Substituted [1,2,4]triazolo[3,4-a]phthalazines as modulators of GABA.SUB.A .receptor activity
11512089 · 2022-11-29
Assignee
- SHANGHAI SIMR BIOTECHNOLOGY CO., LTD (Shanghai, CN)
- SHANGHAI SIMRD BIOTECHNOLOGY CO., LTD (Shanghai, CN)
Inventors
- Fei Wang (Shanghai, CN)
- Jinhua WU (Shanghai, CN)
- Yun Jin (Shanghai, CN)
- Yong SUN (Shanghai, CN)
- Shuai LI (Shanghai, CN)
Cpc classification
A61P29/00
HUMAN NECESSITIES
A61P25/28
HUMAN NECESSITIES
C07D519/00
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention discloses phthalazine isoxazole alkoxy derivatives, a preparation method thereof, a pharmaceutical composition, and a use thereof. The present invention provides a compound represented by Formula I, cis-trans isomers thereof, enantiomers thereof, diastereoisomers thereof, racemates thereof, solvates thereof, hydrates thereof, and pharmaceutically acceptable salts or prodrugs thereof. The compound has an excellent inverse agonist effect with respect to α5-GABA.sub.A. ##STR00001##
Claims
1. A compound represented by formula I: ##STR00176## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Z is a 5- or 6-membered heteroarylene, wherein the 5- or 6-membered heteroarylene contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; A is phenylene, a 5-membered heteroarylene, or a 6-membered heteroarylene; wherein the 5-membered heteroarylene contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; wherein at most 1 of the heteroatoms of the 5-membered heteroarylene is O or S; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; wherein the phenylene is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6alkyl, linear C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl; and wherein the 5-membered heteroarylene or 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; each R.sub.x is independently halogen, CN, C(O)OR.sub.1, OH, OC(O)R.sub.1, OR.sub.1, or R.sub.1; R.sub.1 is C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl, wherein the C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; Y is NY.sub.1Y.sub.2, NHNY.sub.3Y.sub.4, or OH; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, NO.sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, and S(O).sub.2C.sub.1-6 alkyl; Y.sub.2 is H, C.sub.1-6 alkyl, NH.sub.2, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2NH.sub.2, cycloalkyl, heterocycloalkyl, or heteroaryl; wherein the C.sub.1-6 alkyl, OC.sub.1-6alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylene-C(O)OH, C.sub.1-6 alkylene-C(O)OC.sub.1-4 alkyl, C.sub.1-6 alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, acyl, NHC.sub.1-6 alkyl, NHacyl, N(C.sub.1-6 alkyl).sub.2, NO.sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, S(O).sub.2C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein each C.sub.3-6 cycloalkyl substituent is optionally and independently substituted by 1 or more OH substituents; wherein each 4-membered heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; and wherein each C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of halogen, CH.sub.3, and OCH.sub.3; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a 4- to 7-membered heterocycloalkenyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 or more additional heteroatoms independently selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; Y.sub.3 is H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; and Y.sub.4 is H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; or Y.sup.3 and Y.sup.4, taken together with the N atom to which they are attached, form a heterocyclyl, wherein the heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; with the proviso that if A is pyridinylene, then the pyridinylene is optionally an N-oxide thereof.
2. The compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Y.sub.2 is H, C.sub.1-6 alkyl, NH.sub.2, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2NH.sub.2, cycloalkyl, heterocycloalkyl, or heteroaryl; wherein the C.sub.1-6 alkyl, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylene-C(O)OH, C.sub.1-6 alkylene-C(O)OC.sub.1-4 alkyl, C.sub.1-6 alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, acyl, NHC.sub.1-6 alkyl, NHacyl, N(C.sub.1-6 alkyl).sub.2, NO.sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, S(O).sub.2C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein each C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein each C.sub.3-6 cycloalkyl substituent is optionally and independently substituted by 1 or more OH substituents; and wherein each C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of halogen, CH.sub.3, and OCH.sub.3.
