TETRAHYDROPYRROLE COMPOUND, PREPARATION METHOD THEREFOR, PHARMACEUTICAL COMPOSITION CONTAINING SAME, AND USE THEREOF

Abstract

The present invention discloses a tetrahydropyrrole compound, a preparation method therefor, a pharmaceutical composition containing the same, and a use thereof. The tetrahydropyrrole compound of the present invention is represented by general formula (I). The tetrahydropyrrole compound of the present invention has better inhibitory effects on the positive symptoms of schizophrenia, and the potency thereof is equivalent to or slightly stronger than that of the positive drug olanzapine. In addition, the compound of the present invention has dual inhibitory effects on D2 receptors and DAT receptors, and is effective for treating schizophrenia and improving negative symptoms and cognitive functions, while also reducing vertebral side effects and prolactin secretion.

##STR00001##

Claims

1. A tetrahydropyrrole compound represented by general formula (I), an enantiomer, a diastereomer, an isotope compound, a pharmaceutically acceptable prodrug, a pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof: ##STR00310## wherein: A.sup.1 is CR.sup.1 or N; A.sup.2 is CR.sup.1a or N; A.sup.3 is CR.sup.1b or N; A.sup.4 is CR.sup.1c or N; A.sup.5 is CR.sup.1d or N; no more than 3 nitrogen atoms are present in A.sup.1, A.sup.2, A.sup.3, A.sup.4 and A.sup.5; R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are each independently a hydrogen atom, halogen, cyano, nitro, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, substituted or unsubstituted C.sub.2-C.sub.10heteroaryl, ##STR00311## or, adjacent R.sup.1 and R.sup.1a; or R.sup.1a and R.sup.1b; or R.sup.1b and R.sup.1c; or R.sup.1c and R.sup.1d and the atoms attached thereto together form substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.2-C.sub.8heterocyclyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; the heteroatoms in the C.sub.2-C.sub.8heterocyclyl are selected from N, O and S, the number of the heteroatoms is 1-3, and when the number of the heteroatoms is 2 or 3, then the heteroatoms can be the same or different; the C.sub.2-C.sub.8heterocyclyl is a saturated C.sub.2-C.sub.8heterocyclyl or an unsaturated C.sub.2-C.sub.8heterocyclyl, the ring atoms are selected from two, three or four of C, N, O and S, and when the ring atom is C or S, then the C or S can be formed with oxygen into ##STR00312## R.sup.2 and R.sup.3 are each independently a hydrogen atom, hydroxyl, amino, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, substituted or unsubstituted C.sub.2-C.sub.10heteroaryl, ##STR00313## R.sup.2a and R.sup.2b are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, substituted or unsubstituted C.sub.2-C.sub.10heteroaryl, hydroxyl or ##STR00314## R.sup.2c is substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4 alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; R.sup.2d and R.sup.2e are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C 4 alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; R.sup.4 and R.sup.5 are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, substituted or unsubstituted C.sub.2-C.sub.10heteroaryl, ##STR00315## R.sup.4 can also be ##STR00316## wherein R.sup.p1 and R.sup.p2 are independently substituted or unsubstituted C.sub.1-C.sub.4alkyl; R.sup.4a is a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.2-C.sub.4alkenyl, substituted or unsubstituted C.sub.2-C.sub.4alkynyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, substituted or unsubstituted C.sub.2-C.sub.10heteroaryl or ##STR00317## R.sup.4b, R.sup.4c, R.sup.4d and R.sup.4e are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; R.sup.6 is a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, substituted or unsubstituted C.sub.2-C.sub.10heteroaryl, ##STR00318## R.sup.6a, R.sup.6b, R.sup.7 and R.sup.8 are each independently a hydrogen atom, amino, hydroxyl, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; R.sup.6c and R.sup.6d are each independently a hydrogen atom, amino, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; R.sup.9 and R.sup.10 are each independently substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; B.sup.1 is a hydrogen atom, cyano, halogen, sulfydryl, carboxyl, amino, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; B.sup.2, B.sup.3, B.sup.4, B.sup.5, B.sup.6 and B.sup.7 are each independently a hydrogen atom, hydroxyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, cyano, halogen, sulfydryl, carboxyl, amino, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; L and K are each independently C.sub.1-C.sub.4alkylene, direct bond, C.sub.2-C.sub.4alkenylene, ##STR00319## R.sup.11 is a hydrogen atom, hydroxyl, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, substituted or unsubstituted C.sub.2-C.sub.10heteroaryl or ##STR00320## R.sup.11a is a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; Z is substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; the substituents in the substituted C.sub.1-C.sub.4alkyl, the substituted C.sub.1-C.sub.4alkoxy, the substituted C.sub.3-C.sub.8cycloalkyl, the C.sub.6-C.sub.14aryl, the substituted C.sub.2-C.sub.4alkenyl, the substituted C.sub.2-C.sub.4alkynyl and the substituted C.sub.2-C.sub.8heterocyclyl are each independently one or more of C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkyl substituted with halogen and/or hydroxyl, C.sub.3-C.sub.8cycloalkyl, halogen, hydroxyl, amino, cyano, nitro, sulfydryl and carboxyl; when the substituents are plural, then the substituents can be the same or different; the heteroatoms in the C.sub.2-C.sub.10heteroaryl are selected from O, N and S, the number of the heteroatoms is 1-3, and the heteroatoms can be the same or different; carbon labeled with * refers to S-configuration chiral carbon, R-configuration chiral carbon or achiral carbon.

2. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein, when the substituent in the substituted C.sub.1-C.sub.4alkyl, the substituted C.sub.1-C.sub.4alkoxy, the substituted C.sub.3-C.sub.8cycloalkyl, the C.sub.6-C.sub.14aryl, the substituted C.sub.2-C.sub.4alkenyl, the substituted C.sub.2-C.sub.4alkynyl and the substituted C.sub.2-C.sub.8heterocyclyl is C.sub.1-C.sub.4alkyl, then the C.sub.1-C.sub.4alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and/or, when the substituent in the substituted C.sub.1-C.sub.4alkyl, the substituted C.sub.1-C.sub.4alkoxy, the substituted C.sub.3-C.sub.8cycloalkyl, the C.sub.6-C.sub.14aryl, the substituted C.sub.2-C.sub.4alkenyl, the substituted C.sub.2-C.sub.4alkynyl and the substituted C.sub.2-C.sub.8heterocyclyl is C.sub.1-C.sub.4alkyl substituted with halogen and/or hydroxyl, then one or more hydrogens in the C.sub.1-C.sub.4alkyl in the C.sub.1-C.sub.4alkyl substituted with halogen and/or hydroxyl are substituted with halogen and/or hydroxyl; the C.sub.1-C.sub.4alkyl substituted with halogen and/or hydroxyl is preferably ##STR00321## and/or, when the substituent in the substituted C.sub.1-C.sub.4alkyl, the substituted C.sub.1-C.sub.4alkoxy, the substituted C.sub.3-C.sub.8cycloalkyl, the C.sub.6-C.sub.14aryl, the substituted C.sub.2-C.sub.4alkenyl, the substituted C.sub.2-C.sub.4alkynyl and the substituted C.sub.2-C.sub.8heterocyclyl is C.sub.3-C.sub.8cycloalkyl, then the C.sub.3-C.sub.8cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; and/or, when the substituent in the substituted C.sub.1-C.sub.4alkyl, the substituted C.sub.1-C.sub.4alkoxy, the substituted C.sub.3-C.sub.8cycloalkyl, the C.sub.6-C.sub.14aryk the substituted C.sub.2-C.sub.4alkenyl, the substituted C.sub.2-C.sub.4alkynyl and the substituted C.sub.2-C.sub.8heterocyclyl is halogen, then the halogen is F, Cl, Br or I.

3. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein, the substituents in the substituted C.sub.1-C.sub.4alkyl, the substituted C.sub.1-C.sub.4alkoxy, the substituted C.sub.3-C.sub.8cycloalkyl, the C.sub.6-C.sub.14aryl, the C.sub.2-C.sub.10heteroaryl, the substituted C.sub.2-C.sub.4alkenyl, the substituted C.sub.2-C.sub.4alkynyl and the substituted C.sub.2-C.sub.8heterocyclyl are each independently one or more of C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.8cycloalkyl, halogen, hydroxyl, amino, cyano and sulfydryl; the substituents in the substituted C.sub.1-C.sub.4alkyl are preferably one or more of halogen, hydroxyl and C.sub.3-C.sub.8cycloalkyl; the substituents in the substituted C.sub.2-C.sub.10heteroaryl are preferably one or more of halogen and C.sub.1-C.sub.4alkyl; more preferably, in R.sup.2c, the substituents in the substituted C.sub.1-C.sub.4alkyl are selected from one or more of halogen and C.sub.3-C.sub.8cycloalkyl.

4. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein, in R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5, B.sup.6 and B.sup.7, the halogen is F, Cl, Br or I; and/or, in R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.2, R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.2e, R.sup.4, R.sup.4, R.sup.5, R.sup.4a, R.sup.4b, R.sup.4c, R.sup.4d, R.sup.4e, R.sup.6, R.sup.6a, R.sup.6b, R.sup.7, R.sup.8, R.sup.6c, R.sup.6d, R.sup.9, R.sup.10, B.sup.1, B.sup.2, B.sup.3, R.sup.11, R.sup.11a, R.sup.p1 and R.sup.p2, the C.sub.1-C.sub.4alkyl in the substituted or unsubstituted C.sub.1-C.sub.4alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and/or, in R.sup.2, R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.2e, R.sup.4, R.sup.5, R.sup.4a, R.sup.6a, R.sup.6b, R.sup.7, R.sup.8, R.sup.6c, R.sup.6d, B.sup.2 and B.sup.3, the C.sub.1-C.sub.4alkoxy in the substituted or unsubstituted C.sub.1-C.sub.4alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy; and/or, in R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.2, R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.2e, R.sup.4, R.sup.5, R.sup.4a, R.sup.4b, R.sup.4c, R.sup.4d, R.sup.4e, R.sup.6, R.sup.6a, R.sup.6b, R.sup.7, R.sup.8, R.sup.6c, R.sup.6d, R.sup.9, R.sup.10, B.sup.1, B.sup.2, B.sup.3, R.sup.11 and R.sup.11a, the C.sub.3-C.sub.8cycloalkyl in the substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; and/or, in R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.2, R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.2e, R.sup.4, R.sup.5, R.sup.4a, R.sup.4b, R.sup.4c, R.sup.4d, R.sup.4e, R.sup.6, R.sup.6a, R.sup.6b, R.sup.7, R.sup.8, R.sup.6c, R.sup.6d, R.sup.9, R.sup.10, R.sup.11 and R.sup.11a, the C.sub.6-C.sub.14aryl in the substituted or unsubstituted C.sub.6-C.sub.14aryl is phenyl, naphthyl, anthracyl or phenanthryl; and/or in R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.2, R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.2e, R.sup.4, R.sup.5, R.sup.4a, R.sup.4b, R.sup.4c, R.sup.4d, R.sup.4e, R.sup.6, R.sup.6a, R.sup.6b, R.sup.7, R.sup.8, R.sup.6c, R.sup.6d, R.sup.9, R.sup.10, R.sup.11, R.sup.11a and Z, the C.sub.2-C.sub.10heteroaryl in the substituted or unsubstituted C.sub.2-C.sub.10heteroaryl is C.sub.2-C.sub.8heteroaryl; and when adjacent R.sup.1 and R.sup.1a; or R.sup.1a and R.sup.1b; or R.sup.1b and R.sup.1c; or R.sup.1c and R.sup.1d and the atoms attached thereto together form substituted or unsubstituted C.sub.2-C.sub.10heteroaryl, then the C.sub.2-C.sub.10heteroaryl in the substituted or unsubstituted C.sub.2-C.sub.10heteroaryl is C.sub.2-C.sub.8heteroaryl, the C.sub.2-C.sub.8heteroaryl preferably has 1-2 heteroatoms selected from O, N and S, the C.sub.2-C.sub.10heteroaryl is further preferably pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, indolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl, 7-azaindolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, purinyl, indazolyl, benzimidazolyl, benzothienyl, benzofuranyl, benzotriazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl; and/or, when adjacent R.sup.1 and R.sup.1a; or R.sup.1a and R.sup.1b; or R.sup.1b and R.sup.1c; or R.sup.1c and R.sup.1d and the atoms attached thereto together form substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, then the C.sub.3-C.sub.8cycloalkyl in the substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; and/or, when adjacent R.sup.1 and R.sup.1a; or R.sup.1a and R.sup.1b; or R.sup.1b and R.sup.1c; or R.sup.1c and R.sup.1d and the atoms attached thereto together form substituted or unsubstituted C.sub.6-C.sub.14aryl, then the C.sub.6-C.sub.14aryl in the substituted or unsubstituted C.sub.6-C.sub.14aryl is phenyl, naphthyl, anthracyl or phenanthryl; and/or, when adjacent R.sup.1 and R.sup.1a; or R.sup.1a and R.sup.1b; or R.sup.1b and R.sup.1c; or R.sup.1c and R.sup.1d and the atoms attached thereto together form substituted or unsubstituted C.sub.2-C.sub.8heterocyclyl, then the C.sub.2-C.sub.8heterocyclyl is C.sub.2-C.sub.6heterocyclyl; the C.sub.2-C.sub.6heterocyclyl preferably have 2-4 heteroatoms selected from N, O and S; the C.sub.2-C.sub.8heterocyclyl is further preferably tetrahydropyranyl, azetidinyl, 1,4-dioxanyl, piperazinyl, piperidinyl, pyrrolidinyl , morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylene dioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, ##STR00322## ##STR00323##

5. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein: in R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.2, R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.2e, R.sup.4, R.sup.5, R.sup.4a, R.sup.4b, R.sup.4c, R.sup.4d, R.sup.4e, R.sup.6, R.sup.6a, R.sup.6b, R.sup.7, R.sup.8, R.sup.6c, R.sup.6d, R.sup.9, R.sup.10, B.sup.1, B.sup.2, B.sup.3, R.sup.11, R.sup.11a, R.sup.p1 and R.sup.p2, the substituted C.sub.1-C.sub.4alkyl is ##STR00324## and/or, the C.sub.2-C.sub.10heteroaryl in the substituted or unsubstituted C.sub.2-C.sub.10heteroaryl is ##STR00325## ##STR00326## and/or, the substituted C.sub.2-C.sub.10heteroaryl is ##STR00327## and/or, when adjacent R.sup.1 and R.sup.1a; or R.sup.1a and R.sup.1b; or R.sup.1b and R.sup.1c; or R.sup.1c and R.sup.1d and the atoms attached thereto together form substituted or unsubstituted C.sub.2-C.sub.8heterocyclyl, then the C.sub.2-C.sub.8heterocyclyl is ##STR00328##

6. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein: no more than 1 or 2 nitrogen atoms are present in A.sup.1, A.sup.2, A.sup.3, A.sup.4 and A.sup.5; or, A.sup.1 is CR.sup.1; A.sup.2 is CR.sup.1a; A.sup.3 is CR.sup.1b or N; A.sup.4 is CR.sup.1c or N; and A.sup.5 is CR.sup.1d or N; or, A.sup.1 is CH; A.sup.2 is CH; A.sup.3 is CR.sup.1b or N; A.sup.4 is CR.sup.1c or N; and A.sup.5 is CR.sup.1d or N; or A.sup.1 is CR.sup.1; A.sup.2 is CR.sup.1a; A.sup.3 is CR.sup.1b; A.sup.4 is CR.sup.1c and A.sup.5 is CR.sup.1d; or A.sup.1 is CR.sup.1; A.sup.2 is CH; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 is CH; or A.sup.1 is CH; A.sup.2 is CR.sup.1a; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 is CH; or A.sup.1 is CH; A.sup.2 is CH; A.sup.3 is CR.sup.1b; A.sup.4 is CR.sup.1c and A.sup.5 is CH; or A.sup.1 is CH; A.sup.2 is CH; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 CR.sup.1d; or R.sup.1c, R.sup.1d and the C attached thereto together form substituted or unsubstituted C.sub.2-C.sub.8heterocyclyl; or A.sup.1 is CH; A.sup.2 is CH; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 is CH.

7. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein: R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are each independently a hydrogen atom, halogen, cyano, nitro, substituted or unsubstituted C.sub.1-C.sub.4alkyl, ##STR00329## or adjacent R.sup.1 and R.sup.1a; or R.sup.1a and R.sup.1b; or R.sup.1b and R.sup.1c; or R.sup.1c and R.sup.1d and the atoms attached thereto together form substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.2-C.sub.8heterocyclyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or, substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; and/or, R.sup.2 and R.sup.3 are each independently a hydrogen atom, hydroxyl, amino, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, ##STR00330## and/or, R.sup.2a and R.sup.2b are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl or ##STR00331## and/or, R.sup.2c is substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; and/or, R.sup.2d and R.sup.2e are independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; and/or, R.sup.4 and R.sup.5 are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, ##STR00332## R.sup.4 can also be ##STR00333## wherein R.sup.p1 and R.sup.p2 are independently substituted or unsubstituted C.sub.1-C.sub.4alkyl; and/or, R.sup.4a is a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl or ##STR00334## and/or, R.sup.4b, R.sup.4c, R.sup.4d and R.sup.4e are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; and/or, R.sup.6 is a hydrogen atom, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, ##STR00335## and/or, R.sup.6a and R.sup.6b are each independently a hydrogen atom, amino, hydroxyl, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; and/or, R.sup.6c and R.sup.6d are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; and/or, R.sup.7 and R.sup.8 are each independently a hydrogen atom, amino, hydroxyl, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; and/or, R.sup.9 and R.sup.10 are each independently substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; and/or, B.sup.1 is a hydrogen atom, cyano, halogen, sulfydryl, amino, or substituted or unsubstituted C.sub.1-C.sub.4alkyl; and/or, B.sup.2, B.sup.3, B.sup.4, B.sup.5, B.sup.6 and B.sup.7 are each independently a hydrogen atom, hydroxyl, C.sub.1-C.sub.4alkoxy, cyano, halogen, sulfydryl, carboxyl, amino, or substituted or unsubstituted C.sub.1-C.sub.4alkyl; and/or, L and K are each independently C.sub.1-C.sub.4alkylene, direct bond, ##STR00336## and/or, R.sup.11 is a hydrogen atom, hydroxyl, substituted or unsubstituted C.sub.1-C.sub.4alkyl or ##STR00337## and/or, R.sup.11a is a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; and/or, Z is substituted or unsubstituted C.sub.2-C.sub.10heteroaryl containing at least one nitrogen atom.

8. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein: R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are each independently a hydrogen atom, halogen, cyano, nitro, substituted or unsubstituted C.sub.1-C.sub.4alkyl, ##STR00338## or adjacent R.sup.1 and R.sup.1a; or R.sup.1a and R.sup.1b; or R.sup.1b and R.sup.1c; or R.sup.1c and R.sup.1d and the atoms attached thereto together form substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.2-C.sub.8heterocyclyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or, substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; preferably adjacent R.sup.1 and R.sup.1a; or R.sup.1a and R.sup.1b; R.sup.1c and R.sup.1d and the atoms attached thereto together form C.sub.2-C.sub.8heterocyclyl; and/or, R.sup.2 and R.sup.3 are each independently a hydrogen atom, hydroxyl, amino, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, ##STR00339## preferably, one of R.sup.2 and R.sup.3 is hydrogen, the other is substituted or unsubstituted C.sub.1-C.sub.4alkyl, ##STR00340## or R.sup.2 and R.sup.3 are both substituted or unsubstituted C.sub.1-C.sub.4alkyl; most preferably, one of R.sup.2 and R.sup.3 is hydrogen, the other is substituted or unsubstituted C.sub.1-C.sub.4alkyl, ##STR00341## or R.sup.2 and R.sup.3 are both C.sub.1-C.sub.4alkyl; and/or, R.sup.2a and R.sup.2b are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl or ##STR00342## preferably, R.sup.2a is a hydrogen atom, or substituted or unsubstituted C.sub.1-C.sub.4alkyl; most preferably, R.sup.2a is C.sub.1-C.sub.4alkyl; and/or, R.sup.4 is a hydrogen atom, ##STR00343## R.sup.5 is a hydrogen atom; R.sup.p1 and R.sup.p2 are independently C.sub.1-C.sub.4alkyl; and/or, R.sup.4a is a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, preferably a hydrogen atom or C.sub.1-C.sub.4alkyl; and/or, R.sup.6 is ##STR00344## and/or, R.sup.6a and R.sup.6b are each independently a hydrogen atom, amino, hydroxyl, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; preferably are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; further preferably are independently a hydrogen atom or C.sub.1-C.sub.4alkyl; and/or, R.sup.6c and R.sup.6d are H; and/or, R.sup.7 and R.sup.8 are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; preferably are independently a hydrogen atom or C.sub.1-C.sub.4alkyl; and/or, B.sup.1 is a hydrogen atom, cyano, halogen, or substituted or unsubstituted C.sub.1-C.sub.4alkyl; preferably B.sup.1 is a hydrogen atom; and/or, B.sup.2, B.sup.3, B.sup.4, B.sup.5, B.sup.6 and B.sup.7 are hydrogen atoms; and/or, L is ##STR00345## direct bond, ##STR00346## preferably a direct bond; and/or, K is ##STR00347## and/or, Z is substituted or unsubstituted C.sub.6-C.sub.8heteroaryl containing at least one nitrogen atom, and the C.sub.6-C.sub.8heteroaryl is a heteroaryl with two fused rings.

9. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein: R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are each independently H, ##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359##

10. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein: A.sup.1 is CH; A.sup.2 is CH; A.sup.3 is CR.sup.1b or N; A.sup.4 is CR.sup.1c or N; and A.sup.5 is CR.sup.1d or N; or A.sup.1 is CR.sup.1; A.sup.2 is CR.sup.1a; A.sup.3 is CR.sup.1b; A.sup.4 is CR.sup.1c and A.sup.5 is CR.sup.1d; wherein R.sup.1 and R.sup.1a; R.sup.1a and R.sup.1b; or R.sup.1b and R.sup.1c; or R.sup.1c and R.sup.1d and the atoms attached thereto together form substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.2-C.sub.8heterocyclyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or, substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; preferably, R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are each independently a hydrogen atom, halogen, cyano, nitro, substituted or unsubstituted C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, ##STR00360## or adjacent R.sup.1 and R.sup.1a; or R.sup.1a and R.sup.1b; or R.sup.1b and R.sup.1c; or R.sup.1c and R.sup.1d and the atoms attached thereto together form substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted C.sub.2-C.sub.8heterocyclyl, substituted or unsubstituted C.sub.6-C.sub.14aryl, or, substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; R.sup.2 and R.sup.3 are each independently a hydrogen atom, hydroxyl, amino, substituted or unsubstituted C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, ##STR00361## R.sup.2a is a hydrogen atom, or substituted or unsubstituted C.sub.1-C.sub.4alkyl; R.sup.2c is substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; R.sup.4 is a hydrogen atom or ##STR00362## R.sup.5 is a hydrogen atom; R.sup.6 is a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, ##STR00363## R.sup.6a and R.sup.6b are each independently a hydrogen atom, amino, hydroxyl, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; R.sup.6c and R.sup.6d are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; R.sup.7 and R.sup.8 are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; R.sup.9 and R.sup.10 are each independently substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5, B.sup.6 and B.sup.7 are hydrogen atoms; L and K are each independently ##STR00364## direct bond, ##STR00365## and Z is substituted or unsubstituted C.sub.2-C.sub.10heteroaryl containing at least one nitrogen atom.

11. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein: A.sup.1 is CR.sup.1; A.sup.2 is CH; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 is CH; or A.sup.1 is CH; A.sup.2 is CR.sup.1a; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 is CH; or A.sup.1 is CH; A.sup.2 is CH; A.sup.3 is CR.sup.1b; A.sup.4 is CR.sup.1c and A.sup.5 is CH; or A.sup.1 is CH; A.sup.2 is CH; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 CR.sup.1d; or R.sup.1c, R.sup.1d and the carbon attached thereto together form substituted or unsubstituted C.sub.2-C.sub.8heterocyclyl; or A.sup.1 is CH; A.sup.2 is CH; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 is CH; wherein R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are each independently a hydrogen atom, halogen, cyano, nitro, substituted or unsubstituted C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, ##STR00366## one of R.sup.2 and R.sup.3 is hydrogen, the other is substituted or unsubstituted C.sub.1-C.sub.4alkyl, ##STR00367## or R.sup.2 and R.sup.3 are both substituted or unsubstituted C.sub.1-C.sub.4alkyl; R.sup.2a is a hydrogen atom, or substituted or unsubstituted C.sub.1-C.sub.4alkyl; R.sup.2c is substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; R.sup.4 and R.sup.5 are hydrogen atoms; R.sup.6 is a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl, ##STR00368## R.sup.6a and R.sup.6b are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; R.sup.6c and R.sup.6d are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; R.sup.7 and R.sup.8 are each independently a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.4alkyl, or substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl; R.sup.9 and R.sup.10 are each independently substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.3-C.sub.8cycloalkyl or substituted or unsubstituted C.sub.2-C.sub.10heteroaryl; B.sup.1 is a hydrogen atom; B.sup.2, B.sup.3, B.sup.4, B.sup.5, B.sup.6 and B.sup.7 are hydrogen atoms; L is a direct bond; K is ##STR00369## and Z is substituted or unsubstituted C.sub.2-C.sub.10heteroaryl containing at least one nitrogen atom; the substituents in the substituted C.sub.2-C.sub.10heteroaryl are selected from one or more of halogen and C.sub.1-C.sub.4alkyl; or; A.sup.1 is CR.sup.1; A.sup.2 is CH; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 is CH; or A.sup.1 is CH; A.sup.2 is CR.sup.1a; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 is CH; or A.sup.1 is CH; A.sup.2 is CH; A.sup.3 is CR.sup.1b; A.sup.4 is CR.sup.1c and A.sup.5 is CH; or A.sup.1 is CH; A.sup.2 is CH; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 is CR.sup.1d; or R.sup.1c, R.sup.1d and the C attached thereto together form substituted or unsubstituted C.sub.2-C.sub.8heterocyclyl; or A.sup.1 is CH; A.sup.2 is CH; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 is CH; R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d are each independently a hydrogen atom, halogen, substituted or unsubstituted C.sub.1-C.sub.4alkyl, ##STR00370## wherein: in R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d, the substituents in the substituted C.sub.1-C.sub.4alkyl are selected from one or more of hydroxyl and halogen; one of R.sup.2 and R.sup.3 is hydrogen, the other is substituted or unsubstituted C.sub.1-C.sub.4alkyl, ##STR00371## or R.sup.2 and R.sup.3 are both C.sub.1-C.sub.4alkyl; R.sup.2a is C.sub.1-C.sub.4alkyl; R.sup.2c is substituted or unsubstituted C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.8cycloalkyl or C.sub.2-C.sub.10heteroaryl, in R.sup.2c, the substituents in the substituted C.sub.1-C.sub.4alkyl are selected from one or more of halogen and C.sub.3-C.sub.8cycloalkyl; R.sup.4 is a hydrogen atom, ##STR00372## R.sup.4a is a hydrogen atom or C.sub.1-C.sub.4alkyl; R.sup.p1 and R.sup.p2 are independently C.sub.1-C.sub.4alkyl; R.sup.5 is a hydrogen atom; R.sup.6 is ##STR00373## R.sup.6a and R.sup.6b are a hydrogen atom or C.sub.1-C.sub.4alkyl; R.sup.6 is H; R.sup.7 and R.sup.8 are each independently a hydrogen atom or C.sub.1-C.sub.4alkyl; R.sup.9 is substituted or unsubstituted C.sub.1-C.sub.4alkyl; and R.sup.10 is C.sub.1-C.sub.4alkyl; B.sup.1 is a hydrogen atom; B.sup.2, B.sup.3, B.sup.4, B.sup.5, B.sup.6 and B.sup.7 are hydrogen atoms; L is a direct bond; K is ##STR00374## and Z is substituted or unsubstituted C.sub.2-C.sub.10heteroaryl containing at least one nitrogen atom; the substituents in the substituted C.sub.2-C.sub.10heteroaryl are selected from one or more of halogen and C.sub.1-C.sub.4alkyl; or; A.sup.1 is CH; A.sup.2 is CR.sup.1a; A.sup.3 is CH; A.sup.4 is CR.sup.1c and A.sup.5 is CH; R.sup.1a is hydroxyl or ##STR00375## one of R.sup.2 and R.sup.3 is hydrogen, the other is ##STR00376## R.sup.2a is C.sub.1-C.sub.4alkyl; R.sup.2c is substituted or unsubstituted C.sub.1-C.sub.4alkyl or C.sub.2-C.sub.10heteroaryl, in R.sup.2c, the substituents in the substituted C.sub.1-C.sub.4alkyl are substituted with one or more of halogens; B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5, B.sup.6 and B.sup.7 are hydrogen atoms; L is a direct bond; K is ##STR00377## and Z is substituted or unsubstituted C.sub.2-C.sub.10heteroaryl containing at least one nitrogen atom; the substituents in the substituted C.sub.2-C.sub.10heteroaryl are selected from one or more of halogen and C.sub.1-C.sub.4alkyl.

12. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein: the tetrahydropyrrole compound represented by general formula (I) is selected from: ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## wherein, carbon labeled with * refers to S-configuration chiral carbon, R-configuration chiral carbon or achiral carbon.

13. A method for preparing the tetrahydropyrrole compound represented by general formula (I) as defined in claim 1: when L is a direct bond and K is ##STR00397## then the tetrahydropyrrole compound is prepared by the following method 1, which comprises the following steps: compound I-M and ##STR00398## are subjected to a reductive amination reaction as shown below to prepare compound I-A; ##STR00399## wherein B.sub.1-B.sub.7, A.sup.1-A.sup.5, Z and * are defined as in claim 1; when Z is substituted or unsubstituted C.sub.2-C.sub.10 heteroaryl containing at least one N atom, then the tetrahydropyrrole compound is prepared by the following method 2, which comprises the following steps: compound I-Ma is subjected to the following deamination reaction to remove amino protecting group so as to prepare the tetrahydropyrrole compound represented by general formula (I); ##STR00400## wherein L, Z, K, B.sub.1-B.sub.7, A.sup.1-A.sup.5, Z and * are defined as in claim 1; in compound I-Ma, G is an amino protecting group, wherein G is connected to a nitrogen atom in Z.

14. A pharmaceutical composition, which comprises the tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, and a pharmaceutically acceptable excipient.

15. A pharmaceutical composition, which comprises the tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1, and additional therapeutic drugs; the additional therapeutic drugs are drugs for treating or preventing lesions and central nervous system diseases associated with dopamine receptor and dopamine transporter dysfunction.

16. (canceled)

17. (canceled)

18. The tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 7, wherein R.sup.2c is substituted or unsubstituted C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.8cycloalkyl or C.sub.2-C.sub.10heteroaryl; and/or, R.sup.9 is substituted or unsubstituted C.sub.1-C.sub.4alkyl, R.sup.10 is C.sub.1-C.sub.4alkyl; and/or, B.sup.1 is a hydrogen atom, cyano, halogen, or substituted or unsubstituted C.sub.1-C.sub.4alkyl.

19. The pharmaceutical composition as defined in claim 15, wherein the lesions and central nervous system diseases associated with dopamine receptor and dopamine transporter dysfunction are preferably one or more of schizophrenia, and positive symptoms, negative symptoms, cognitive impairment, schizoaffective disorder, bipolar disorder, mania, depression, anxiety disorder, dementia, memory impairment and psychosis involving paranoia and/or delusion associated with schizophrenia.

20. A method for inhibiting D2 receptor and DAT receptor in a subject in need thereof, comprising administering a therapeutically effective amount of the tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject.

21. A method for treating or preventing schizophrenia or diseases associated with schizophrenia in a subject in need thereof, comprising administering a therapeutically effective amount of the tetrahydropyrrole compound represented by general formula (I), the enantiomer, the diastereomer, the isotope compound, the pharmaceutically acceptable prodrug, the pharmaceutically acceptable ester or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject.

22. The method as defined in claim 21, wherein the diseases associated with pschizophrenia are one or more of positive symptoms, negative symptoms, cognitive impairment, schizoaffective disorder, bipolar disorder, mania, depression, anxiety disorder, dementia, memory impairment and psychosis involving paranoia and/or delusion associated with schizophrenia.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0244] In the following examples, room temperature means 10 C.-30 C. Where the specific operating temperature is not defined, the operating temperature is room temperature (e.g., 10 C.-30 C.). Overnight refers to 8-15 hours. The purity of a compound is determined by high performance liquid chromatography (HPLC). Min refers to minutes.

EXAMPLE 1

1-(indole-3-methyl)-3-(3-hydroxyphenyl)pyrrolidine (MDC-161502-002)

[0245] Step 1

Synthesis of 1-benzyl-3-(3-methoxyphenyl)pyrrolidine

[0246] ##STR00156##

[0247] 3-methoxyvinylbenzene (10 g, 74.5 mmol, 10.34 mL, 1 eq) was dissolve in dichloromethane (250 mL), trifluoroacetic acid (0.85 g, 7.45 mmol, 552 uL, 0.1 eq) was added, and N-(methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (35.4 g, 149 mmol, 2 eq) was added dropwise at 0 C. within 30 minutes. The temperature of the reaction was raised to room temperature and then the reaction was stirred for 48 hours, the reaction solution was diluted with dichloromethane (250 mL) and washed 3 times with water (300 mL), the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel chromatography (eluent:petroleum ether:ethyl acetate=10:1-1:1) to give a yellowish solid (13 g, yield 65%). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.35-7.08 (m, 6H), 6.80-6.75 (m, 2H), 6.70-6.60 (m, 1H), 3.72 (s, 3H), 3.59 (s, 2H), 3.32-3.20 (m, 1H), 2.93 (t, J=8.4 Hz, 1H), 2.80-2.70 (m, 1H), 2.65-2.55 (m, 1H), 2.43 (t, J=8.4 Hz, 1H), 2.30-2.20 (m, 1H), 1.85-1.75 (m, 1H).

[0248] Step 2

Synthesis of 3-(3-methoxyphenyl)pyrrolidine

[0249] ##STR00157##

[0250] 1-benzyl-3-(3-methoxyphenyl)pyrrolidine (13.0 g, 48.6 mmol, 1 eq) was dissolved in methanol (150 mL), Pd(OH).sub.2 (20%, 3.41 g, 4.86 mmol, 0.1 eq) was added, the resulting solution was subjected to nitrogen replacement three times, and stirred at room temperature for 4 hours under a hydrogen atmosphere (50 Psi). After filtration, the filtrate was evaporated to dry to give a gray solid (7.0 g, yield 81%), and the crude product was directly used in the next step.

