[0698] 2. Experimental Protocol:

[0699] 2.1 Test Compounds:

[0700] Compounds of the Examples of the present invention, prepared by the applicant.

[0701] 2.2 Test Animals:

[0702] 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.

[0703] 2.3 Formulation of the Preparation:

[0704] The test compound was dissolved in 0.5% CMC-Na (1% Tween80) by sonication to formulate a clear solution or homogeneous suspension.

[0705] 2.4 Administration:

[0706] After an overnight fast, male Balb/c mice (12 mice per group) were administered p.o. with the test compound at a dose of 5 mg/kg and a volume of 10 mL/kg.

[0707] 2.5 Sample Collection:

[0708] 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.

[0709] 2.6 Sample Process:

[0710] 1) 160 μL of acetonitrile was added to 40 μL of the plasma sample for precipitation, and then the mixture was centrifuged at 3500×g for 5 to 20 minutes.

[0711] 2) 90 μL of acetonitrile containing internal standard (100 ng/mL) was added to 30 μL of the plasma and brain homogenate sample for precipitation, and then the mixture was centrifuged at 13000 rpm for 8 minutes.

[0712] 3) 70 μL of water was added to 70 μL of the treated supernatant and mixed by vortex for 10 minutes. 20 μL of the solution was taken to analyze the concentration of the test compound by LC/MS/MS. LC/MS/MS analytical instrument: AB Sciex API 4000 Qtrap.

[0713] 2.7 Liquid Chromatography Analysis: [0714] Liquid chromatography condition: Shimadzu LC-20AD pump [0715] Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1 mm, 3.5 μm); Mobile phase: Eluent A was 0.1% formic acid in water, and Eluent B was acetonitrile [0716] Flow rate: 0.4 mL/min [0717] Elution time: 0-4.0 minutes the eluent is as follows:

TABLE-US-00005 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

[0718] 3. Experimental Results and Analysis:

[0719] 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-00006 TABLE 5 Results of pharmacokinetic test in mice Pharmacokinetic test (5 mg/kg) Peak Plasma Area under Area under Half Average time concentration curve curve life residence time Example t.sub.max C.sub.max AUC.sub.0-t AUC.sub.0-∞ t.sub.1/2 MRT No. (ng/mL) (ng/mL) (ng/mL × h) (ng/mL × h) (h) (h) 40 6.0 192.0 3073.3 3391.3 7.3 9.21 Plasma 40 1.0 328.0 4594.4 4961.0 NA NA Brain 41 1.0 452.3 5209.9 6370.8 10.2 13.5 Plasma 41 1.0 730.7 8119.8 13005.7 NA NA Brain 42 1.0 476.7 4240.5 4369.6 4.84 6.84 Plasma 42 1.0 330.0 3611.0 3890.8 NA NA Brain 43 1.0 403.0 4139.7 4859.6 8.9 11.8 Plasma 43 1.0 1392.0 14103.7 16534.3 NA NA Brain

[0720] 4. Experimental Conclusion:

[0721] It can be seen from the results of pharmacokinetic test in mice in the table that the compounds of the Examples of the present invention show good pharmacokinetic properties, both the exposure AUC and maximum plasma concentration C.sub.max are good.

IV. Stability Assay in Liver Microsome In Vitro

[0722] 1. Experimental Objective:

[0723] To evaluate the metabolic stability of the compounds of the present invention in liver microsome in vitro.

[0724] 2. Experimental Instruments and Reagents:

[0725] 2.1 Instruments:

TABLE-US-00007 Instrument Brand Model Vortex mixer IKA Vortex Thermostatic mixer SpecificAction Incubation-micro mixer Centrifuge Eppendorf Centrifuge 5804R Liquid chromatograph Shimadzu LC-30AD Mass spectrometer AB Sciex API5500

[0726] 2.2 Reagents:

TABLE-US-00008 Reagent Brand Article number 7-Hydroxy coumarin J&K Scientific 153384 DMSO Sigma  34869 PBS Gibco 10010-023 CD-1 mouse liver microsome BD M1000 NADPH Bide BD11658 UDPGA Sigma U6751 Avermectin J&K Scientific 622045

[0727] 3. Experimental Procedure:

[0728] 3.1. Formulation of the Working Solution of the Compound

[0729] Formulation of the working solution of the compound: 2 μL of the stock solution of the compound was added to 998 μL of phosphate buffer, and the final concentration was 20 μM.

[0730] Formulation of the working solution of the control compound (7-hydroxycoumarin): The formulation was consistent with that of the compound.