3. The compound as defined in claim 2, wherein the compound is represented by formula II: ##STR00177## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: A is phenylene, a 5-membered heteroarylene, or a 6-membered heteroarylene; wherein the 5-membered heteroarylene contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; wherein at most 1 of the heteroatoms of the 5-membered heteroarylene is O or S; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; wherein the phenylene is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, and C.sub.1-6 alkyl; and wherein the 5-membered heteroarylene or 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; each R.sub.x is independently halogen or CN; Y is NY.sub.1Y.sub.2, NHNY.sub.3Y.sub.4, or OH; Y.sub.1 is H or C.sub.1-5 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, and S(O).sub.2C.sub.1-6 alkyl; Y.sub.2 is C.sub.1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bridged C.sub.4-6 cycloalkyl, C.sub.4-6 heterocycloalkyl, or C.sub.5-6 heteroaryl; wherein the C.sub.4-6 heterocycloalkyl or C.sub.5-6 heteroaryl contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, OH, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, C.sub.4-6 cycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, C.sub.1-6 alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, OH, OC.sub.1-6 alkyl, and S(O).sub.2C.sub.1-6 alkyl; wherein the C.sub.4-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, C.sub.1-6 alkyl, C.sub.1-6 alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, acyl, OH, OC.sub.1-6 alkyl, and S(O).sub.2C.sub.1-6 alkyl; and wherein the C.sub.5 heteroaryl is optionally substituted by 1, 2, or 3 independently selected C.sub.1-6 alkyl substituents; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 or more additional heteroatoms independently selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; Y.sub.3 is H, C.sub.1-6 alkyl, or S(O).sub.2C.sub.1-6 alkyl; and Y.sub.4 is H, C.sub.1-6 alkyl or S(O).sub.2C.sub.1-6 alkyl; or Y.sup.3 and Y.sup.4, taken together with the N atom to which they are attached, form a piperidin-1-yl, morpholin-4-yl, or thiomorpholin-4-yl, wherein the thiomorpholin-4-yl is substituted by 1 or 2=0 substituents.
4. The compound as defined in claim 2, wherein the compound is represented by formula II: ##STR00178## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: A is pyridinylene; Y is NY.sub.1Y.sub.2 or OH; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of OH, OC.sub.1-6 alkyl, and OC.sub.1-6 haloalkyl; and Y.sub.2 is H, C.sub.1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bridged C.sub.4-6 cycloalkyl, or C.sub.4-6 heterocycloalkyl; wherein the C.sub.4-6 heterocycloalkyl contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, C.sub.4-6 cycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, C.sub.1-6 alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, OH, and OC.sub.1-6 alkyl; wherein the C.sub.4-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, C.sub.1-6 alkyl, C.sub.1-6 alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, acyl, OH, and OC.sub.1-6 alkyl; and wherein each C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 O heteroatoms; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O.
5. The compound as defined in claim 2, wherein the compound is represented by formula II: ##STR00179## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: A is pyridinylene; Y is NY.sub.1Y.sub.2 or OH; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected OC.sub.1-6 alkyl substituents; and Y.sub.2 is H, C.sub.1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bridged C.sub.4-6 cycloalkyl, or C.sub.4-6 heterocycloalkyl; wherein the C.sub.4-6 heterocycloalkyl contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, OH, OC.sub.1-6 alkyl, C.sub.4-6 cycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen and CN; wherein the C.sub.4-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 independently selected acyl substituents; and wherein each C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 O heteroatoms; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O.
6. The compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, NO.sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, and S(O).sub.2C.sub.1-6 alkyl; and Y.sub.2 . . . is H, methyl, cyclopropylmethyl, oxetanylmethyl, (methyloxetanyl)methyl, tetrahydrofuranylmethyl, ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methoxyethyl, trifluoromethoxyethyl, cyanopropyl, trifluoropropyl, difluorohydroxypropyl, methoxypropyl, dimethoxypropyl, isopropyl, trifluoroisopropyl, methoxyisopropyl, cyclopropyl, cyanocyclopropyl, cyclobutyl, fluorocyclobutyl, difluorocyclobutyl, difluorocyclopentyl, difluorocyclohexyl, acetylazetidinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form difluoroazetidin-1-yl, hydroxyazetidin-1-yl, methoxyazetidin-1-yl, pyrrolidin-1-yl, difluoropyrrolidin-1-yl, piperidin-1-yl, difluoropiperidin-1-yl, hydroxypiperidin-1-yl, methoxypiperidin-1-yl, methylpiperazinon-1-yl, morpholin-4-yl, methylmorpholin-4-yl, dimethylmorpholin-4-yl, 1,2-oxazepan-2-yl, 1,3-oxazepan-3-yl, or 1,4-oxazepan-4-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 3-oxo-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, or 2-oxazolyl-7-azaspiro[3.5]nonan-7-yl.