[0251] Step 3

Synthesis of 1-(indole-3-methyl)-3-(3-methoxyphenyl)pyrrolidine (MDC-161502-001)

[0252] ##STR00158##

[0253] 3-(3-methoxyphenyl)pyrrolidine (4.91 g, 33.8 mmol, 1 eq) and 3-indolealdehyde were dissolved in tetrahydrofuran (120 mL), and then NaBH (OAc).sub.3 (14.35 g, 67.7 mmol, 2 eq) was added and stirred at room temperature for 5 hours. The resulting mixture was quenched by adding saturated aqueous solution of ammonium chloride (50 mL) under ice bath, extracted 3 times with ethyl acetate (200 mL). The organic phase was washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent:dichloromethane:methanol=100:1-20:1) to give a yellowish solid (5.5 g, yield 51%, purity 96%). .sup.1H NMR (400 MHz, CDCl.sub.3): 9.05 (s, 1H), 7.70-7.65 (m, 1H), 7.52 (s, 1H), 7.50-7.45 (m, 1H), 7.25-7.20 (m, 3H), 6.85-6.25 (m, 3H), 4.22 (s, 2H), 3.78 (s, 3H), 3.57-3.42 (m, 2H), 3.30-3.12 (m, 2H), 3.30-2.90 (m, 1H), 2.45-2.35 (m, 1H), 2.15-2.00 (m, 1H); .sup.13C NMR (200 MHz, CDCl.sub.3): 160.12, 136.17, 130.11, 128.15, 127.18, 122.68, 120.74, 119.36, 117.48, 113.18, 112.95, 112.48, 58.33, 58.30, 55.47, 49.39, 42.82; High Resolution Mass Spectrometry HRMS (ESI): C.sub.20H.sub.23N.sub.2O.sup.+ [M+H].sup.+ calculated value: 307.1810, measured value: 307.1802; HPLC purity: 96.4%.

[0254] Step 4

Synthesis of 1-(indole-3-methyl)-3-(3-hydroxyphenyl)pyrrolidine (MDC-161502-002)

[0255] ##STR00159##

[0256] Compound 1-(indole-3-methyl)-3-(3-methoxyphenyl)pyrrolidine (700 mg, 2.28 mmol) was placed in a reaction flask, and the reaction flask was subjected to argon replacement three times. Anhydrous dichloromethane (20 mL) was added, and the resulting mixture was cooled to 20 C. Subsequently, a solution of boron tribromide in dichloromethane (boron tribromide content being 17%, 3.23 mL, 5.70 mmol) was slowly added and stirred for 30 minutes while keeping the temperature constant. The reaction solution was then warmed to room temperature and the reaction was stirred overnight. After the reaction was completed, the reaction system was cooled to 20 C. Methanol (3 mL) was slowly added dropwise to quench the reaction. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate (10 mL) three times. The aqueous phase and the organic phase were all concentrated, then methanol was added for dissolution. Inorganic salts were removed by extraction filtration, and then the resulting mixture was purified on a silica gel column (dichloromethane:methanol=19:1) to give a desired compound (480 mg, yield 72%). .sup.1H NMR (800 MHz, CDCl.sub.3): 8.37 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.18 (dd, J=10.9, 3.8 Hz, 2H), 7.11 (ddd, J=28.3, 11.7, 4.3 Hz, 2H), 6.70 (d, J=7.6 Hz, 1H), 6.66-6.62 (m, 1H), 6.61 (s, 1H), 4.02-3.96 (m, 2H), 3.31-3.25 (m, 1H), 3.19-3.14 (m, 1H), 2.99 (dd, J=16.9, 7.5 Hz, 1H), 2.93 (dt, J=14.7, 7.4 Hz, 1H), 2.70 (t, J=9.2 Hz, 1H), 2.30-2.23 (m, 1H), 1.90-1.84 (m, 1H); HRMS (ESI) C.sub.19H.sub.21N.sub.2O [M+H].sup.+ calculated value: 293.1654, measured value: 293.1653; HPLC purity: 97.5%.

[0257] The racemate obtained above can be resolved by chiral HPLC using the following method.

[0258] Analysis Method:

TABLE-US-00001 Column CHIRALCE OJ-H(OJH0CE-VD046) Column 0.46 cm I.D. 25 cm L Specifications Injection volume 10.0 ul Mobile phase MeOH/DEA = 100/0.1 (V/V) Flow rate 1.0 ml/min Detection UV 254 nm wavelength Column 35 C. temperature HPLC equipment Shimadzu LC-20AD CP-HPLC-05

[0259] Peak 1 (MDC-161502-010): RT=6.17 min, [].sub.D.sup.20=+34 (c 0.5, CH.sub.3OH); Peak 2 (MDC-161502-011): RT=8.74 min, [].sub.D.sup.20=32 (c 0.5, CH.sub.3OH).

[0260] Preparation Conditions:

TABLE-US-00002 Column CHIRALCEL OJ Column Specifications 5.0 cm I.D. 25 cm L Mobile phase MeOH/DEA = 100/0.1 (V/V) Flow rate 60 ml/min Detection wavelength UV 214 nm Column temperature 35 C.

[0261] Referring to the method described in Example 1, the compounds listed in Table 1 can be prepared using different substituted styrene as starting materials.

TABLE-US-00003 TABLE 1 Structure MS Structure MS [00160] 309.1 [00161] 294.2 [00162] 309.2 [00163] 309.1 [00164] 309.2 [00165] 293.2 [00166] 309.2 [00167] 293.2 [00168] 309.1 [00169] 293.2 [00170] 321.2 [00171] 294.2 [00172] 328.2 [00173] 356.1 [00174] 328.2 [00175] 384.2 [00176] 311.2 [00177] 307.2 [00178] 311.2 [00179] 307.2 [00180] 278.2 [00181] 312.1 [00182] 293.2 [00183] 295.2 [00184] 293.2 [00185] 345.2

[0262] Compounds having phenolic hydroxyl substitution can be reacted with alkyl anhydrides to prepare esters, e.g. Table 2:

TABLE-US-00004 TABLE 2 Structure MS Structure MS [00186] 335.2 [00187] 336.2 [00188] 349.2 [00189] 350.2 [00190] 369.1 [00191] 383.1

EXAMPLE 2

1-(indole-3-methyl)-3-(3-acetylaminophenyl)pyrrolidine (MDC-161502-003)

[0263] Step 1

Synthesis of 3-(2-chloro-5-nitrophenyl)pyrrolidine

[0264] ##STR00192##

[0265] 3-(2-chlorophenyl)pyrrolidine hydrochloride (900 mg, 4.12 mmol) was dissolved in concentrated sulfuric acid (15 mL). Fuming nitric acid (1.0 mL) was added dropwise at 15 C. and stirred at low temperature for 1 hour. The reaction solution was added dropwise into ice water (150 mL) under an ice bath, adjusted to pH 8-9 with 1N NaOH solution, extracted with ethyl acetate (200 mL) 3 times. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oily liquid (900 mg, crude yield 96%), and the crude product was directly used for the next step. .sup.1H NMR (800 MHz, CDCl.sub.3) 8.26 (s, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 3.83 (p, J=8.2 Hz, 1H), 3.61-3.58 (m, 1H), 3.40-3.33 (m, 1H), 3.28-3.22 (m, 1H), 3.04 (dd, J=11.0, 8.1 Hz, 1H), 2.43-2.38 (m, 1H), 2.03-1.95 (m, 1H). .sup.13C NMR (200 MHz, CDCl.sub.3) 146.89, 142.44, 141.06, 130.56, 122.59, 122.45, 52.33, 46.58, 41.37, 32.44; HRMS(ESI) C.sub.10H.sub.12ClN.sub.2O.sub.2.sup.+ [M+H].sup.+ calculated value: 227.0582, measured value: 227.0583.

[0266] Step 2

Synthesis of 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(2-chloro-5-nitrophenyl)pyrrolidine

[0267] ##STR00193##

[0268] 3-(2-chloro-5-nitrophenyl)pyrrolidine (900 mg, 3.97 mmol) and 1-tert-butoxycarbonyl 3-indolealdehyde (1.2 g, 4.8 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL). Acetic acid (240 mg, 4 mmol) and NaBH(OAc).sub.3 (2.5 g, 12 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), washed once with saturated sodium bicarbonate solution (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified on a silica gel column (petroleum ether:ethyl acetate=3:1) to give a yellow oily liquid (1.4 g, yield 77%). HRMS (ESI) C.sub.24H.sub.27ClN.sub.3O.sub.4.sup.+ [M+H].sup.+ calculated value: 456.1685, measured value: 456.1674.

[0269] Step 3

Synthesis of 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-aminophenyl)pyrrolidine

[0270] ##STR00194##

[0271] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(2-chloro-5-nitrophenyl)pyrrolidine (1.4 g, 3.07 mmol) was dissolved in methanol (40 mL). Palladium carbon (1.4 g, 10%) was added, and the resulting mixture was stirred at room temperature for 2 hours under hydrogen atmosphere (20 Psi). After filtration, the filtrate was concentrated to give a brown oily liquid (1.1 g, crude yield 92%), which was directly used for the next reaction. .sup.1H NMR (800 MHz, Methanol-d.sub.4) 8.18 (d, J=8.3 Hz, 1H), 7.97 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.43-7.38 (m, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.65 (s, 1H), 6.62 (dd, J=7.8, 2.0 Hz, 2H), 4.56 (ABq, 2H), 3.73 (dd, J=11.2, 8.1 Hz, 1H), 3.60-3.45 (m, 3H), 3.28 (t, J=10.8 Hz, 1H), 2.47-2.41 (m, 1H), 2.20-2.14 (m, 1H), 1.70 (s, 9H). HRMS(ESI) C.sub.24H.sub.30N.sub.3O.sub.2.sup.+ [M+H].sup.+ calculated value: 392.2333, measured value: 392.2334.

[0272] Step 4

Synthesis of 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-acetylaminophenyl)pyrrolidine

[0273] ##STR00195##

[0274] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-aminophenyl)pyrrolidine (100 mg, 0.25 mmol), triethylamine (80 mg, 0.78 mmol) and DMAP (5 mg, 0.04 mmol) were dissolved in dichloromethane (5 mL). Acetyl chloride (30 mg, 0.38 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol=10:1) to give a colorless oily liquid (90 mg, yield 80%). HRMS(ESI) C.sub.26H.sub.32N.sub.3O.sub.3.sup.+ [M+H].sup.+ calculated value: 434.2438, measured value: 434.2424.

[0275] Step 5

Synthesis of 1-(indole-3-methyl)-3-(3-acetylaminophenyl)pyrrolidine (MDC-161502-003)

[0276] ##STR00196##

[0277] 1-(1-Tert-butoxycarbonylindole-3-methyl)-3-(3-acetylaminophenyl)pyrrolidine (90 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2.0 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, the residue was purified by preparative HPLC to give a white solid (35 mg, yield 50%). .sup.1H NMR (500 MHz, Methanol-d.sub.4) 7.77 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.57 (s, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.32-7.25 (m, 2H), 7.22 (t, J=8.1 Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 7.04 (d, J=6.7 Hz, 1H), 4.67 (AB q, J=22.4 Hz, 6.4 Hz, 2H), 3.83 (dd, J=11.5, 8.0 Hz, 1H), 3.68-3.60 (m, 1H), 3.59-3.51 (m, 1H), 3.42-3.34 (m, 1H), 3.21 (q, J=7.3 Hz, 1H), 2.54-2.45 (m, 1H), 2.19 (t, J=7.6 Hz, 1H), 2.12 (s, 3H); HRMS(ESI) C.sub.21H.sub.24N.sub.3O.sup.+ [M+H].sup.+ calculated value: 334.1914, measured value: 334.1925; HPLC purity: 97.7% (RT=13.82 min, =254 nm).

[0278] The purification condition for preparative liquid phase chromatography: Shim-pack GIST C18 column (25020 mm, particle size 5 M); water (containing 0.05% trifluoroacetic acid)/methanol (containing 0.05% trifluoroacetic acid) gradient elution; the flow rate was 10.0 mL/min.

EXAMPLE 3

1-(indole-3-methyl)-3-(3-methanesulfonamidophenyl)pyrrolidine (MDC-161502-005)

[0279] Step 1

Synthesis of 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-methanesulfonamidophenyl)pyrrolidine

[0280] ##STR00197##

[0281] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-aminophenyl)pyrrolidine (100 mg, 0.25 mmol), pyridine (65 mg, 0.78 mmol) and DMAP (5 mg, 0.04 mmol) were dissolved in dichloromethane (5 mL). Methanesulfonyl chloride (30 mg, 0.26 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol=10:1) to give a colorless oily liquid (70 mg, yield 60%). HRMS(ESI) C.sub.25H.sub.32N.sub.3O.sub.4S.sup.+ [M+H].sup.+ calculated value: 470.2108, measured value: 470.2111.

[0282] Step 2

Synthesis of 1-(indole-3-methyl)-3-(3-methanesulfonamidophenyl)pyrrolidine (MDC-161502-005)

[0283] ##STR00198##

[0284] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-methanesulfonamidophenyl)pyrrolidine (70 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2.0 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, the residue was purified by preparative high performance liquid chromatography to give a white solid (25 mg, yield 45%). .sup.1H NMR (800 MHz, Methanol-d.sub.4) 7.78 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.28-7.22 (m, 2H), 7.19 (t, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.12 (d, J=7.7 Hz, 1H), 4.67 (ABq, J=22.4 Hz, 13.6 Hz, 2H), 3.84 (dd, J=11.6, 8.1 Hz, 1H), 3.66-3.61 (m, 2H), 3.59-3.54 (m, 1H), 3.37 (t, J=11.1 Hz, 1H), 2.96 (s, 3H), 2.54-2.48 (m, 1H), 2.23-2.16 (m, 1H); HRMS(ESI) C.sub.20H.sub.24N.sub.3O.sub.2S.sup.+ [M+H].sup.+ calculated value: 370.1584, measured value: 370.1590; HPLC purity: 95.7% (RT=13.42 min, =280 nm).

[0285] The purification condition for preparative liquid phase chromatography: Shim-pack GIST C18 column (25020 mm, particle size 5 M); water (containing 0.05% trifluoroacetic acid)/methanol (containing 0.05% trifluoroacetic acid) gradient elution; the flow rate was 10.0 mL/min.

EXAMPLE 4

1-(indole-3-methyl)-3-(3-trifluoroethanesulfonamidophenyl)pyrrolidine (MDC-161502-006)

[0286] Step 1

Synthesis of 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-trifluoroethanesulfonamidophenyl)pyrrolidine

[0287] ##STR00199##

[0288] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-aminophenyl)pyrrolidine (90 mg, 0.23 mmol), pyridine (65 mg, 0.78 mmol) and DMAP (5 mg, 0.04 mmol) were dissolved in dichloromethane (5 mL). Trifluoroethylsulfonyl chloride (45 mg, 0.25 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was purified on a silica gel column (dichloromethane/methanol=10:1) to give a colorless oily liquid (70 mg, yield 57%). HRMS(ESI) C.sub.26H.sub.31F.sub.3N.sub.3O.sub.4S.sup.+ [M+H].sup.+ calculated value: 538.1982, measured value: 538.1969.

[0289] Step 2

Synthesis of 1-(indole-3-methyl)-3-(3-trifluoroethanesulfonamidophenyl)pyrrolidine (MDC-161502-006)

[0290] ##STR00200##

[0291] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-trifluoroethanesulfonamidophenyl)pyrrolidine (70 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2.0 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, the residue was purified by preparative high performance liquid chromatography to give a white solid (35 mg, yield 62%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.86 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.21 (s, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.96 (t, J=7.4 Hz, 1H), 6.87 (t, J=7.7 Hz, 1H), 6.70 (s, 1H), 6.67 (d, J=8.6 Hz, 1H), 6.46 (d, J=7.4 Hz, 1H), 4.10 (s, 1H), 3.73 (s, 2H), 3.46 (q, J=10.8 Hz, 2H), 3.12-3.03 (m, 1H), 2.91 (t, J=8.4 Hz, 1H), 2.71 (q, J=8.1 Hz, 1H), 2.57 (q, J=8.5 Hz, 1H), 2.36 (t, J=8.3 Hz, 1H), 2.18-2.08 (m, 1H), 1.75-1.65 (m, 1H); HRMS(ESI) C.sub.21H.sub.23F.sub.3N.sub.3O.sub.2S.sup.+ [M+H].sup.+ calculated value: 438.1458, measured value: 438.1454; HPLC purity: 98.6% (RT=15.34 min, =254 nm).

[0292] The purification condition for preparative liquid phase chromatography: Shim-pack GIST C18 column (25020 mm, particle size 5 M); water (containing 0.05% trifluoroacetic acid)/methanol (containing 0.05% trifluoroacetic acid) gradient elution; the flow rate was 10.0 mL/min.

EXAMPLE 5

1-(indole-3-methyl)-3-[3-(2-thiophenesulfonamido)phenyl]pyrrolidine (MDC-161502-008)

[0293] Step 1

Synthesis of 1-(1-tert-butoxycarbonylindole-3-methyl)-3-[3-(2-thiophenesulfonamido)phenyl]pyrrolidine

[0294] ##STR00201##

[0295] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-aminophenyl)pyrrolidine (90 mg, 0.23 mmol), pyridine (5 mL) and DMAP (5 mg, 0.04 mmol) were dissolved in dichloromethane (5 mL). 2-thiophenesulfonyl chloride (70 mg, 0.38 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol=10:1) to give a colorless oily liquid (90 mg, yield 67%). HRMS(ESI) C.sub.28H.sub.32N.sub.3O.sub.4S.sub.2.sup.+ [M+H].sup.+ calculated value: 538.1829, measured value: 538.1834.

[0296] Step 2

Synthesis of 1-(indole-3-methyl)-3-[3-(2-thiophenesulfonamido)phenyl]pyrrolidine (MDC-161502-008)

[0297] ##STR00202##

[0298] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-[3-(2-thiophenesulfonamido)phenyl]pyrrolidine (90 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2.0 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, the residue was purified by preparative high performance liquid chromatography to give a white solid (45 mg, yield 60%). .sup.1H NMR (800 MHz, Methanol-d.sub.4) 7.66 (d, J=7.9 Hz, 1H), 7.52 (d, J=5.0 Hz, 1H), 7.40-7.35 (m, 2H), 7.25 (s, 1H), 7.11 (t, J=8.1 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.94-6.91 (m, 2H), 6.87 (d, J=7.6 Hz, 1H), 3.92 (s, 2H), 3.26 (t, J=8.4 Hz, 1H), 3.13 (t, J=9.8 Hz, 1H), 2.99-2.95 (m, 1H), 2.80-2.75 (m, 1H), 2.47 (t, J=9.4 Hz, 1H), 2.28-2.21 (m, 1H), 1.83-1.77 (m, 1H); HRMS(ESI) C.sub.23H.sub.24N.sub.3O.sub.2S.sub.2.sup.+ [M+H].sup.+ calculated value: 438.1304, measured value: 438.1309; HPLC purity: 95.3% (RT=15.55 min, =254 nm).