[0731] 3.2. Formulation of the working solution of liver microsome

[0732] 78.1 μL of 20 mg/mL microsome was diluted to 2.5 mL with 100 mM phosphate buffer and mixed well, and the final concentration was 0.625 mg/mL.

[0733] 3.3. Formulation of NADPH and UDPGA

[0734] 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.

[0735] 3.4. Formulation of the Channel-Forming Reagent (Alamethicin)

[0736] 1 mg of Alamethicin was weighed, to which 200 μL of DMSO was added to obtain a 5 mg/mL solution. 10 μL of this solution was added to 990 μL of phosphate buffer (pH 7.4), and the final concentration was 50 μg/mL.

[0737] 3.5. Formulation of the Reaction Stop Solution

[0738] Stop solution: Cold acetonitrile containing 100 ng/mL labetalol hydrochloride and 400 ng/mL tolbutamide was used as internal standards, and stored in a refrigerator at 2 to 8° C.

[0739] 3.6. Incubation Procedure

[0740] 400 μL of the formulated liver microsome, 25 μL of the working solution of the compound (10 μM) and 25 μL of Alamethicin (50 μg/mL) were added to a 96-well plate successively, which was then pre-incubated at 37° C. for 10 min. 50 μL 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 μL. The final contents of the components were as follows:

TABLE-US-00009 Components Content Liver microsome   0.5 mg/mL Compound 1 μM NADPH 2 mM UDPGA 2 mM Alamethicin 2.5 μg/mL

[0741] 50 μL 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 μL 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.

[0742] 4. Experimental Results:

TABLE-US-00010 TABLE 6 Stability in liver microsome in vitro Intrinsic clearance Half life rate (CL.sub.int) Remaining (t.sub.1/2) (μL/min/mg (%, Species No. min protein) 120 min) Mouse Cariprazine 65.8 21.1 30.5 Example 41 163.0 21.3 80.6 Note: Intrinsic clearance rate (uL/min/mg protein) Type of clearance rate Mouse Slow <8.8 Rapid >48.0

[0743] 5. Experimental Conclusion:

[0744] The above data show that the compounds of the Examples of the present invention are moderately metabolized in mouse liver microsome.

V. Pharmacodynamic Model of Active Escape Experiment in Rats

[0745] 1. Experimental Objective:

[0746] To evaluate the anti-schizophrenic effect of the compounds using the pharmacodynamic model of the active escape experiment in rats.

[0747] 2. Experimental Instruments and Reagents:

[0748] 2.1 Instruments:

TABLE-US-00011 Instrument No. Instrument name model Source Manufacturer 1 Active and passive MED-APA-D1R Imported Med Associates, Inc. shuttle device 2 Thermostatic 85-2 Domestic Shanghai Sile Instrument magnetic stirrer Co., Ltd. 3 Vortex mixer H-101 Domestic Shanghai Kanghe Photoelectric Instrument Co., Ltd. 4 Ultrasonic cleaner KQ3200DE Domestic Kunshan Ultrasonic Instruments Co., Ltd

[0749] 2.2 Reagents:

TABLE-US-00012 No. Name Purity Batch number Storage condition Manufacturer 1 CMC-Na 100% SLBV9664 RT Sigma 2 Tween 80 100% BCBV8843 RT Sigma

[0750] 2.3 Test Compounds:

[0751] Compounds of the Examples of the present invention, prepared by the applicant.

[0752] 3. Test Animals:

TABLE-US-00013 Animal species Strain Age Gender Supplier Rats F344 6-8 Male Beijing Vital River Laboratory weeks Animal Technology Co., Ltd.

[0753] 4. Formulation of the Vehicle and Compounds:

[0754] 4.1 Vehicle (0.5% CMC-Na+1% Tween80)

[0755] 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.

[0756] 4.2 Formulation of the Compounds:

[0757] A formula amount of the compound was weighed, followed by the addition of a formula 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.

[0758] 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.

[0759] 5. Experimental Protocol:

[0760] After arriving at the experimental facility, the animals were acclimatized for one week before starting the experiment.

[0761] 5.1 Establishment of the Pharmacodynamic Model:

[0762] 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;

[0763] 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, which would be recorded as avoids, and the single training ended;

[0764] 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 with the current intensity of 0.6 mA and the duration of 10 seconds. If the animal avoided to the other side during the 10 seconds of electric shock, then the electric shock would stop, which would be recorded as escapes, and the single training ended;

[0765] 5.1.4 If the animal failed to avoid during the 10 seconds of electric shock, then the electric shock would stop, which would be recorded as escape failures, and the single training ended;

[0766] 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.