7. The compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, NO.sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, and S(O).sub.2C.sub.1-6 alkyl; and Y.sub.2 is H, methyl, cyclopropylmethyl, (tetrahydrofuran-2-yl)methyl, (3-methyloxetanyl)methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-trifluoromethoxyethyl, 1,1,1-trifluoropropyl, 2,2-difluoro-3-hydroxypropyl, 3-cyanopropyl, 3-methoxypropyl, 1-methoxy-2-methylprop-2-yl, isopropyl, 1,1,1-trifluoroisopropyl, 1-methoxyisopropyl, 1,3-dimethoxyisopropyl, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 3,3-difluorocyclopentyl, bicyclo[1.1.1]pentan-1-yl, 4,4-difluorocyclohexyl, 1-acetylazetidin-3-yl, oxetan-3-yl, 3-methyloxetanyl, tetrahydrofuran-3-yl, or tetrahydro-2H-pyran-4-yl; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form 3,3-difluoroazetidin-1-yl, 3-hydroxyazetidin-1-yl, 3-methoxyazetidin-1-yl, pyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, piperidin-1-yl, 4.4-difluoropiperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-methoxypiperidin-1-yl, 4-methyl-3-oxopiperazin-1-yl, morpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl, 1,4-oxazepan-4-yl, (1S,4S)-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 2-oxa-6-azaspiro[30.3]heptan-6-yl, or 2-oxazolyl-7-azaspiro[3.5]nonan-1-yl.
8. The compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: A is a 6-membered heteroarylene; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; and wherein the 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; R.sub.1 is C.sub.1-6 alkylene-OC.sub.1-6 alkyl, wherein the C.sub.1-6 alkylene-OC.sub.1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; Y is NY.sub.1Y.sub.2 or OH; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, or 5 independently selected OC.sub.1-6 alkyl substituents; and Y.sub.2 is H, C.sub.1-6 alkyl, cycloalkyl, or heterocycloalkyl; wherein the C.sub.1-6 alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, acyl, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, cyclopropyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; or Y.sup.1 and Y.sup.2; taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O.
9. The compound as defined in claim 1, or a pharmaceutically acceptable, salt, stereoisomer, or tautomer thereof, wherein: A is a 6-membered heteroarylene; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; and wherein the 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; R.sub.1 is C.sub.1-6 alkylene-OC.sub.1-6 alkyl, wherein the C.sub.1-6 alkylene-OC.sub.1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; Y is NY.sub.1Y.sub.2 or OH; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected OC.sub.1-6 alkyl substituents; and Y.sub.2 is H, C.sub.1-6 alkyl, cycloalkyl, or heterocycloalkyl; wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, cyclopropyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein the cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and CN; wherein the heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected acyl substituents; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; or Y.sup.1 and taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O.
10. The compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: A is a 6-membered heteroarylene; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; and wherein the 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; R.sub.1 is C.sub.1-6 alkylene-OC.sub.1-6 alkyl, wherein the C.sub.1-6 alkylene-OC.sub.1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; Y is NY.sub.1Y.sub.2; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected OC.sub.1-6 alkyl substituents; and Y.sub.2 is C.sub.1-6 alkyl, cycloalkyl, or heterocycloalkyl; wherein the C.sub.1-6 alkyl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of CN, OH, OC.sub.1-6 alkyl, cyclopropyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein the cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and CN; wherein the heterocycloalkyl is optionally substituted by 1 or 2 independently selected acyl substituents; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O.
11. The compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: A is a 6-membered heteroarylene; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; and wherein the 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; R.sub.1 is C.sub.1-6 alkylene-OC.sub.1-6 alkyl, wherein the C.sub.1-6 alkylene-OC.sub.1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; Y is NY.sub.1Y.sub.2; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected OC.sub.1-6 alkyl substituents; and Y.sub.2 is C.sub.1-6 alkyl or heterocycloalkyl; wherein the C.sub.1-6 alkyl is optionally substituted by 1 substituent selected from the group consisting of OH, OC.sub.1-6 alkyl, cyclopropyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted by 1 acyl substituents; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 6- to 9-membered heterocyclyl; or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of C.sub.1-6 alkyl and ═O.