[0299] The purification condition for preparative liquid phase chromatography: Shim-pack GIST C18 column (25020 mm, particle size 5 M); water (containing 0.05% trifluoroacetic acid)/methanol (containing 0.05% trifluoroacetic acid) gradient elution; the flow rate was 10.0 mL/min.

EXAMPLE 6

1-(indole-3-methyl)-3-(3-ethanesulfonamidophenyl)pyrrolidine (MDC-161502-009)

[0300] Step 1

Synthesis of 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-ethanesulfonamidophenyl)pyrrolidine

[0301] ##STR00203##

[0302] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-aminophenyl)pyrrolidine (100 mg, 0.25 mmol), pyridine (65 mg, 0.78 mmol) and DMAP (5 mg, 0.04 mmol) were dissolved in dichloromethane (5 mL). Ethylsulfonyl chloride (50 mg, 0.38 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was purified on a silica gel column (dichloromethane/methanol=10:1) to give a colorless oily liquid (70 mg, yield 58%). HRMS(ESI) C.sub.26H.sub.34N.sub.3O.sub.4S.sup.+ [M+H].sup.+ calculated value: 484.2265, measured value: 484.2263.

[0303] Step 2

Synthesis of 1-(indole-3-methyl)-3-(3-ethanesulfonamidophenyl)pyrrolidine (MDC-161502-009)

[0304] ##STR00204##

[0305] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-ethanesulfonamidophenyl)pyrrolidine (70 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (2 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, the residue was purified by preparative high performance liquid chromatography to give a white solid (40 mg, yield 74%). .sup.1H NMR (800 MHz, Methanol-d.sub.4) 7.66 (d, J=7.9, 1H), 7.35 (d, J=8.1, 1H), 7.24 (s, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.12 (s, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.07 (dd, J=8.1, 2.2 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 7.01 (d, J=7.8 Hz, 1H), 3.93 (ABq, J=16.8, 12.8 Hz, 2H), 3.37-3.33 (m, 1H), 3.18 (dd, J=9.8, 8.1 Hz, 1H), 3.03 (q, J=7.4 Hz, 2H), 2.98-2.94 (m, 1H), 2.82 (td, J=9.2, 6.3 Hz, 1H), 2.58 (t, J=8.8 Hz, 1H), 2.36-2.26 (m, 1H), 1.91-1.84 (m, 1H), 1.26 (t, J=7.4 Hz, 3H); HRMS(ESI) C.sub.21H.sub.26N.sub.3O.sub.2S.sup.+ [M+H].sup.+ calculated value: 384.1740, measured value: 384.1730; HPLC purity: 95.7% (RT=14.06 min, =280 nm).

[0306] The purification condition for preparative liquid phase chromatography: Shim-pack GIST C18 column (25020 mm, particle size 5 M); water (containing 0.05% trifluoroacetic acid)/methanol (containing 0.05% trifluoroacetic acid) gradient elution; the flow rate was 10.0 mL/min.

[0307] The compounds listed in Table 3 below can also be prepared by referring to the methods of Examples 2 to 6:

TABLE-US-00005 TABLE 3 Structure MS Structure MS [00205] 306.2 [00206] 421.2 [00207] 320.2 [00208] 422.2 [00209] 439.1 [00210] 422.1 [00211] 422.2 [00212] 396.2 [00213] 423.1 [00214] 410.2 [00215] 423.1 [00216] 410.2 [00217] 439.1 [00218] 424.2 [00219] 424.1 / /

EXAMPLE 7

Synthesis of 1-(indole-3-methyl)-3-(3-hydroxy-4-chlorophenyl)pyrrolidine (MDC-161502-013)

[0308] Step 1

Synthesis of 1-tert-butoxycarbonyl-3-(3-hydroxy-4-chlorophenyl)-2,5-dihydropyrrole

[0309] ##STR00220##

[0310] 2-chloro-5-bromophenol (253 mg, 1.22 mmol, 1.2 eq), 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (300 mg, 1.02 mmol, 1 eq), K.sub.2CO.sub.3 (564 mg, 4.08 mmol, 4 eq) and Pd(dppf)Cl.sub.2 (75 mg, 0.103 mmol, 0.1 eq) were mixed in DMF (6 mL), stirred overnight at 100 C. under the protection of nitrogen. After the reaction was completed, ethyl acetate (400 mL) was added, and the resulting mixture was successively washed with water (50 mL2) and saturated sodium chloride solution (50 mL3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give a pale yellow solid (230 mg, yield 76%). LCMS(ESI) [M56+H].sup.+: 240.0.

[0311] Step 2

Synthesis of 1-tert-butoxycarbonyl-3-(3-hydroxy-4-chlorophenyl)-pyrrolidine

[0312] ##STR00221##

[0313] 1-tert-butoxycarbonyl-3-(3-hydroxy-4-chlorophenyl)-2,5-dihydropyrrole (200 mg, 0.676 mmol, 1 eq) was dissolved in ethyl acetate (50 mL). Pd/C (40 mg, 10%) was added, and the resulting mixture was stirred overnight at room temperature under H.sub.2 (20 Psi). Pd/C was removed by filtration, the filtrate was subjected to reduced pressure to remove solvent, and was purified by column chromatography (petroleum ether/ethyl acetate=10/1-5/1) to give a yellowish solid (130 mg, yield 65%). LCMS(ESI) [M56+H].sup.+: 242.0.

[0314] Step 3

Synthesis of 3-(3-hydroxy-4-chlorophenyl)-pyrrolidine

[0315] ##STR00222##

[0316] 1-tert-butoxycarbonyl-3-(3-hydroxy-4-chlorophenyl)-pyrrolidine (130 mg, 0.437 mmol, 1 eq) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL), stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure to give a crude product, which was directly used in the next reaction. LCMS(ESI) [M+H].sup.+: 198.0.

[0317] Step 4

Synthesis of 1-(indole-3-methyl)-3-(3-hydroxy-4-chlorophenyl)pyrrolidine (MDC-161502-013)

[0318] ##STR00223##

[0319] The crude product from the previous step and 3-indolealdehyde (76 mg, 0.524 mmol, 1.2 eq) were dissolved in dry tetrahydrofuran (5 mL). Acetic acid (0.2 mL) was added and stirred at room temperature for 2 h, then sodium triacetoxyborohydride (400 mg, 1.89 mmol, 4 eq) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated and purified by preparative TLC (dichloromethane/methanol=8/1), and then purified by column chromatography (dichloromethane/methanol=20/1) to give a nearly white solid (80 mg, yield 56.0%). LCMS(ESI) [M+H].sup.+: 327.0. HNMR (400 MHz, DMSO-d.sub.6) : 11.44 (bs, 1H), 10.17 (bs, 1H), 7.82 (d, J=6.4 Hz, 1H), 7.65 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.07-7.21 (m, 2H), 6.89 (s, 1H), 6.79 (d, J=6.8 Hz, 1H), 4.55 (s, 2H), 3.50-3.75 (m, 2H), 3.05-3.21 (m, 1H), 2.27-2.42 (m, 1H), 1.85-2.13 (m, 1H).

EXAMPLE 8

Synthesis of 1-(indole-3-methyl)-3-(2-chloro-3-hydroxyphenyl)pyrrolidine (MDC-161502-014)

[0320] Step 1

Synthesis of 1-tert-butoxycarbonyl-3-(2-chloro-3-hydroxyphenyl)-2,5-dihydropyrrole

[0321] ##STR00224##

[0322] 2-chloro-3-bromophenol (338 mg, 1.63 mmol, 1.2 eq), 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (400 mg, 1.36 mmol, 1 eq), K.sub.2CO.sub.3 (770 mg, 5.57 mmol, 4 eq) and Pd(dppf)Cl.sub.2 (100 mg, 0.137 mmol, 0.1 eq) were mixed in DMF (10 mL), stirred overnight at 100 C. under the protection of nitrogen. After the reaction was completed, ethyl acetate (400 mL) was added, and the resulting mixture was successively washed with water (50 mL2) and saturated sodium chloride solution (50 mL3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give a pale yellow solid (350 mg, yield 87%). LCMS(ESI) [M56+H].sup.+: 240.0.

[0323] Step 2

Synthesis of 1-tert-butoxycarbonyl-3-(2-chloro-3-hydroxyphenyl)-pyrrolidine

[0324] ##STR00225##

[0325] 1-tert-butoxycarbonyl-3-(2-chloro-3-hydroxyphenyl)-2,5-dihydropyrrole (220 mg, 0.744 mmol, 1 eq) was dissolved in ethyl acetate (10 mL). Pd/C (50 mg, 10%) was added, and the resulting mixture was stirred overnight at room temperature under H.sub.2 (20 Psi). Pd/C was removed by filtration, the filtrate was subjected to reduced pressure to remove solvent, and was purified by column chromatography (petroleum ether/ethyl acetate=10/1-5/1) to give a yellowish solid (180 mg, yield 81%). LCMS(ESI) [M56+H].sup.+: 242.0.

[0326] Step 3

Synthesis of 3-(2-chloro-3-hydroxyphenyl)-pyrrolidine

[0327] ##STR00226##

[0328] 1-tert-butoxycarbonyl-3-(2-chloro-3-hydroxyphenyl)-pyrrolidine (90 mg, 0.302 mmol, 1 eq) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL), stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure to give a crude product, which was directly used in the next reaction. LCMS(ESI) [M+H].sup.+: 198.0.

[0329] Step 4

Synthesis of 1-(indole-3-methyl)-3-(2-chloro-3-hydroxyphenyl)pyrrolidine (MDC-161502-014)

[0330] ##STR00227##

[0331] The crude product from the previous step and 3-indolealdehyde (50 mg, 0.344 mmol, 1.2 eq) were dissolved in dry tetrahydrofuran (5 mL). Acetic acid (0.1 mL) was added and stirred at room temperature for 2 h, then sodium triacetoxyborohydride (300 mg, 1.42 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated and purified by preparative TLC (dichloromethane/methanol=8/1), and then purified by column chromatography (dichloromethane/methanol=20/1) to give a nearly white solid (45 mg, yield 46%). LCMS(ESI) [M+H].sup.+: 327.0. HNMR (400 MHz, DMSO-d.sub.6) : 11.43 (bs, 1H), 10.23 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.64 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.07-7.19 (m, 3H), 6.95 (d, J=7.2 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 4.57 (s, 1H), 3.79-4.06 (m, 1H), 3.61-3.76 (m, 1H), 3.38-3.57 (m, 1H), 3.15-3.27 (m, 1H), 2.30-2.42 (m, 1H), 1.94-2.12 (m, 1h).

EXAMPLE 9

1-(indole-3-methyl)-3-(3-cyclopropylsulfonamidophenyl)pyrrolidine (MDC-161502-015)

[0332] Step 1

Synthesis of 3-nitrovinylbenzene

[0333] ##STR00228##

[0334] Methyltriphenylphosphine iodide (64.2 g, 158.8 mmol, 1.2 eq) was dissolved in 1,4-dioxane (500 ml). Potassium carbonate (27.4 g, 198.5 mmol, 1.5 eq) was added under nitrogen protection, and the resulting mixture was stirred at room temperature for 1 hour. 3-nitrobenzaldehyde (20 g, 132.3 mmol, 1.0 eq) was added to the reaction system. The resulting mixture was stirred at 110 C. for 16 hours under nitrogen protection. The solvent was removed under reduced pressure. Ethyl acetate (200 ml) was added, and the resulting mixture was washed with water (80 ml3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (n-hexane) to give a yellow oily liquid (17.8 g, yield 90%). HNMR (400 MHz, CDCl.sub.3) 8.22 (t, 1H), 8.08 (dt, J=8.0 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 6.76 (dd, J.sub.1=17.2 Hz, J.sub.2=10.8 Hz, 1H), 5.88 (d, J=17.6 Hz, 1H), 5.43 (d, J=10.8 Hz, 1H).

[0335] Step 2

Synthesis of 1-benzyl-3-(3-nitrophenyl) pyrrolidine

[0336] ##STR00229##

[0337] 3-nitrovinylbenzene (13.2 g, 88.4 mmol, 1 eq) was dissolve in dichloromethane (90 mL). Trifluoroacetic acid (1.0 g, 8.84 mmol, 0.1 eq) was added. N-(methoxymethyl)-N-(trimethyl silylmethyl)benzyl amine (45.7 g, 192.5 mmol, 2.1 eq) was added dropwise at 0 C. within 30 minutes. The temperature of the reaction was raised to room temperature and then the reaction was stirred for 16 hours. The solvent was removed under reduced pressure, the residue was diluted with dichloromethane (250 mL) and washed 3 times with water (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel chromatography (dichloromethane:methanol=100:1) to give a yellowish oily liquid (21.5 g, yield 86%). LCMS(ESI) [M+H].sup.+: 283.1.

[0338] Step 3

Synthesis of 1-benzyl-3-(3-aminophenyl)pyrrolidine

[0339] ##STR00230##

[0340] 1-benzyl-3-(3-nitrophenyl)pyrrolidine (19.82 g, 70.2 mmol, 1 eq) was dissolved in water (50 mL) and ethanol (300 mL). Reduced iron powder (31.35 g, 561.6 mmol, 8 eq) and NH.sub.4Cl (30.04 g, 561.6 mmol, 8 eq) were added, and the resulting mixture was stirred at 70 C. for 16 hours. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL) and washed once with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL) respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (dichloromethane:methanol=30:1, 10:1) to give a yellowish oily liquid (13.8 g, yield 78%). LCMS(ESI) [M+H].sup.+: 253.0.

[0341] Step 4

Synthesis of 1-benzyl-3-(3-aminophenyl)pyrrolidine

[0342] ##STR00231##

[0343] 1-benzyl-3-(3-aminophenyl)pyrrolidine (190 mg, 0.79 mmol, 1 eq), DMAP (10 mg, 0.08 mmol, 0.1 eq) and pyridine (1 mL) were mixed in dichloromethane (3 mL). Cyclopropyl sulfonyl chloride (127 mg, 0.90 mmol, 1.1 eq) was added under stirring and reacted at room temperature for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure and ethyl acetate (100 mL) was added. The resulting mixture was successively washed with water (20 mL2) and saturated sodium chloride solution (20 mL). The organic phase was dried over sodium sulfate, concentrated, and purified by column chromatography (dichloromethane/methanol=50/1) to give a colorless oily liquid (190 mg, yield 71%).

[0344] Step 5

Synthesis of 3-(3-aminophenyl)pyrrolidine

[0345] ##STR00232##

[0346] 1-benzyl-3-(3-cyclopropylsulfonamidophenyl)pyrrolidine (140 mg, 0.39 mmol, 1 eq), ammonium formate (247 mg, 3.9 mmol, 10 eq), Pd/C (20 mg, 10%) were mixed in a solution of methanol (3 mL) and ammonia/methanol (3 mL, 2 mol/L), stirred at 70 C. for 16 hours and filtered. The filtrate was subjected to reduced pressure to remove solvent, and the residue was purified by column chromatography (dichloromethane/methanol=20/1, 10/1) to give a white solid (50 mg, yield 48%).

[0347] Step 6

Synthesis of 1-(indole-3-methyl)-3-(3-cyclopropylsulfonamidophenyl)pyrrolidine (MDC-161502-015)

[0348] ##STR00233##

[0349] 3-(3-cyclopropylsulfonamidophenyl)pyrrolidine (50 mg, 0.19 mmol, 1 eq) and 3-indolealdehyde (30 mg, 0.21 mmol, 1.1 eq) were dissolved in dry tetrahydrofuran (3 mL). Acetic acid (0.1 mL) was added and stirred at room temperature for 2 h. Sodium triacetoxyborohydride (162 mg, 0.77 mmol, 4 eq) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated and purified by column chromatography (dichloromethane/methanol=20/1) to give a white solid (25 mg, yield 34%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) 7.76 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.32-7.29 (m, 1H), 7.29-7.24 (m, 4H), 7.09 (d, J=8.0 Hz, 1H), 4.61 (s, 2H), 3.79 (dd, J=12, 8.0 Hz, 1H), 3.60-3.51 (m, 3H), 2.53-2.49 (m, 2H), 2.48-2.16 (m, 1H), 1.41-1.36 (m, 1H), 1.02-0.94 (m, 2H), 0.93-0.89 (m, 2H); LCMS(ESI) [M+H].sup.+: 396.2.

EXAMPLE 10

1-(indole-3-methyl)-3-(3-cyclobutylmethylsulfonamidophenyl)pyrrolidine (MDC-161502-017)

[0350] Step 1

Synthesis of 1-benzyl-3-(3-cyclobutylmethylsulfonamidophenyl)pyrrolidine

[0351] ##STR00234##

[0352] 1-benzyl-3-(3-aminophenyl)pyrrolidine (200 mg, 0.793 mmol, 1 eq), DMAP (10 mg, 0.0820 mmol, 0.1 eq) and pyridine (1 mL) were mixed in dichloromethane (3 mL). Cyclobutyl methanesulfonyl chloride (150 mg, 0.890 mmol, 1.1 eq) was added under stirring and reacted overnight at room temperature. After the reaction was completed, the solvent was removed under reduced pressure and ethyl acetate (100 mL) was added. The resulting mixture was successively washed with water (20 mL2) and saturated sodium chloride solution (20 mL). The organic phase was dried over sodium sulfate, concentrated, and purified by column chromatography (dichloromethane/methanol=50/1) to give a yellowish solid (160 mg, yield 53%). LCMS(ESI) [M+H].sup.+: 385.0.