[0767] 5.2 Baseline Test and Grouping

[0768] The day before the compound screening test, a baseline test was performed. The test procedure 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.

[0769] 5.3 Compound Screening Test

[0770] The compound was administered orally (5 mL/kg) one hour before the test;

[0771] The test procedure was the same as 5.1.1 to 5.1.4, and the number of the test was 20.

[0772] 6. Data Process:

[0773] The following data was collected by the software for data analysis:

[0774] Number of avoids of the animal;

[0775] Number of escape failures of the animal;

[0776] Escape latency of the animal;

[0777] 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.

[0778] 7. Experimental Results:

TABLE-US-00014 TABLE 7 Dose CAR value Example No. (mg/kg) (%) EF (%) Vehicle — 91 0 Cariprazine 1 45.5 5.5 42 1 46.5 0

[0779] 8. Experimental Conclusion:

[0780] 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.

VI. Toxicity Test by Repeated Intragastric Administration for 14 Days in SD Rats

[0781] 6.1 Experimental Objective

[0782] The objective of this study was to investigate the possible toxicity of compounds after repeated intragastric administration to SD rats for 14 days.

[0783] 6.2 Experimental Materials and Instruments:

[0784] 6.2.1 Test Compound

[0785] Test compound 1: the compound of Example 42.

[0786] 6.2.2 Vehicle:

[0787] Name: 0.5% CMC-Na (1% tween80) aqueous solution

[0788] 6.2.3 Animal Information:

[0789] Species & strain: Sprague-Dawley (SD) rats

[0790] Animal grade: SPF grade

[0791] Number and sex of animals: 60, half male and half female

[0792] 6.3 Experimental Method:

[0793] 60 rats (30 rats/sex) were divided into 20 groups according to their sex and body weight. 40 rats were used for toxicology study (groups 1 to 4, 5 rats/sex/group), and 24 rats were used for toxicokinetics study (groups 5 to 8, 3 rats/sex/group). The animals in groups 1 and 5 were intragastrically administered with 0.5% CMC-Na (1% tween80) aqueous solution as the vehicle control groups. The animals in groups 2 and 6, 3 and 7, 4 and 8 were intragastrically administered with the compound of Example 42 at a dose of 2, 10 and 30 mg/kg, respectively. The animals were administered once a day for 14 consecutive days. The administration volumes were 10 mL/kg. During the experiment, clinical observation, body weight, food intake, body temperature, clinicopathological indicators (blood cell count, coagulation function, blood biochemistry) and toxicokinetics were monitored. All animals were euthanized on D15. During the experiment, the animals in groups 1 to 4 were subjected to gross anatomical observation. Histopathological examination was carried out on abnormal tissue and brain, kidney, adrenal gland, lung and bronchi, prostate, testis and epididymis.

[0794] 6.4 List of Test Data

[0795] 6.4.1 Dying/Death

[0796] During the experiment, there was no death/dying in each group of animals.

[0797] 6.4.2 Toxokinetics

[0798] The mean systemic exposure (as AUC.sub.last) ratios of female animals to male animals in each dose group of the compound of Example 42 on D1 and D14 were between 0.83 and 2.52, indicating that the exposure of the compound of Example 42 in female animals was overall higher than that in male animals. Two-sided t-test and one-sided t-test were carried out on the mean systemic exposure (as AUC.sub.last) of female animals and male animals in each dose group on D1 and D14, respectively. The results showed that there was no statistical significance between female animals and male animals (P>0.05).

[0799] On D1 and D14, the average exposure of the compound of Example 42 in both female and male animals increased with the increase of the dose, and the extent of the increase of the average exposure was greater than that of the dose.

[0800] After 14 days of intragastric administration at a dose of 2, 10 or 30 mg/kg respectively, the ratio of average AUC.sub.last of female and male animals in each dose group of the compound of Example 42 at the last dose (D14) to that at the first dose (D1) was between 1.03 and 2.12, and no accumulation was observed.

[0801] 6.5 Experimental Conclusion:

[0802] In this experiment, the compound of Example 42 was intragastrically administered to SD rats at a dose of 2, 10 or 30 mg/kg for two weeks (once a day). The main toxic responses are: body weight, food intake and body temperature are decreased; regarding to blood counts, WBC, Lymph, Retic and PLT are decreased; regarding to coagulation function, FIB wis decreased, and APTT is shortened; the main target organs for toxicity are the lungs and adrenal glands. Under this experimental condition, the maximum tolerated dose (MTD) of the compound of Example 42 is 30 mg/kg.