12. The compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: A is a 6-membered heteroarylene; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; and wherein the 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; R.sub.1 is C.sub.1-6 alkylene-OC.sub.1-6 alkyl, wherein the C.sub.1-6 alkylene-OC.sub.1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; Y is NY.sub.1Y.sub.2; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected OC.sub.1-6 alkyl substituents; and Y.sub.2 is C.sub.1-6 alkyl; wherein the C.sub.1-6 alkyl is optionally substituted by 1 substituent selected from the group consisting of OH, OC.sub.1-6 alkyl, and cyclopropyl; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of C.sub.1-6 alkyl and ═O.
13. The compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Z is a 5-membered heteroarylene, wherein the 5-membered heteroarylene contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; A is a 6-membered heteroarylene; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; and wherein the 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; R.sub.1 is C.sub.1-6 alkylene-OC.sub.1-6 alkyl, wherein the C.sub.1-6 alkylene-OC.sub.1-6 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; Y is NY.sub.1Y.sub.2 or OH; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected OC.sub.1-6 alkyl substituents; and Y.sub.2 is H, C.sub.1-6 alkyl, cycloalkyl, or heterocycloalkyl; wherein the C.sub.1-6 alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, acyl, OH, OC.sub.1-4 alkyl, OC.sub.1-6 haloalkyl, cyclopropyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a 4- to 7-membered heterocycloalkenyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O.
14. The compound as defined in claim 13, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: A is a 6-membered heteroarylene, wherein the 6-membered heteroarylene contains 1 N heteroatom; Y is NY.sub.1Y.sub.2; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected OC.sub.1-6 alkyl substituents; Y.sub.2 is H, C.sub.1-6 alkyl, cycloalkyl, or heterocycloalkyl; wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, cyclopropyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein the cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and CN; wherein the heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected acyl substituents; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O.
15. The compound as defined in claim 14, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected OC.sub.1-6 alkyl substituents; and Y.sub.2 is C.sub.1-6 alkyl, cycloalkyl, or heterocycloalkyl; wherein the C.sub.1-6 alkyl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of CN, OH, OC.sub.1-6 alkyl, cyclopropyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein the cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and CN; wherein the heterocycloalkyl is optionally substituted by 1 or 2 independently selected acyl substituents; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O.
16. The compound as defined in claim 15, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Y.sub.2 is C.sub.1-6 alkyl; wherein the C.sub.1-6 alkyl is substituted by 1 substituent selected from the group consisting of OH, OC.sub.1-6 alkyl, and cyclopropyl.
17. The compound as defined in claim 14, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected OC.sub.1-6 alkyl substituents; and Y.sub.2 is C.sub.1-6 alkyl or heterocycloalkyl; wherein the C.sub.1-6 alkyl is substituted by 1 substituent selected from the group consisting of halogen, CN, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, cyclopropyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted by 1 acyl substituent; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of C.sub.1-6 alkyl and ═O.
18. The compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Z is a 5-membered heteroarylene, wherein the 5-membered heteroarylene contains 2 heteroatoms independently selected from the group consisting of N, O, and S; A is pyridinylene; R.sub.1 is C.sub.1-3 alkylene-OC.sub.1-3 alkyl, wherein the C.sub.1-3 alkylene-OC.sub.1-3 alkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; Y is NY.sub.1Y.sub.2; Y.sub.1 is H or C.sub.1-3 alkyl, wherein the C.sub.1-3 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of OH, OC.sub.1-3 alkyl, and OC.sub.1-6 haloalkyl; and Y.sub.2 is H, C.sub.1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, or a 4- to 6-membered heterocycloalkyl; wherein the 4- to 6-membered heterocycloalkyl contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein the C.sub.1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, or 4- to 6-membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of F, Cl, Br, I, C(O)C.sub.1-3 alkyl, OC.sub.1-3 alkyl, OC.sub.1-3 fluoroalkyl, OC.sub.1-3 chloroalkyl, OC.sub.1-3 bromoalkyl, OC.sub.1-3 iodoalkyl, oxetanyl, and tetrahydrofuranyl; wherein each oxetanyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; and wherein each tetrahydrofuranyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 7- to 9-membered heterocyclyl, a bicyclic, bridged 7-membered heterocyclyl, or a tricyclic, bridged 7-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 7- to 9-membered heterocyclyl, bicyclic, bridged 7-membered heterocyclyl, or tricyclic, bridged 7-membered heterocyclyl optionally contains 1 or 2 additional heteroatoms independently selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 7- to 9-membered heterocyclyl, bicyclic, bridged 7-membered heterocyclyl, or tricyclic, bridged 7-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of F, Cl, Br, I, C.sub.1-3 alkyl, and OC.sub.1-3 alkyl.