[0353] Step 2

Synthesis of 3-(3-cyclobutylmethylsulfonamidophenyl)pyrrolidine

[0354] ##STR00235##

[0355] 1-benzyl-3-(3-cyclobutylmethylsulfonamidophenyl)pyrrolidine (62 mg, 0.161 mmol, 1 eq), ammonium formate (82 mg, 1.30 mmol, 8 eq) and Pd/C (10 mg, 10%) were mixed in methanol (5 mL), stirred at 70 C. for 3 hours and filtered. The filtrate was subjected to reduced pressure to remove solvent, and the residue was purified by column chromatography (dichloromethane/methanol=20/1, 10/1) to give a white solid (40 mg, 85% yield). LCMS(ESI) [M+H].sup.+: 295.0.

[0356] Step 3

Synthesis of 1-(indole-3-methyl)-3-(3-cyclobutylmethylsulfonamidophenyl)pyrrolidine (MDC-161502-017)

[0357] ##STR00236##

[0358] 3-(3-cyclobutylmethylsulfonamidophenyl)pyrrolidine (40 mg, 0.136 mmol, 1 eq) and 3-indolealdehyde (25 mg, 0.172 mmol, 1.2 eq) were dissolved in dry tetrahydrofuran (5 mL). Acetic acid (0.1 mL) was added and stirred at room temperature for 2 h. Sodium triacetoxyborohydride (120 mg, 0.566 mmol, 4 eq) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated and purified by column chromatography (dichloromethane/methanol=20/1) to give a white solid (28 mg, yield 49%). LCMS(ESI) [M+H].sup.+: 424.0; HNMR (400 MHz, DMSO-d.sub.6) : 11.43 (bs, 1H), 9.75 (s, 1H), 7.82 (d, J=5.6 Hz, 1H), 7.64 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.05-7.10 (m, 4H), 4.58 (s, 2H), 3.37-3.81 (m, 3H), 3.07-3.25 (m, 3H), 2.61-2.72 (m, 1H), 2.31-2.43 (m, 1H), 1.94-2.11 (m, 3 h), 1.67-1.87 (m, 4H).

EXAMPLE 11

1-(3-indolylmethyl)-3-(3-diethoxyphosphoryloxyphenyl) pyrrolidine (MDC-161502-030)

[0359] ##STR00237##

[0360] 3-(3-hydroxyphenyl)pyrrolidine (1.65 g, 10.1 mmol) and 1-tert-butoxycarbonyl 3-indolealdehyde (2.75 g, 11.2 mmol) were dissolved in dry tetrahydrofuran (40 mL). Acetic acid (2 mL) was added and stirred at room temperature for 2 hours. And then sodium borohydride triacetate (8.60 g, 40.6 mmol) was added and stirred at room temperature for 16 hours. Ethyl acetate (450 mL) was added to dilute the reaction system. The system was successively washed with saturated sodium bicarbonate solution (100 mL3) and saturated brine (100 mL 2). The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and then purified by column chromatography (dichloromethane/methanol=8/1) to give a pale yellow solid (3.5 g, 76% yield). LCMS: m/z=393 [M+H].sup.+.

##STR00238##

[0361] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-hydroxyphenyl)pyrrolidine (400 mg, 1.02 mmol) was dissolved in dry acetonitrile (20 mL) and cooled to 10 C. Diisopropylethylamine (264 mg, 2.04 mmol), N,N-dimethylpyridine (13 mg, 0.106 mmol), carbon tetrachloride (786 mg, 5.11 mmol), and diethylphosphite (212 mg, 1.54 mmol) were added successively, and then the resulting mixture was stirred at room temperature for 16 hours. The system was diluted by adding ethyl acetate (300 mL), washed successively with water (80 mL2) and saturated brine (80 mL2), dried over anhydrous sodium sulfate, filtered to remove desiccant, subjected to reduced pressure to remove solvent, and purified with flash silica gel column chromatography (petroleum ether/ethyl acetate/ethanol=12/3/1-4/3/1) to give a yellowish solid (360 mg, yield 67%). LCMS: m/z=529 [M+H].sup.+.

##STR00239##

[0362] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-diethoxyphosphoryloxyphenyl)pyrrolidine (300 mg, 0.568 mmol) was dissolved in dry dichloromethane (10 mL). Trifluoroacetic acid (8 mL) was added and stirred at room temperature for 3 hours, and the solvent was removed under reduced pressure. Triethylamine alkalization system was added, and the solvent was removed under reduced pressure again. The resulting product was purified by preparative liquid phase chromatography (acetonitrile-water-acetic acid) to give a yellowish viscous solid (180 mg, yield 74%). LCMS: m/z=429 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.18 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 7.15 (s, 1H), 7.12 (td, J.sub.1=8.0 Hz, J.sub.2=0.5 Hz, 1H), 7.03-7.08 (m, 2H), 4.09-4.23 (m, 6H), 3.73 (m, 1H), 3.14 (m, 1H), 3.03 (m, 1H), 2.88 (m, 1H), 2.33 (m, 1H), 1.87 (m, 1H), 1.25 (m, 3H), 1.13 (m, 1H).

EXAMPLE 12

MDC-161502-031

[0363] Step 1

##STR00240##

[0364] 1-tert-butoxycarbonyl-3-pyrrolidone (15 g, 80.98 mmol, 1.0 eq) was placed in a 1 L three-necked reaction flask and the flask was subjected to replacement with nitrogen three times. Anhydrous tetrahydrofuran (200 mL) was added, and the temperature was reduced to 78 C. Subsequently, a solution of lithium bis(trimethylsilyl)amide (121 ml, 1M) in tetrahydrofuran was slowly added and stirred for 1 h while keeping the temperature constant. N-phenyl bis(trifluoromethanesulfonimide) (43.4 g, 121.5 mmol, 1.5 eq) was then dissolved in tetrahydrofuran solution (80 ml) and slowly added to the reaction system. Then the temperature of the reaction solution was raised to room temperature and the reaction was stirred overnight. Saturated sodium bicarbonate solution (100 ml) was added to the reaction solution. The resulting mixture was extracted 3 times with ethyl acetate (80 ml). The organic phases were combined and washed 3 times with saturated brine (80 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give 60 g of yellow crude product. LCMS: m/z=318[M+H].sup.+.

[0365] Step 2

##STR00241##

[0366] 3-(trifluoromethylsulfonyloxy)-2H-pyrrole-1(5H)-carboxylic acid tert-butyl ester crude product (6 g), pinacol borate (2.45 g, 9.64 mmol, 1.2 eq), potassium acetate (1.32 g, 16.1 mmol, 2 eq) and [1,1-bis(diphenylphosphine)ferrocene] palladium dichloride dichloromethane complex (131 mg, 0.16 mmol, 0.02 eq) were dissolved in 1,4-dioxane (60 ml). The mixture was subjected to replacement with nitrogen three times. The temperature of the mixture was raised to 95 C. and the reaction was stirred for 5 h while keeping the temperature constant. Water (80 ml) was added to the reaction solution. The resulting mixture was extracted 3 times with ethyl acetate (80 ml). The organic phases were combined and washed three times with saturated brine (80 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give a black crude product. LCMS: m/z=296[M+H].sup.+.

[0367] Step 3

##STR00242##

[0368] 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (1220 mg, 5.08 mmol, 1.0 eq), 5-bromo-2-fluorophenol (970 mg, 5.08 mmol, 1.0 eq), potassium carbonate (2.11 g, 15.24 mmol, 3 eq) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (82 mg, 0.1 mmol, 0.02 eq) were dissolved in N,N-dimethylformamide (20 ml). The mixture was subjected to replacement with nitrogen three times. The temperature of the mixture was raised to 90 C. and the reaction was stirred overnight. Water (50 ml) was added to the reaction solution. The resulting mixture was extracted 3 times with ethyl acetate (30 ml). The organic phases were combined and washed three times with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, concentrated and purified on a silica gel column (dichloromethane:methanol=19:1) to give a desired white compound (500 mg, 1.79 mmol, 35%). LCMS: m/z=280[M+H].sup.+.

[0369] Step 4

##STR00243##

[0370] 1-tert-butoxycarbonyl-3-(4-fluoro-3-hydroxyphenyl)-2,5-dihydro-1H-pyrrolidine (500 mg, 1.79 mmol) was dissolved in methanol (30 ml). Palladium carbon (200 mg) was added, and the resulting mixture was stirred at room temperature for 16 hours under hydrogen atmosphere (15 Psi). After filtration, the filtrate was concentrated to give a white solid (450 mg, 1.60 mmol, 89.3% yield). The crude product was directly used for the next step. LCMS: m/z=282[M+H].sup.+.

[0371] Step 5

##STR00244##

[0372] 1-tert-butoxycarbonyl-3-(4-fluoro-3-hydroxyphenyl)pyrrolidine (450 mg, 1.6 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give a white solid (280 mg, 1.54 mmol, yield: 96.6%). LCMS: m/z=182[M+H].sup.+.

[0373] Step 6

##STR00245##

[0374] 3-(4-fluoro-3-hydroxyphenyl)pyrrolidine (170 mg, 0.939 mmol) and 1-tert-butoxycarbonyl-3-indolealdehyde (230 mg, 0.94 mmol, 1.0 eq) were dissolved in anhydrous tetrahydrofuran (10 ml). Acetic acid (60 mg, 1 mmol) and NaBH(OAc).sub.3 (795 mg, 3.75 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (50 ml) and the resulting mixture was washed with saturated sodium bicarbonate solution (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified on a silica gel column (dichloromethane/methanol=10:1) to give a white solid (150 mg, 0.37 mmol, yield: 38.9%). LCMS: m/z=411[M+H].sup.+.

[0375] Step 7

##STR00246##

[0376] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(4-fluoro-3-hydroxyphenyl)pyrrolidine (150 mg, 0.37 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, the residue was purified by prep-HPLC to give a white solid (70 mg, 0.23 mmol, yield: 62%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.18 (s, 1H), 9.81 (brs, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.44(s, 1H), 7.40(d, J=8.0 Hz, 1H), 7.13-7.10 (m, 1H), 7.06-7.02 (m, 2H), 6.88 (dd, J.sub.1=2.0 Hz, J.sub.2=8.5 Hz,1H), 6.71-6.68 (m, 1H), 4.19 (s, 2H), 3.34-3.32 (m, 1H), 3.11-3.05 (m, 3H), 2.82-2.80 (m, 1H), 2.28-2.25 (m, 1H), 1.85-1.79 (m, 1H). LCMS: m/z=311[M+H].sup.+; Prep-HPLC method: Shim-pack GIST C18 column (25050 mm, particle size 5 M); 0.1% CH.sub.3COOH in H.sub.2O/0.1% CH.sub.3COOH in ACN gradient eluting system; flow rate=40.0 mL/min.

EXAMPLE 13

MDC-161502-032

[0377] Step 1

##STR00247##

[0378] 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (584 mg, 2.43 mmol, 1.0 eq), 3-difluoromethylbromobenzene (500 mg, 2.43 mmol, 1.0 eq), potassium carbonate (1 g, 7.25 mmol, 3 eq) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (40 mg, 0.05 mmol, 0.02 eq) were dissolved in N,N-dimethylformamide (20 ml). The mixture was subjected to replacement with nitrogen three times. The temperature of the mixture was raised to 90 C. and the reaction was stirred overnight. Water (50 ml) was added to the reaction solution. The resulting mixture was extracted 3 times with ethyl acetate (30 ml). The organic phases were combined and washed three times with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, concentrated and purified on a silica gel column (dichloromethane:methanol=19:1) to give a desired compound (500 mg, 1.69 mmol, 69.5%). LCMS: m/z=296[M+H].sup.+;

[0379] Step 2

##STR00248##

[0380] 1-tert-butoxycarbonyl-3-(3-difluoromethylphenyl)-2,5-dihydro-1H-pyrrolidine (400 mg, 1.35 mmol) was dissolved in methanol (30 ml). Palladium carbon (200 mg) was added, and the resulting mixture was stirred at room temperature for 16 hours under hydrogen atmosphere (15 Psi). After filtration, the filtrate was concentrated to give a white solid (370 mg, 1.24 mmol, 91.8% yield), and the crude product was directly used for the next reaction. LCMS: m/z=298[M+H].sup.+;

[0381] Step 3

##STR00249##

[0382] 1-tert-butoxycarbonyl-3-(3-difluoromethylphenyl) pyrrolidine (370 mg, 1.25 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give a brown oil (245 mg, 1.24 mmol, yield: 99.2%). LCMS: m/z=198[M+H].sup.+;

[0383] Step 4

##STR00250##

[0384] 3-(3-difluoromethylphenyl) pyrrolidine (245 mg, 1.24 mmol) and 1-tert-butoxycarbonyl 3-indolealdehyde (304 mg, 1.24 mmol, 1.0 eq) were dissolved in anhydrous tetrahydrofuran (10 ml). Acetic acid (72 mg, 1.2 mmol) and NaBH(OAc)3 (1.04 g, 4.96 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dissolved with ethyl acetate (50 ml), washed with saturated sodium bicarbonate solution (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified on a silica gel column (dichloromethane/methanol=10:1) to give a white solid (280 mg, 0.66 mmol, yield: 53.2%). LCMS: m/z=427[M+H].sup.+.

[0385] Step 5

##STR00251##

[0386] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(3-difluoromethylphenyl)pyrrolidine (280 mg, 0.66 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by prep-HPLC to give a white solid (150 mg, 0.46 mmol, yield: 70%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.38 (s, 1H), 10.09 (brs, 1H),7.79 (d, J=7.5 Hz, 1H), 7.57-7.43 (m, 5H), 7.15 (d, J=7.5 Hz, 1H), 7.12-7.08 (m, 1H), 6.95 (d, J=55.5 Hz, 1H), 4.50 (s, 2H), 3.54-3.53 (m, 3H), 3.32-3.31 (m, 2H), 2.41-2.36 (m, 1H), 2.01-2.00 (m, 1H). LCMS: m/z=327[M+H].sup.+; Prep-HPLC method: Shim-pack GIST C18 column (25050 mm, particle size 5 M); 0.1% CH.sub.3COOH in H.sub.2O/0.1% CH.sub.3COOH in ACN gradient eluting system; flow rate=40.0 mL/min.

EXAMPLE 14

MDC-161502-033

[0387] ##STR00252##

[0388] 3-bromophenol (13.6 g, 78.6 mmol), 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (16.8 g, 57.1 mmol), 1,1-bis-diphenylphosphinoferrocene palladium dichloride (2.1 g, 2.87 mmol) and potassium carbonate (23.7 g, 172 mmol) were mixed in N,N-dimethylformamide (100 mL). The mixture was subjected to replacement with nitrogen to remove oxygen and then the mixture was raised to 95 C. in temperature and reacted for 16 hours. The reaction system was diluted with ethyl acetate (300 mL), washed successively with water (300 mL2) and saturated brine (200 mL5), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and then purified by column chromatography (petroleum ether/ethyl acetate=3/1, 2/1, ethyl acetate) to give a yellowish solid (3.1 g, yield 21%). LCMS: m/z=262 [M+H].sup.+.

##STR00253##

[0389] 1-tert-butoxycarbonyl-3-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrolidine (400 mg, 1.53 mmol) was dissolved in methanol (40 mL). Palladium carbon (80 mg) was added, and the resulting mixture was stirred at room temperature for 3 hours under hydrogen (1 atm). Palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to give a pale yellow solid (402 mg, yield>99%). LCMS: m/z=208 [M56+H].sup.+.

##STR00254##

[0390] 1-tert-butoxycarbonyl-3-(3-hydroxyphenyl)pyrrolidine (380 mg, 1.44 mmol) was dissolved in dry dichloromethane (15 mL). Trifluoroacetic acid (10 mL) was added, and the resulting mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure to remove dichloromethane and excess trifluoroacetic acid to give a light brown viscous oil. LCMS: m/z=164 [M+H].sup.+.

##STR00255##

[0391] The crude 3-(3-hydroxyphenyl)pyrrolidine (375 mg, 1.44 mmol) and 3-indazolecarbaldehyde (220 mg, 1.51 mmol) were dissolved in dry tetrahydrofuran (20 mL). Acetic acid (0.3 mL) was added and stirred at room temperature for 4 hours. And then sodium borohydride triacetate (1.50 g, 7.08 mmol) was added and stirred at room temperature for 16 hours. The reaction system was diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate solution (50 mL3), and the organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and purified on a preparative silica gel plate (dichloromethane/methanol=9/1) and then by preparative liquid phase chromatography (acetonitrile-water-acetic acid) to give a white solid (80 mg, yield 19%). LCMS: m/z=294 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.82 (bs, 1H), 9.23 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.33 (ddd, J.sub.1=8.0 Hz, J.sub.2=7.0 Hz, J.sub.3=1.0 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.65-6.68 (m, 2H), 6.55 (ddd, J.sub.1=8.0 Hz, J.sub.2=2.0 Hz, J.sub.3=1.0 Hz, 1H), 4.03 (s, 2H), 3.22 (m, 1H), 2.98 (m, 1H), 2.72-2.81 (m, 2H), 2.54 (m, 1H), 2.21 (m, 1H), 1.74 (m, 1H).

EXAMPLE 15

MDC-161502-034

[0392] ##STR00256##

[0393] The crude 3-(3-hydroxyphenyl)pyrrolidine (210 mg, 0.759 mmol) and 1H-pyrrolo[2,3-b]pyridin-3-carbaldehyde (115 mg, 0.787 mmol) were dissolved in dry tetrahydrofuran (10 mL). Acetic acid (0.2 mL) was added and stirred at room temperature for 4 hours. And then sodium borohydride triacetate (805 mg, 3.80 mmol) was added and stirred at room temperature for 16 hours. The reaction system was diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate solution (50 mL3), and the organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and purified on a preparative silica gel plate (dichloromethane/methanol=8/1) and then by preparative liquid phase chromatography (acetonitrile-water-acetic acid) to give a white solid (60 mg, yield 27%). LCMS: m/z=294 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.61 (s, 1H), 9.29 (s, 1H), 8.22 (dd, J.sub.1=4.5 Hz, J.sub.2=1.5 Hz, 1H), 8.11 (d, J=7.0 Hz, 1H), 7.50 (s, 1H), 7.08 (dd, J.sub.1=8.0 Hz, J.sub.2=4.5 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 6.69 (d, J=3.5 Hz, 1H), 6.68 (d, J=1.5 Hz, 1H), 6.59 (dd, J.sub.1=7.0 Hz, J.sub.2=1.5 Hz, 1H), 4.04 (s, 2H), 3.14 (m, 1H), 2.92 (m, 2H), 2.70 (m, 1H), 2.25 (m, 1H), 1.81 (m, 1H).