19. The compound as defined in claim 18, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Z is isoxazolylene; A is 2,5-pyridinylene; R.sub.1 is C.sub.1-3 alkylene-OC.sub.1-3 alkyl; Y.sub.1 is H or C.sub.1-3 alkyl, wherein the C.sub.1-3 alkyl is optionally substituted by 1 or 2 independently selected OC.sub.1-3 alkyl substituents; and Y.sub.2 is H, C.sub.1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentan-1-yl, azetidinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; wherein the C.sub.1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, azetidinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of F, C(O)CH.sub.3, OC.sub.1-3 alkyl, OC.sub.1-3 fluoroalkyl, oxetan-3-yl, and tetrahydrofuran-3-yl; wherein each oxetan-3-yl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; and wherein each tetrahydrofuran-3-yl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form azetidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, 1,4-oxazepin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, or (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, wherein the azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, 1,4-oxazepin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, or (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of F, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, and OCH(CH.sub.3).sub.2.
20. The compound as defined in claim 19, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Z is 3,5-isoxazolylene; A is 2,5-pyridinylene, wherein the 2,5-pyridinylene is bonded to —CH.sub.2— at the 2-position and bonded to —C(O)— at the 5-position; R.sub.1 is CH.sub.2OCH.sub.3; Y.sub.1 is H, CH.sub.3, or CH.sub.2CH.sub.3, wherein the CH.sub.3 or CH.sub.2CH.sub.3 is optionally substituted by 1 or 2 OCH.sub.3 substituents; and Y.sub.2 is CH.sub.3, cyclopropyl, cyclobutyl, azetidin-3-yl, oxetan-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl, wherein the CH.sub.3, cyclopropyl, cyclobutyl, azetidin-3-yl, oxetan-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of F, OCH.sub.3, OCH.sub.2F, OCHF.sub.2, OCF.sub.3, and 3-methyloxetan-3-yl; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, 1,4-oxazepin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, or (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, wherein the azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, 1,4-oxazepin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, or (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of CH.sub.3 and OCH.sub.3.
21. The compound as defined in claim 20, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Z is 3,5-isoxazolylene, wherein the 3,5-isoxazolylene is bonded to the [1,2,4]triazolo[3,4-a]phthalazinyl ring at the 3-position and bonded to R.sup.1 at the 5-position; Y.sub.1 is H, CH.sub.3, CH.sub.2CH.sub.3, or CH.sub.2CH.sub.2OCH.sub.3; and Y.sub.2 is CH.sub.3, cyclopropyl, cyclobutyl, azetidin-3-yl, oxetan-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl, wherein the CH.sub.3, cyclopropyl, cyclobutyl, azetidin-3-yl, oxetan-3-yl, tetrahydrofuran-3-yl, or tetrahydropyran-4-yl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of F, OCH.sub.3, OCF.sub.3, and 3-methyloxetan-3-yl.
22. The compound as defined in claim 1, wherein the compound is represented by formula II: ##STR00180## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: A is pyridinylene; Y is NY.sub.1Y.sub.2; Y.sub.1 is H, CH.sub.3, or CH.sub.2OCH.sub.3; and Y.sub.2 is C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, or heterocycloalkyl; wherein the heterocycloalkyl contains 1 N heteroatom; wherein the C.sub.1-6 alkyl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of CN, OH, OC.sub.1-6 alkyl, cyclopropyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted by 1 acyl substituent; wherein each 4-membered heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein each C.sub.4-6 heterocycloalkyl substituent independently contains 1 heteroatom selected from the group consisting of N and O; and wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 additional heteroatom selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O.
23. The compound as defined in claim 1, wherein the compound is represented by formula III: ##STR00181## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Y is NY.sub.1Y.sub.2 or OH; Y.sub.1 is H, CH.sub.3, CH(OCH.sub.3)CH.sub.3, or CH.sub.2CH.sub.2OCH.sub.3; and Y.sub.2 is H, methyl, cyclopropylmethyl, oxetanylmethyl, (methyloxetanyl)methyl, tetrahydrofuranylmethyl, ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, hydroxyethyl, methoxyethyl, trifluoromethoxyethyl, cyanopropyl, trifluoropropyl, difluorohydroxypropyl, methoxypropyl, dimethoxypropyl, isopropyl, trifluoroisopropyl, methoxyisopropyl, cyclopropyl, cyanocyclopropyl, cyclobutyl, fluorocyclobutyl, difluorocyclobutyl, difluorocyclopentyl, difluorocyclohexyl, acetylazetidinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form difluoroazetidin-1-yl, hydroxyazetidin-1-yl, methoxyazetidin-1-yl, pyrrolidin-1-yl, difluoropyrrolidin-1-yl, piperidin-1-yl, difluoropiperidin-1-yl, hydroxypiperidin-1-yl, methoxypiperidin-1-yl, methylpiperazinon-1-yl, morpholin-4-yl, methylmorpholin-4-yl, dimethylmorpholin-4-yl, 1,2-oxazepan-2-yl, 1,3-oxazepan-3-yl, or 1,4-oxazepan-4-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 3-oxo-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, or 2-oxazolyl-7-azaspiro[3.5]nonan-7-yl.