EXAMPLE 16

MDC-161502-035

[0394] Step 1

##STR00257##

[0395] 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (584 mg, 2.43 mmol, 1.0 eq), 2-hydroxy-5-bromopyridine (500 mg, 2.43 mmol, 1.0 eq), potassium carbonate (1 g, 7.25 mmol, 3.0 eq) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (40 mg, 0.05 mmol. 0.02 eq) were dissolved in N,N-dimethylformamide (20 ml). The mixture was subjected to replacement with nitrogen three times. The temperature of the mixture was raised to 90 C. and the reaction was stirred overnight. Water (50 ml) was added to the reaction solution. The resulting mixture was extracted 3 times with ethyl acetate (30 ml). The organic phases were combined and washed three times with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, concentrated and purified on a silica gel column (dichloromethane:methanol=19:1) to give a desired compound (350 mg, 1.34 mmol, 54.9%). LCMS: m/z=262[M+H].sup.+.

[0396] Step 2

##STR00258##

[0397] 1-tert-butoxycarbonyl-3-(6-hydroxy-3-pyridinyl)-2,5-dihydro-1H-pyrrolidine (370 mg, 1.34 mmol) was dissolved in methanol (30 ml). Palladium carbon (180 mg) was added, and the resulting mixture was stirred at room temperature for 16 hours under hydrogen atmosphere (15 Psi). After filtration, the filtrate was concentrated to give a white solid (350 mg, 1.33 mmol, 98.8% yield), and the crude product was directly used for the next reaction. LCMS: m/z=264[M+H].sup.+.

[0398] Step 3

##STR00259##

[0399] 1-tert-butoxycarbonyl-3-(6-hydroxy-3-pyridinyl)pyrrolidine (350 mg, 1.33 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give a brown oil (210 mg, 1.28 mmol, yield: 96.2%). LCMS: m/z=164[M+H].sup.+.

[0400] Step 4

##STR00260##

[0401] 3-(6-hydroxy-3-pyridinyl) pyrrolidine (210 mg, 1.28 mmol) and 1-tert-butoxycarbonyl 3-indolealdehyde (313 mg, 1.28 mmol, 1.0 eq) were dissolved in anhydrous tetrahydrofuran (10 ml). Acetic acid (90 mg, 1.5 mmol) and NaBH(OAc).sub.3 (1.08 g, 5.12 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dissolved with ethyl acetate (50 ml), washed with saturated sodium bicarbonate solution (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified on a silica gel column (dichloromethane/methanol=10:1) to give a white solid (120 mg, 0.31 mmol, yield: 24.2%). LCMS: m/z=394[M+H].sup.+.

[0402] Step 5

##STR00261##

[0403] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(6-hydroxy-3-pyridinyl)pyrrolidine (120 mg, 0.31 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by prep-HPLC to give a white solid (60 mg, 0.204 mmol, yield: 84.6%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.49-11.48 (m, 1H), 10.13-10.08 (m, 2H), 8.07-7.04 (m, 2H), 7.84-7.80 (m, 1H), 7.65-7.63 (m, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.26-7.06 (m, 2H), 4.62 (s, 2H), 3.79-3.54 (m, 3H), 3.42-3.37 (m, 1H), 3.31-3.28 (m, 2H), 2.47-2.35 (m, 1H), 2.17-1.95 (m, 1H). LCMS: m/z=294[M+H].sup.+; Prep-HPLC method: Shim-pack GIST C18 column (25050 mm, particle size 5 M); 0.1% CH.sub.3COOH in H.sub.2O/0.1% CH.sub.3COOH in ACN gradient eluting system; flow rate=40.0 mL/min.

EXAMPLE 17

MDC-161502-036

[0404] Step 1

##STR00262##

[0405] 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (610 mg, 2.54 mmol, 1.0 eq), 6-bromoindazole (500 mg, 2.54 mmol, 1.0 eq), potassium carbonate (1.05 g, 7.61 mmol, 3.0 eq) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (40 mg, 0.05 mmol, 0.02 eq) were dissolved in N,N-dimethylformamide (20 ml). The mixture was subjected to replacement with nitrogen 3 times. The temperature of the mixture was raised to 90 C. and the reaction was stirred overnight. Water (50 ml) was added to the reaction solution. The resulting mixture was extracted 3 times with ethyl acetate (30 ml). The organic phases were combined and washed 3 times with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, concentrated and purified on a silica gel column (dichloromethane:methanol=19:1) to give a desired compound (320 mg, 1.12 mmol, 44%). LCMS: m/z=286[M+H].sup.+;

[0406] Step 2

##STR00263##

[0407] 1-tert-butoxycarbonyl-3-(6-indazolyl)-2,5-dihydro-1H-pyrrolidine (320 mg, 1.12 mmol) was dissolved in methanol (30 ml). Palladium carbon (160 mg) was added, and the resulting mixture was stirred at room temperature for 16 hours under hydrogen atmosphere (15 Psi). After filtration, the filtrate was concentrated to give a white solid (260 mg, 0.91 mmol, 80.9% yield), and the crude product was directly used for the next reaction. LCMS: m/z=288[M+H].sup.+;

[0408] Step 3

##STR00264##

[0409] 1-tert-butoxycarbonyl-3-(6-indazolyl)pyrrolidine (260 mg, 0.91 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give a brown oil (160 mg, 0.85 mmol, yield: 93.5%). LCMS: m/z=188[M+H].sup.+;

[0410] Step 4

##STR00265##

[0411] 3-(6-indazolyl)pyrrolidine (160 mg, 0.85 mmol) and 1-tert-butoxycarbonyl 3-indolealdehyde (209 mg, 0.85 mmol, 1.0 eq) were dissolved in anhydrous tetrahydrofuran (10 ml). Acetic acid (60 mg, 1.0 mmol) and NaBH(OAc).sub.3 (724 mg, 3.42 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dissolved with ethyl acetate (50 ml), washed with saturated sodium bicarbonate solution (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified on a silica gel column (dichloromethane/methanol=9:1) to give a white solid (200 mg, 0.48 mmol, yield: 56.4%). LCMS: m/z=417[M+H].sup.+;

[0412] Step 5

##STR00266##

[0413] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(6-indazolyppyrrolidine (200 mg, 0.47 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 0.5 hour and then concentrated under reduced pressure. The residue was purified by prep-HPLC to give a white solid (120 mg, 0.378 mmol, yield: 80.5%). .sup.1H NMIR (500 MHz, DMSO-d.sub.6) 13.05 (s, 1H), 11.45 (s, 1H), 8.03 (s, 1H), 7.82 (d, J.sub.1=7.5 Hz, 1H), 7.73 (d, J.sub.1=8.5 Hz, 1H), 7.63 (s, 1H), 7.45-7.44 (m, 2H), 7.18-7.09 (m, 3H), 4.62 (s, 2H), 3.78-3.55 (m, 4H), 3.34-3.33 (m, 1H), 2.50-2.48 (m, 1H), 2.18-2.03 (m, 1H). LCMS: m/z=317[M+H].sup.+; Prep-HPLC method: Shim-pack GIST C18 column (25050 mm, particle size 5 M); 0.1% CH.sub.3COOH in H.sub.2O/0.1% CH.sub.3COOH in ACN gradient eluting system; flow rate=40.0 mL/min.

EXAMPLE 18

MDC-161502-037

[0414] Step 1

##STR00267##

[0415] 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (610 mg, 2.54 mmol, 1.0 eq), 5-bromo-1H-benzimidazole (500 mg, 2.54 mmol, 1.0 eq), potassium carbonate (1.05 g, 7.61 mmol, 3 eq) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (40 mg, 0.05 mmol. 0.02 eq) were dissolved in N,N-dimethylformamide (20 ml). The mixture was subjected to replacement with nitrogen three times. The temperature of the mixture was raised to 90 C. and the reaction was stirred overnight. Water (50 ml) was added to the reaction solution. The resulting mixture was extracted 3 times with ethyl acetate (30 ml). The organic phases were combined and washed 3 times with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, concentrated and purified on a silica gel column (dichloromethane:methanol=19:1) to give a desired compound (100 mg, 0.35 mmol, 13.8%). LCMS: m/z=286[M+H].sup.+;

[0416] Step 2

##STR00268##

[0417] 1-tert-butoxycarbonyl-3-(6-benzimidazolyl)-2,5-dihydro-1H-pyrrolidine (320 mg, 1.12 mmol) was dissolved in methanol (30 ml). Palladium carbon (160 mg) was added, and the resulting mixture was stirred at room temperature for 16 hours under hydrogen atmosphere (15 Psi). After filtration, the filtrate was concentrated to give a white solid (260 mg, 0.91 mmol, 80.9% yield), and the crude product was directly used for the next reaction. LCMS: m/z=288[M+H].sup.+;

[0418] Step 3

##STR00269##

[0419] 1-tert-butoxycarbonyl-3-(6-benzimidazolyl)pyrrolidine (260 mg, 0.91 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give a brown oil (160 mg, 0.85 mmol, yield: 93.5%). LCMS: m/z=188[M+H].sup.+;

[0420] Step 4

##STR00270##

[0421] 3-(6-benzimidazolyl)pyrrolidine (160 mg, 0.85 mmol) and 1-tert-butoxycarbonyl-3-indolealdehyde (209 mg, 0.85 mmol, 1.0 eq) were dissolved in anhydrous tetrahydrofuran (10 ml). Acetic acid (60 mg, 1.0 mmol) and NaBH(OAc).sub.3 (724 mg, 3.42 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dissolved with ethyl acetate (50 ml), washed with saturated sodium bicarbonate solution (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified on a silica gel column (dichloromethane/methanol=10:1) to give a white solid (200 mg, 0.48 mmol, yield: 56.4%). LCMS: m/z=417[M+H].sup.+;

[0422] Step 5

##STR00271##

[0423] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(6-benzimidazolyl) pyrrolidine (200 mg, 0.47 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by prep-HPLC to give a white solid (120 mg, 0.378 mmol, yield: 80.5%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.28 (s, 1H), 10.91 (brs, 1H), 8.13 (s, 1H),7.67 (d, J=7.5 Hz, 1H), 7.49-7.48 (m, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.26 (d, J=2.0 Hz,1H), 7.12 (d, J=8.0 Hz, 1H), 7.08-7.05 (m, 1H), 7.01-6.98 (m, 1H), 3.84 (s, 2H), 3.42-3.37 (m, 1H), 3.00 (t, J=8.0 Hz, 1H), 2.78-2.76 (m, 2H), 2.57-2.54 (m, 1H), 2.32-2.25 (m, 1H), 1.85-1.79 (m, 1H). LCMS: m/z=317[M+H].sup.+; Prep-HPLC method: Shim-pack GIST C18 column (25050 mm, particle size 5 M); 0.1% CH.sub.3COOH in H.sub.2O/0.1% CH.sub.3COOH in ACN gradient eluting system; flow rate=40.0 mL/min.

EXAMPLE 19

MDC-161502-038

[0424] ##STR00272##

[0425] 4-bromo-1H-indazole (421 g, 2.14 mmol), 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (630 mg, 2.13 mmol), 1,1-bis-diphenylphosphinoferrocene palladium dichloride (157 mg, 0.215 mmol) and potassium carbonate (890 mg, 6.44 mmol) were mixed in N,N-dimethylformamide (20 mL). The mixture was subjected to replacement with nitrogen to remove oxygen and then the mixture was raised to 110 C. in temperature and reacted for 7 hours. The reaction system was diluted with ethyl acetate (500 mL), washed successively with water (200 mL) and saturated brine (100 mL5), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and then purified by flash column chromatography (petroleum ether/ethyl acetate/ethanol=40/3/1-16/3/1-3/3/1) to give a yellowish solid (450 mg, yield 33%). LCMS: m/z=286 [M+H].sup.+;

##STR00273##

[0426] 1-(1-tert-butoxycarbonyl)-3-(4-indazolyl)-2,5-dihydro-1H-pyrrolidine (300 mg, 1.05 mmol) was dissolved in methanol (30 mL). Palladium carbon (60 mg) was added, and the resulting mixture was stirred at room temperature for 16 hours under hydrogen (1 atm). Palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to remove solvent to give a pale yellow solid (301 mg, yield 97%). LCMS: m/z=288 [M+H].sup.+;

##STR00274##

[0427] 1-(1-tert-butoxycarbonyl)-3-(4-indazolyl)pyrrolidine (301 mg, 1.05 mmol) was dissolved in dry dichloromethane (10 mL). Trifluoroacetic acid (10 mL) was added and the resulting mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in dry tetrahydrofuran (15 mL). 1-tert-butoxycarbonyl 3-indolealdehyde (260 mg, 1.06 mmol) and acetic acid (0.2 mL) were added and stirred at room temperature for 2 hours. And then sodium borohydride triacetate (1.12 mg, 5.28 mmol) was added and stirred at room temperature for 2 hours. Ethyl acetate (300 mL) was added to dilute the reaction system. The system was successively washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL2). The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and then purified on a preparative silica gel plate (dichloromethane/methanol=12/1) to give a pale yellow solid (180 mg, yield 41%). LCMS: m/z=417 [M+H].sup.+.

##STR00275##

1-(1-tert-butoxycarbonylindole-3-methyl)-3-(4-indazolyl) pyrrolidine

[0428] (150 mg, 0.360 mmol) was dissolved in dry dichloromethane (8 mL). Trifluoroacetic acid (8 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane. A alkalization system (a solution of ammonia in methanol) was added. The solvent was removed under reduced pressure again, and then the resulting product was purified by preparative liquid phase chromatography (acetonitrile-water-acetic acid) to give a white solid (30 mg, yield 26%). LCMS: m/z=317 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.06 (s, 1H), 11.09 (s, 1H), 8.22 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.40 (s, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 7.25 (t, J=7.5 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 7.00 (d, J=7.0 Hz, 1H), 4.13 (s, 2H), 3.80 (m, 1H), 3.14 (m, 1H), 2.39 (m, 1H), 2.03 (m, 1H).

EXAMPLE 20

MDC-161502-039

[0429] ##STR00276##

[0430] 4-bromo-1H-benzimidazole (1.20 g, 6.09 mmol), 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (1.77 g, 6.00 mmol), 1,1-bis-diphenylphosphinoferrocene palladium dichloride (230 mg, 0.314 mmol) and potassium carbonate (2.49 g, 18.0 mmol) were mixed in N,N-dimethylformamide (30 mL). The mixture was subjected to replacement with nitrogen to remove oxygen and then the mixture was raised to 100 C. in temperature and reacted for 16 hours. The reaction system was diluted with ethyl acetate (300 mL), and the organic phase was washed successively with water (100 mL) and saturated brine (100 mL5), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and then purified by flash column chromatography (petroleum ether/ethyl acetate/ethanol=40/3/1-3/3/1) to give a yellowish solid (450 mg, yield 26%). LCMS: m/z=286 [M+H].sup.+;

##STR00277##

[0431] 1-(1-tert-butoxycarbonyl)-3-(4-benzimidazolyl)-2,5-dihydro-1H-pyrrolidine (450 mg, 1.58 mmol) was dissolved in methanol (30 mL). Palladium carbon (90 mg) was added, and the resulting mixture was stirred at room temperature for 48 hours under hydrogen (1 atm). Palladium carbon was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent, and purified on a flash silica gel column (dichloromethane/methanol=20/1) to obtain light brown solid (210 mg, yield 44%). LCMS: m/z=288 [M+H].sup.+;

##STR00278##

[0432] 1-(1-tert-butoxycarbonyl)-3-(4-benzimidazolyl)pyrrolidine (210 mg, 0.731 mmol) was dissolved in dry dichloromethane (10 mL). Trifluoroacetic acid (8 mL) was added and the resulting mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in dry tetrahydrofuran (10 mL). 1-tert-butoxycarbonyl 3-indolealdehyde (180 mg, 0.734 mmol) and acetic acid (0.2 mL) were added and stirred at room temperature for 3 hours. And then sodium borohydride triacetate (620 mg, 2.93 mmol) was added and stirred at room temperature for 3 hours. Ethyl acetate (300 mL) was added to dilute the reaction system. The system was successively washed with saturated sodium bicarbonate solution (100 mL2) and saturated brine (100 mL2). The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and then purified on a preparative silica gel plate (dichloromethane/methanol=20/1) to give a pale yellow solid (47 mg, yield 15%). LCMS: m/z=417 [M+H].sup.+.

##STR00279##

[0433] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(4-benzimidazolyl)pyrrolidine (35 mg, 0.0840 mmol) was dissolved in dry dichloromethane (10 mL). Trifluoroacetic acid (8 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane. A alkalization system (a solution of ammonia in methanol) was added. The solvent was removed under reduced pressure again, and then the resulting product was purified by preparative liquid phase chromatography (acetonitrile-water-acetic acid) to give a white solid (14 mg, yield 54%). LCMS: m/z=317 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.06 (s, 1H), 8.03 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.37-7.42 (m, 3H), 7.05-7.14 (m, 4H), 4.16 (d, J=13.0 Hz, 1H), 4.04 (d, J=13.0 Hz, 1H), 3.81 (m, 1H), 3.20 (m, 1H), 2.96 (m, 1 h), 2.88 (m, 1H), 2.39 (m, 1H), 1.95 (m, 2H).

EXAMPLE 21

MDC-161502-040

[0434] ##STR00280##

[0435] 5-bromo-1H-benzotriazole (423 g, 2.14 mmol), 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (630 mg, 2.13 mmol), 1,1-bis-diphenylphosphinoferrocene palladium dichloride (157 mg, 0.215 mmol) and potassium carbonate (890 mg, 6.44 mmol) were mixed in N,N-dimethylformamide (20 mL). The mixture was subjected to replacement with nitrogen to remove oxygen and then the mixture was raised to 96 C. in temperature and reacted for 16 hours. The reaction system was diluted with ethyl acetate (400 mL), washed successively with water (100 mL) and saturated brine (100 mL5), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and then purified by flash column chromatography (petroleum ether/ethyl acetate/ethanol=16/3/1-3/3/1) to give a yellowish solid (100 mg, yield 11%). LCMS: m/z=287 [M+H].sup.+;

##STR00281##

[0436] 1-(1-tert-butoxycarbonyl)-3-(5-benzotriazolyl)-2,5-dihydro-1H-pyrrolidine (96 mg, 0.335 mmol) was dissolved in methanol (20 mL). Palladium carbon (20 mg) was added, and the resulting mixture was stirred at room temperature for 16 hours under hydrogen (1 atm). Palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to remove solvent to give a pale yellow solid (96 mg, yield 97%). LCMS: m/z=289 [M+H].sup.+;

##STR00282##

[0437] 1-(1-tert-butoxycarbonyl)-3-(5-benzotriazolyl)pyrrolidine (96.0 mg, 0.335 mmol) was dissolved in dry dichloromethane (6 mL). Trifluoroacetic acid (6 mL) was added and the resulting mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in dry tetrahydrofuran (10 mL). 1-tert-butoxycarbonyl 3-indolealdehyde (85 mg, 0.347 mmol) and acetic acid (0.1 mL) were added and stirred at room temperature for 2 hours. And then sodium borohydride triacetate (360 mg, 1.70 mmol) was added and stirred at room temperature for 2 hours. Ethyl acetate (150 mL) was added to dilute the reaction system. The system was successively washed with saturated sodium bicarbonate solution (60 mL) and saturated brine (50 mL2). The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and then purified on a preparative silica gel plate (dichloromethane/methanol=12/1) to give a pale yellow solid (65 mg, yield 46%). LCMS: m/z=418 [M+H].sup.+.

##STR00283##

[0438] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-(5-benzotriazolyl) pyrrolidine (60 mg, 0.144 mmol) was dissolved in dry dichloromethane (5 mL). Trifluoroacetic acid (5 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane. A alkalization system (a solution of ammonia in methanol) was added. The solvent was removed under reduced pressure again, and then the resulting product was purified by preparative liquid phase chromatography (acetonitrile-water-acetic acid) to give a white solid (18 mg, yield 39%). LCMS: m/z=318 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.93 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.71 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.40 (dd, J.sub.1=9.0 Hz, J.sub.2=1.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.07 (td, J.sub.1=7.5 Hz, J.sub.2=1.0 Hz, 1H), 7.00 (td, J.sub.1=7.5 Hz, J.sub.2=1.0 Hz, 1H), 3.88 (s, 2H), 3.50 (m, 1H), 3.01 (m, 1H), 2.86 (m, 1H), 2.75 (m, 1H), 2.63 (m, 1H), 2.32 (m, 1H), 1.84 (m, 1H).

EXAMPLE 22

MDC-161502-041

[0439] Step 1

##STR00284##

[0440] 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (452 mg, 2 mmol, 1.2 eq), 2,3-dicarbonyl-4-bromoindole (491 mg, 1.67 mmol, 1.0 eq), potassium carbonate (690 mg, 5 mmol, 3 eq) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (25 mg, 0.03 mmol. 0.02 eq) were dissolved in N,N-dimethylformamide (15 ml). The mixture was subjected to replacement with nitrogen three times. The temperature of the mixture was raised to 90 C. and the reaction was stirred overnight. Water (50 ml) was added to the reaction solution. The resulting mixture was extracted 3 times with ethyl acetate (30 ml). The organic phases were combined and washed 3 times with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, concentrated and purified on a silica gel column (dichloromethane:methanol=19:1) to give a desired compound (150 mg, 0.477 mmol, 28.6%). LCMS: m/z=315[M+H].sup.+;

[0441] Step 2

##STR00285##

[0442] 1-tert-butoxycarbonyl-3-[4-(2,3-dicarbonylindolyl)]-2,5-dihydro-1H-pyrrolidine (150 mg, 0.477 mmol) was dissolved in methanol (30 ml). Palladium carbon (80 mg) was added, and the resulting mixture was stirred at room temperature for 16 hours under hydrogen atmosphere (15 Psi). After filtration, the filtrate was concentrated to give a yellow solid (90 mg, 0.284 mmol, 59.7% yield), and the crude product was directly used for the next reaction. LCMS: m/z=263 [M56].sup.+;

[0443] Step 3

##STR00286##

[0444] 1-tert-butoxycarbonyl-3-[4-(2-carbonyl-3-hydroxyindolyl)] pyrrolidine (90 mg, 0.284 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give a brown oil (50 mg, 0.23 mmol, yield: 80.7%). LCMS: m/z=219[M+H].sup.+;

[0445] Step 4

##STR00287##

[0446] 3-[4-(2-carbonyl-3-hydroxyindolyl)]pyrrolidine (50 mg, 0.23 mmol) and 1-tert-butoxycarbonyl-3-indolealdehyde (56 mg, 0.23 mmol, 1.0 eq) were dissolved in anhydrous tetrahydrofuran (10 ml). Acetic acid (20 mg, 0.3 mmol) and NaBH(OAc)3 (194 mg, 0.92 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was dissolved with ethyl acetate (50 ml), washed with saturated sodium bicarbonate solution (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified on a silica gel column (dichloromethane/methanol=10:1) to give a yellow solid (50 mg, 0.11 mmol, yield: 48.6%). LCMS: m/z=448[M+H].sup.+;

[0447] Step 5

##STR00288##

[0448] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-[4-(2-carbonyl-3-hydroxyindolyl)]pyrrolidine (50 mg, 0.11 mmol) was dissolved in dichloromethane (8 ml). Dess-Martin reagent (73 mg, 0.167 mmol, 1.5 eq) was added, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated sodium bicarbonate solution (20 ml) was added, then ethyl acetate (20 ml) was added for dissolution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified on a TLC plate (dichloromethane/methanol=9:1) to give a yellow solid (30 mg, 0.07 mmol, yield: 61.2%). LCMS: m/z=446[M+H].sup.+;

[0449] Step 6

##STR00289##

[0450] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-[4-(2,3-dicarbonylindolyl)]pyrrolidine (30 mg, 0.07 mmol) was dissolved in dichloromethane (2 ml). Trifluoroacetic acid (2 ml) was added dropwise and the resulting mixture was stirred at room temperature for 0.5 hour and then concentrated under reduced pressure. The residue was purified by prep-HPLC to give a yellow solid (20 mg, 0.06 mmol, yield: 82.5%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.98 (brs, 1H), 10.87 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.10-7.04 (m, 2H), 6.99-6.96(m, 1H), 6.69-6.67 (m, 1H), 4.12-4.08 (m, 1H), 3.80-3.78 (m, 2H), 2.80-2.76 (m, 2H), 2.66-2.60 (m, 1H), 2.54-2.52 (m, 1H), 2.25-2.17 (m, 1H), 1.74-1.68 (m, 1H). LCMS: m/z=346[M+H].sup.+; Prep-HPLC method: Shim-pack GIST C18 column (25050 mm, particle size 5 M); 0.1% CH.sub.3COOH in H.sub.2O/0.1% CH.sub.3COOH in ACN gradient eluting system; flow rate=40.0 mL/min.

EXAMPLE 23

MDC-161502-042

[0451] ##STR00290##

[0452] 6-Bromoisatin (540 mg, 2.39 mmol), 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (700 mg, 2.37 mmol), 1,1-bis-diphenylphosphinoferrocene palladium dichloride (180 mg, 0.246 mmol) and potassium carbonate (1.53 g, 7.21 mmol) were mixed in N,N-dimethylformamide (20 mL). The mixture was subjected to replacement with nitrogen to remove oxygen and then the mixture was raised to 93 C. in temperature and reacted for 2 hours. The reaction system was diluted with ethyl acetate (500 mL), washed successively with water (200 mL) and saturated brine (100 mL5), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and then purified by flash column chromatography (petroleum ether/ethyl acetate=4/1-1/1) to give a yellowish solid (106 mg, yield 14%). LCMS: m/z=315 [M+H].sup.+;

##STR00291##

[0453] 1-tert-butoxycarbonyl-3-[6-(2,3-dicarbonylindolyl)]-2,5-dihydro-1H-pyrrolidine (106 mg, 0.337 mmol) was dissolved in methanol (20 mL). Palladium carbon (21 mg) was added, and the resulting mixture was stirred at room temperature for 16 hours under hydrogen (latm). Palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to remove solvent to give a pale yellow solid (100 mg, yield 93%). LCMS: m/z=319 [M+H].sup.+;

##STR00292##

[0454] 1-tert-butoxycarbonyl-3-[6-(2-carbonyl-3-hydroxyindolyl)]pyrrolidine (301 mg, 1.05 mmol) was dissolved in dry dichloromethane (10 mL). Trifluoroacetic acid (8 mL) was added and the resulting mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in dry tetrahydrofuran (15 mL). 1-tert-butoxycarbonyl-3-indolealdehyde (80 mg, 0.326 mmol) and acetic acid (0.1 mL) were added and stirred at room temperature for 2 hours. And then sodium borohydride triacetate (333 mg, 1.57 mmol) was added and stirred at room temperature for 2 hours. Ethyl acetate (300 mL) was added to dilute the reaction system. The system was successively washed with saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL2). The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent. The residue was dissolved in dry dichloromethane, stirred at room temperature for 16 hours while keeping the container open. The solvent was removed under reduced pressure and the resulting product was purified on a preparative silica gel plate (dichloromethane/methanol=12/1) to give a pale yellow solid (50 mg, yield 36%). LCMS: m/z=446 [M+H].sup.+.

##STR00293##

[0455] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-[6-(2-carbonyl-3-hydroxyindolyl)]pyrrolidine (50 mg, 0.112 mmol) was dissolved in dry dichloromethane (5 mL). Trifluoroacetic acid (3 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane. A alkalization system (triethylamine) was added. The solvent was removed under reduced pressure again, and then the resulting product was purified by preparative liquid phase chromatography (acetonitrile-water-acetic acid) to give a pale yellow solid (6 mg, yield 15%). LCMS: m/z=346 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.99 (bs, 1H), 10.89 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 7.06 (td, J.sub.1=7.5 Hz, J.sub.2=1.0 Hz, 1H), 7.00 (td, J.sub.1=7.5 Hz, J.sub.2=1.0 Hz, 1H), 6.98 (dd, J.sub.1=7.5 Hz, J.sub.2=1.5 Hz, 1H), 6.85 (s, 1H), 3.78 (m, 2H), 3.34 (m, 1H), 2.76-2.84 (m, 2H), 2.59 (m, 1h), 2.53 (m, 1H), 2.26 (m, 1H), 1.72 (m, 1H).

EXAMPLE 24

MDC-161502-043

[0456] ##STR00294##

[0457] 5-bromo-1,3-dihydrobenzimidazol-2-one (1.30 g, 6.10 mmol), 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester (1.77 g, 6.00 mmol), 1,1-bis-diphenylphosphinoferrocene palladium dichloride (230 mg, 0.314 mmol) and potassium carbonate (2.49 g, 18.0 mmol) were mixed in N,N-dimethylformamide (30 mL). The mixture was subjected to replacement with nitrogen to remove oxygen and then the mixture was raised to 100 C. in temperature and reacted for 16 hours. The reaction system was diluted with ethyl acetate (300 mL), and the organic phase was washed successively with water (100 mL2) and saturated brine (100 mL5), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and then purified by column chromatography (petroleum ether/ethyl acetate/ethanol=12/3/1, 3/3/1) to give a yellowish solid (300 mg, yield 17%). LCMS: m/z=302 [M+H].sup.+.

##STR00295##

[0458] 1-tert-butoxycarbonyl-3-[5-(1,3-dihydrobenzimidazol-2-one)]-2,5-dihydro-1H-pyrrolidine (300 mg, 0.996 mmol) was dissolved in methanol (30 mL). Palladium carbon (60 mg) was added, and the resulting mixture was stirred at room temperature for 16 hours under hydrogen (1 atm). Palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to give a pale yellow solid (300 mg, yield>99%). LCMS: m/z=304 [M+H].sup.+.

##STR00296##

[0459] 1-tert-butoxycarbonyl-3-[5-(1,3-dihydrobenzimidazol-2-one)]pyrrolidine (120 mg, 0.396 mmol) was dissolved in dry dichloromethane (10 mL). Trifluoroacetic acid (8 mL) was added and the resulting mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in dry tetrahydrofuran (10 mL). 1-tert-butoxycarbonyl-3-indolealdehyde (100 mg, 0.408 mmol) and acetic acid (0.2 mL) were added and stirred at room temperature for 3 hours. And then sodium borohydride triacetate (420 mg, 1.98 mmol) was added and stirred at room temperature for 16 hours. Ethyl acetate (300 mL) was added to dilute the reaction system. The system was successively washed with saturated sodium bicarbonate solution (50 mL3), water (100 mL) and saturated brine (100 mL2). The organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to remove solvent and then purified on a preparative silica gel plate (dichloromethane/methanol=20/1) to give a pale yellow solid (60 mg, yield 35%). LCMS: m/z=433 [M+H].sup.+.

##STR00297##

[0460] 1-(1-tert-butoxycarbonylindole-3-methyl)-3-[5-(1,3-dihydrobenzimidazol-2-one)]pyrrolidine (60 mg, 0.139 mmol) was dissolved in dry dichloromethane (5 mL). Trifluoroacetic acid (5 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane. A alkalization system (triethylamine) was added. The solvent was removed under reduced pressure again, and then the resulting product was purified by preparative liquid phase chromatography (acetonitrile-water-acetic acid) to give a white solid (20 mg, yield 43%). LCMS: m/z=333 [M+H].sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.93 (s, 1H), 10.49 (s, 1H), 10.46 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.08 (td, J.sub.1=7.5 Hz, J.sub.2=1.0 Hz, 1H), 7.00 (td, J.sub.1=7.5 Hz, J.sub.2=1.0 Hz, 1H), 6.85 (s, 1H), 6.82 (dd, J.sub.1=8.0 Hz, J.sub.2=1.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 3.86 (s, 2H), 3.28 (m, 1H), 2.96 (m, 1H), 2.76 (m, 2H), 2.23 (m, 1H), 1.74 (m, 1H).

[0461] Bioactivity Test [0462] I. D2 receptor affinity assay: The affinity of the compound to D2 receptor was determined by radioligand competition assay, and the cloned D2 receptor was expressed in HEK293 cell line. [0463] II. D2 receptor function assay: The ability of the compound to antagonize the D2 receptor was determined using a calcium mobilization assay (FLIPR). [0464] III. DAT receptor function assay: The ability of the compound to inhibit DAT was determined by neurotransmitter transporter absorption assay.

I. D2 Receptor Affinity Assay

1. Experimental Materials

1.1. Reagents and Compounds

[0465] 3H-7-OH-DPAT (PerkinElmer) [0466] Tris base (Sigma, Cat: T1503-1KG), formulated as a 1M solution, pH adjusted to 7.4 [0467] PEI (Sigma-P3143) [0468] Microscint 20 cocktail scintillation fluid (PerkinElmer-6013329) [0469] 7-OH-DPAT (Sigma) [0470] Droperidol (Sigma)

1.2. Instruments and Consumables

[0471] Unifilter-96 GF/C micropore plate (Perkin Elmer-6005174) [0472] 96-well polypropylene plate (Agilent-5042-1385) [0473] TopSeal-A sealing film (Perkin Elmer-6005250) [0474] MicroBeta2 microplate detector platform (PerkinElmer) [0475] Cell counter (Perkin Elmer)

2. Experimental Steps:

2.1. Preparation of Buffers:

[0476] Experimental buffer: 50 mM Tris-HCl, pH 7.4, 5 mM MgCl.sub.2 [0477] Washing buffer: 50 mM Tris-HCl pH 7.4, stored at 4 C. ready for use.

2.2. Compound Formulation:

[0478] The compound and positive control 7-OH-DPAT were serially diluted with DMSO, with the initial concentration of 2 mM and 4 times serial dilution, a total of 10 concentrations. 1 L was transferred to the designated position of the 96-well plate. [0479] 1 L droperidol (final concentration 10 M) was added to the positive control well. 1 L DMSO was added to the negative control well.

2.3. Cell Membrane Formulation:

[0480] Receptor cell membrane was diluted to 10 g/well with corresponding experimental buffer, with 100 L cell membrane/well.

2.4. Isotope Formulation:

[0481] 3H-7-OH-DPAT was diluted to 2 nM with corresponding experimental buffer, and the final concentration was 1 nM.

2.5. Experimental Steps

[0482] After 100 L of cell membrane and isotope were added, respectively, the reaction plate of the D2 receptor was incubated at room temperature for 1 hour. The GF/C filter plate was soaked in 0.3% PEI solution for more than half an hour. After the reaction was completed, the cell membrane was collected on the GF/C filter plate using the cell counter, washed 4 times with cold washing buffer, and then dried in an oven at 50 C. for 1 hour. The dried GF/C filter plate was sealed at the bottom, 50 L of scintillation fluid was added to each well and the well was sealed. Reads were obtained by MicroBeta and the data was analyzed using GraphPad Prism 5.0.

3. Calculation Formula for Data in the Project:

[0483]
% inhibition rate=100[1(reading value for sample wellreading value for negative control well)/(reading value for positive control wellreading value for negative control well)]

Ki=IC.sub.50/(1+isotope concentration/Kd)

II. D2 Receptor Function Assay

1. Experimental Materials

1.1. Cell Line and Media

[0484] Cell line: HEK293 [0485] DMEM medium (Invitrogen) [0486] Fetal bovine serum (FBS, Invitrogen) [0487] L-Glutamine (Invitrogen) G418 (Invitrogen) [0488] Blasticidin (Invitrogen)

1.2. Reagent

[0489] Fluo-4 Direct Kit (Invitrogen)

1.3. Instruments

[0490] 384-well polylysine coated cell plate (Greiner) [0491] 384-well compound plate (Greiner) [0492] FLIPR instrument (Molecular Device) [0493] POD810 instrument (Labcyte) [0494] Cell counter (Beckman, Vi-cell XR) [0495] Micro reagent dispenser (Thermo)

1.4. Reference Compound

[0496] Amisulpride (Sigma)

2. Experimental Method

2.1. Preparation of Reagent

[0497] 250 mM Probenecid solution was formulated: according to the kit instructions, 1 mL of FLIPR buffer salt solution was added to 77 mg probenecid just before needed. [0498] 2 (8 M) Fluo-4 Direct loading buffer was formulated: the number of tubes in Fluo-4 Direct needed for the experiment was melted in advance. Just before needed, 10 ml of FLIPR buffer salt solution and 0.2 mL of 250 mM Probenecid solution were added to each tube and vortexed in dark for more than 5 minutes.

2.2. Preparation of Cells

[0499] a) One tube of cells was taken from the liquid nitrogen tank and quickly thawed in 37 C. water bath. [0500] b) The cell suspension was added to a centrifuge tube to which the preheated 20 ml medium was added in advance. [0501] c) The centrifuge tube was centrifuged at 1000 rpm for 5 minutes at room temperature. [0502] d) The supernatant was slowly decanted to avoid affecting the precipitated cells. [0503] e) The cells were resuspended with 10-30 ml medium by pipetting the cells gently with a pipette. [0504] f) The viability and number of cells were calculated with the cell counter. [0505] g) The cells were diluted to 110.sup.5 cells/ml with medium, and inoculated in the 384-well polylysine coated cell plate at 20 L/well. [0506] h) The plate was incubated in an incubator at 5% CO.sub.2, 37 C. for 16 to 20 hours.

2.3. FLIPR Assay

[0507] a) Compound dose curve plate: The compound to be tested had an initial concentration of 2 mM and was diluted in 100% DMSO using Bravo at 4 gradient to form 10 concentration points, and then 900 nL thereof was transferred to the compound plate using Echo. [0508] b) 30 L of FLIPR buffer salt solution was added to the corresponding compound plate, ready for use. [0509] c) The cell plate prepared the previous day was taken out of the incubator, 20 L of 2 Fluo-4 Direct buffer was added to each well, incubated in a incubator at 37 C. under 5% CO2 for 50 minutes, and left at room temperature for 10 minutes. [0510] d) The compound plate was taken out, and run on FLIPR after tip placement in position. [0511] e) The FLIPR instrument software was run. 10 L of experimental buffer salt solution was added into the cell plate according to the set program, and the fluorescence signal was read. 10 L of agonist reference compound was further added at a given concentration to the cell plate and the fluorescence signal was read. After reading, the data was derived by Max-Min and Read 90 to Maximum Allowed methods in the software and EC80 of the corresponding cell line was calculated, and the reference compound with a concentration of 6 EC80 was prepared. [0512] f) The FLIPR instrument software was run. 10 L of the compound to be tested and the reference compound at a given concentration were added into the cell plate according to the set program, and the fluorescence signal was read. 10 L of reference compound agonist was further added at a concentration of 6 EC80 to the cell plate and the fluorescence signal was read. [0513] g) Data Analysis [0514] Calculation formula for data in the project:

Inhibitor % activity=100(signal value per wellaverage value for high dose control group of inhibitor)/(average value for DMSO control groupaverage value for high dose control group of inhibitor)*100%.

III. DAT Transporter Assay

1. Experimental Materials

1.1. Reagents and Consumables

[0515] Neurotransmitter transporter reuptake assay kit (Molecular devices) [0516] HEPES, Invitrogen (Cat #15630130) [0517] HBSS, Invitrogen (Cat #14025126) [0518] BSA, Sigma (Cat #7030)

1.2. Detection Buffer

[0519] HBSS 1, HEPES 20 mM.

1.3. Detection Buffer Containing BSA

[0520] HBSS1, REPES 20 mM, BSA 0.1%.

1.4. Dye Solution

[0521] Lyophilized fluorescent dye 1 vial, Assay buffer 10 mL.

1.5. Reference Compound

[0522] BTCPhydrochloride (Sigma)

1.6. Instruments

[0523] 384-well polylysine coated cell plate (Greiner) [0524] Vi-cell XR cell viability analyzer (Beckman Coulter) [0525] Incubator (Thermo) [0526] Flexstation multi-mode microplate reader (Molecular devices)

2. Experimental Steps:

2.1. Preparation of Cells

[0527] i) The medium was preheated in 37 C. water bath in advance for more than 30 minutes for later use. [0528] j) The preheated medium was taken out, disinfected with 75% alcohol, and put into a biosafety cabinet. [0529] k) The cultured cells were taken out from the cabinet, and the medium was removed by a vacuum pump. 1 DPBS was added, incubated for a moment, and then removed by a vacuum pump. Appropriate amount of 0.05% trypsin-EDTA was added for cell digestion. The digestion was terminated by 10% FBS medium, and the cells were pipetted and dispersed. [0530] l) The dispersed cells were transferred into a 50 mL centrifuge tube with a pipette. The tube was centrifuged at 800 rpm for 5 minutes, and then the cells were resuspended with medium, pipetted and dispersed, and counted. [0531] m) The cells were diluted to 1106 cells/mL with medium, and inoculated in the 384-well polylysine coated cell plate at 20 L/well.

2.2. DAT Transporter Assay

[0532] a) The reference compound was diluted in a ratio of 1:3 to 10 concentration gradients with the detection buffer containing 0.1% BSA, with the highest concentration being 2 M. The compound to be tested was diluted to 20 uM with the detection buffer containing 0.1% BSA. [0533] b) A centrifuge (750 rpm, 15 s) was used to spin off the culture solution in the cell culture plate, and the compound solution in step 1 was transferred to the cell culture plate (25 uL/well). [0534] HC (High control): 25 L of 0.1% BSA detection buffer containing 0.2% DMSO. [0535] LC (Low control): 25 L of solution containing 2 M positive antagonist. [0536] c) After centrifugation at 300 rpm for 15 seconds, the plate was incubated at 37 C. for 30 minutes. After the incubation with the compound was completed, a dye solution (25 L/well) was added and incubated at 37 C. for 30 minutes. Reading was performed in Flexstation after the incubation. [0537] The parameters are shown in Table 4:

TABLE-US-00006 TABLE 4 Temperature setting 37 C. Excitation wavelength (nM) 440 Emission wavelength (nM) 520 Emission cut-off (nM) 515 PMT sensitivity medium Reads/well 3 [0538] d) Data Analysis [0539] Calculation formula for data in the project:

Inhibitor % activity=100(signal value per wellaverage value for LC well)/(average value for H wellaverage value for LC well)*100%.

[0540] The compounds of the present invention are dual modulators of D2 receptor and DAT, as shown in Table 5 below. Examples above in which various assays were performed reveal about 10 nM to 1 M of Ki (D2) and 100 nM to 1 M of Ki (DAT).

TABLE-US-00007 TABLE 5 Neuro- transmitter transporter Calcium (DAT) D2 affinity mobilization absorption assay assay assay No. Structure IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) MDC- 161502- 002 [00298] 14 2.0 181 MDC- 2.35 144 218.1 161502- 010 MDC- 3.46 2.002 14.72 161502- 011 MDC- 161502- 006 [00299] 639 171 762 MDC- 161502- 008 [00300] 120 5.4 936 MDC- 161502- 031 [00301] 22.38 14.48 28.31 MDC- 161502- 033 [00302] 6.83 2.283 110.7 MDC- 161502- 034 [00303] 2.02 1.99 684.7 MDC- 161502- 036 [00304] 298.38 470.8 841.4 MDC- 161502- 037 [00305] 461.12 269.1 190.5 MDC- 161502- 038 [00306] 10.16 6.216 87.46 MDC- 161502- 040 [00307] 545.74 505.2 52.82 Olanzapine [00308] 7.1 296 >10000 Aripiprazole [00309] 4.4 16.78 >10000

IV. Assay of Therapeutic Activity of the Compound for Schizophreniform Disorder Activity in Mice

[0541] 1. The effect of the compound on phencyclidine (PCP) induced high locomotor activity (LMA) in mice was detected.

[0542] The test compound MDC was milky white powder and stored in a shade and cool place (freshly formulated with 1% DMSO before use). Olanzapine, purchased from Adamas, was a yellowish powder (freshly formulated with 1% DMSO before use). Phencyclidine (PCP), purchased from Sigma Aldrich, was a grayish white powder (freshly formulated with normal saline before use). 1% DMSO was formulated by diluting pure DMSO (purity>99.5, purchased from Sigma-Aldrich) with normal saline.

[0543] Male ICR mice having weight 222 g were kept at 8 mice/cage with 12/12 hours light/dark cycle, temperature 23 C.1 C., humidity 50% to 60%, free to eat and drink water.

[0544] The test compound and olanzapine were formulated with DMSO, and the doses of the test compound were 5 mg, 10 mg and 20 mg. The dose of olanzapine was 5 mg/kg. The administration volume was 0.1 ml/10 g body weight; PCP was formulated with normal saline at a dose of 5 mg/kg.

[0545] The test compound MDC and olanzapine were administered by gavage and PCP was administered by subcutaneous injection.

[0546] After one week of acclimation, mice were randomly divided into 6 groups according to their body weight: negative control group, model group, positive control group, and low dose group, medium dose group and high dose group for the test compound. 8-10 animals/group.

[0547] Group 1: Negative control group: Normal saline (s.c.)+1% DMSO (10.0 ml/kg, p.o.);

[0548] Group 2: Model group: PCP (5.0 mg/kg, s.c.)+1% DMSO (10.0 ml/kg, p.o.);

[0549] Group 3: Positive control group: PCP (5.0 mg/kg, s.c.)+olanzapine (5 mg/kg, p.o.);

[0550] Group 4: MDC low dose group: PCP (5.0 mg/kg, s.c.)+MDC (5 mg/kg, p.o.);

[0551] Group 5: MDC medium dose group: PCP (5.0 mg/kg, s.c.)+MDC (10 mg/kg, p.o.);

[0552] Group 6: MDC high dose group: PCP (5.0 mg/kg, s.c.)+MDC (20 mg/kg, p.o.).

[0553] Mice were injected subcutaneously with PCP (5.0 mg/kg, s.c.) or normal saline, and then administrated with DMSO, and low, medium or high doses of MDC, or olanzapine by oral gavage half an hour later.

[0554] After oral administration, the animals were immediately placed in a locomotor activity box and recorded by Shanghai Jiliang () animal video analysis system for 1 hour.

[0555] After the experiment, the activity of the animals within 1 hour was analyzed using the trajectory analysis software of Shanghai Jiliang animal video analysis system to obtain the total distance resulting from the activity.

[0556] Test Results

TABLE-US-00008 TABLE 6 Grouping Distance resulting from the activity (n = 8-10) First 30 min Last 30 min Negative control group 145612 16487 96956 10529 Model group 313147 17696** 269080 21931** Positive control group 208491 24344# 80518 12716## MDC-161502-002 low 241185 23865# 265712 34806 dose group MDC-161502-002 211543 30690# 206789 26215# medium dose group MDC-161502-002 high 158231 21482## 110918 14982## dose group MDC-161502-006 low 327586 25347 302499 26738 dose group MDC-161502-006 286745 28976 267834 26876 medium dose group MDC-161502-006 high 248576 22456# 230867 25347# dose group MDC-161502-008 low 299745 21356 2808492 23864 dose group MDC-161502-008 246900 21879# 230876 24875# medium dose group MDC-161502-008 high 220968 23069## 189765 20771## dose group **P < 0.01 (ANNOVA followed by Dunnett's t test, compared with the value of the negative control group during the corresponding time period); ##P < 0.01 (ANNOVA followed by Dunnett's t test, compared with the value of the model group during the corresponding time period); #P < 0.05 (ANNOVA followed by Dunnett' s t test, compared with the value of the model group during the corresponding time period);

[0557] Subcutaneous injection of PCP (5.0 mg/kg, s.c.) significantly increased the locomotor activity of mice (P<0.01). Compounds MDC-161502-002, MDC-161502-006, and MDC-161502-008 (5, 10, 20 mg/kg, p.o.) all inhibited PCP-induced high locomotor activity in mice (P<0.05-0.01), which was equivalent to the effect of the positive drug olanzapine on PCP-induced high locomotor activity in mice. Wherein, MDC-161502-002 had significant advantages over olanzapine in inhibiting PCP-induced high locomotor activity.

[0558] Conclusion: Oral administration of the compound MDC can effectively inhibit PCP-induced high locomotor activity in mice, indicating that such compound may have better inhibitory effect on positive symptoms of schizophrenia. The potency thereof was equivalent to or slightly stronger than that of positive drug olanzapine.

V. Effect of Representative Examples on Amphetamine-Induced High Locomotor Activity (LMA) in Mice

[0559] The test compound MDC was a milky white powder and stored in a shade and cool place (formulated with 1% DMSO before use). Olanzapine, purchased from Adamas, was a yellow powder (formulated with 1% DMSO before use). Amphetamine, purchased from Sigma-Aldrich, was a white powder (formulated with normal saline before use). 1% DMSO was formulated by diluting pure DMSO (purity>99.5, purchased from Sigma) with normal saline.

[0560] Male ICR mice having weight 222 g were kept at 8 mice/cage with 12/12 hours light/dark cycle, temperature 23 C.1 C., humidity 50% to 60%, free to eat and drink water.

[0561] The test compound and olanzapine were freshly formulated with DMSO, and the test compound MDC was administrated at doses of 5 mg, 10 mg and 20 mg and administrated by gavage. Olanzapine was administrated a dose of 5 mg/kg and administrated by gavage. The administration volume was 0.1 ml/10 g body weight; Amphetamine was freshly formulated with normal saline at a dose of 1.0 mg/kg and administered subcutaneously.

[0562] After one week of acclimation, mice were randomly divided into 6 groups according to their body weight: negative control group, model group, positive control group, and low dose group, medium dose group and high dose group for the test compound. 8-10 animals/group.

[0563] Group 1: Negative control group: Normal saline (s.c.)+1% DMSO (10.0 ml/kg, p.o.);

[0564] Group 2: Model group: Amphetamine (1.0 mg/kg, s.c.)+1% DMSO (10.0 ml/kg, p.o.);

[0565] Group 3: Positive control group: Amphetamine (1.0 mg/kg, s.c.)+olanzapine (5 mg/kg, p.o.);

[0566] Group 4: MDC low dose group: Amphetamine (1.0 mg/kg, s.c.)+MDC (5 mg/kg, p.o.);

[0567] Group 5: MDC medium dose group: Amphetamine (1.0 mg/kg, s.c.)+MDC (10 mg/kg, p.o.);

[0568] Group 6: MDC high dose group: Amphetamine (1.0 mg/kg, s.c.)+MDC (20 mg/kg, p.o.).

[0569] Mice were injected subcutaneously with Amphetamine (1.0 mg/kg, s.c.) or normal saline, and then administrated with DMSO, and low, medium or high doses of MDC, or positive drug olanzapine by gavage half an hour later.

[0570] After administration, the animals were immediately placed in a locomotor activity box and recorded by Shanghai Jiliang animal video analysis system for 1 hour.

[0571] After the experiment, the activity of the animals within 1 hour was analyzed using the trajectory analysis software of Shanghai Jiliang animal video analysis system to obtain the total distance resulting from the activity.

[0572] The test results are shown in Table 7.

TABLE-US-00009 TABLE 7 Grouping Distance resulting from the activity (n = 8-10) First 30 min Last 30 min Negative control group 128651 15767 118648 13202 Model group 384624 15879** 307965 20864** Positive control group 227653 23869## 158673 15636## MDC-161502-002 low 284824 25868# 257329 25036# dose group MDC-161502-002 250678 28765## 231296 20254## medium dose group MDC-161502-002 high 180127 22036## 148036 13897## dose group MDC-161502-006 low 340368 24769 318973 24896 dose group MDC-161502-006 298763 20845# 257632 23035# medium dose group MDC-161502-006 high 270378 25867# 231584 18762## dose group MDC-161502-008 low 287643 25867# 264309 22736# dose group MDC-161502-008 253945 28973# 220678 20419## medium dose group MDC-161502-008 high 209673 20694## 219876 21540## dose group **P < 0.01 (ANNOVA followed by Dunnett's t test, compared with the value of the negative control group during the corresponding time period) ##P < 0.01 (ANNOVA followed by Dunnett's t test, compared with the value of the model group during the corresponding time period) #P < 0.05 (ANNOVA followed by Dunnett's t test, compared with the value of the model group during the corresponding time period)

[0573] Amphetamine (1.0 mg/kg, s.c.) significantly increased the locomotor activity of mice (P<0.01). Compounds MDC-161502-002, MDC-161502-006 and MDC-161502-008 (5, 10, 20 mg/kg, p.o.) significantly inhibited the Amphetamine (1.0 mg/kg, s.c.)-induced high locomotor activity in mice (P<0.05-0.01), which inhibition was equivalent to olanzapine (5.0 mg/kg, p.o.), wherein, MDC-161502-002 was better than olanzapine in inhibiting Amphetamine-induced high locomotor activity.

[0574] The test results showed that oral administration of the compound of the present invention can effectively inhibit Amphetamine-induced high locomotor activity in mice, indicating that such compound may have better inhibitory effect on positive symptoms of schizophrenia. The potency thereof was equivalent to or slightly stronger than that of positive drug olanzapine.

[0575] Although the specific embodiments of the present invention have been described above, it will be understood by those skilled in the art that these are merely illustrative, and that various alterations or modifications can be made to these embodiments without departing from the principle and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.