24. The compound as defined in claim 1, wherein the compound is represented by formula III: ##STR00182## or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Y is NY.sub.1Y.sub.2 or OH; Y.sub.1 is H, CH.sub.3, or CH.sub.2CH.sub.2OCH.sub.3; and Y.sub.2 is H, methyl, cyclopropylmethyl, (tetrahydrofuran-2-yl)methyl, (3-methyloxetanyl)methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-trifluoromethoxyethyl, 1,1,1-trifluoropropyl, 2,2-difluoro-3-hydroxypropyl, 3-cyanopropyl, 3-methoxypropyl, 1-methoxy-2-methylprop-2-yl, isopropyl, 1,1,1-trifluoroisopropyl, 1-methoxyisopropyl, 1,3-dimethoxyisopropyl, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 3,3-difluorocyclopentyl, bicyclo[1.1.1]pentan-1-yl, 4,4-difluorocyclohexyl, 1-acetylazetidin-3-yl, oxetan-3-yl, 3-methyloxetanyl, tetrahydrofuran-3-yl, or tetrahydro-2H-pyran-4-yl; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form 3,3-difluoroazetidin-1-yl, 3-hydroxyazetidin-1-yl, 3-methoxyazetidin-1-yl, pyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, piperidin-1-yl, 4.4-difluoropiperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-methoxypiperidin-1-yl, 4-methyl-3-oxopiperazin-1-yl, morpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl, 1,4-oxazepan-4-yl, (1S,4S)-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, or 2-oxazolyl-7-azaspiro[3.5]nonan-1-yl.
25. The compound as defined in claim 1, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of: ##STR00183## ##STR00184## ##STR00185## ##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195## ##STR00196## ##STR00197## or a pharmaceutically acceptable salt or tautomer thereof.
26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or adjuvant and a compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
27. A method for modulating α5-GABA.sub.A receptor in vivo, in vitro, or ex vivo, wherein the method comprises contacting the α5-GABA.sub.A receptor with a compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
28. A method for modulating α5-GABA.sub.A receptor activity in a patient, wherein the method comprises administering to the patient in need thereof an effective dose of a compound as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
29. The method as defined in claim 28, wherein the patient has a disease or disorder selected from the group consisting of amyotrophic lateral sclerosis, attention deficit disorder, a cognitive disease, a cognitive deficiency, Down's syndrome, drug addiction, multi-infarct dementia, pain, restless leg syndrome, and stroke.
30. The method as defined in claim 29, wherein the cognitive disease or cognitive deficiency is Alzheimer's disease or dysmnesia.
31. The method as defined in claim 29, wherein the pain is selected from the group consisting of abdominal pain, arthritis pain, autonomic nerve reflex pain, back pain, bone pain, boniness pain, cancer pain, cervix radiculopathy, chronic pain caused by injury, chronic pain caused by surgery, degenerative osteoarthropathy pain, dorsopathy, facial pain, glossopharyngeal neuralgia, gout, headache, inflammatory pain, lower limb pain, muscle pain, neck pain, nerve root avulsion pain, neuropathic pain, nociceptive pain, nutrition deficiency pain, painful diabetes, reflex sympathetic dystrophy pain, shoulder pain, thoracic pain, toxin pain, trigeminal neuralgia, vascular pain, visceral pain, waist pain, waist radiculopathy, pain associated with an autoimmune disease, pain associated with inflammation, pain associated with multiple sclerosis, pain associated with sickle cell anemia, and pain caused by an infectious disease.
32. The method as defined in claim 31, wherein the chronic pain caused by injury is chemical injury pain.
33. The method as defined in claim 31, wherein the pain caused by an infectious disease is pain caused by a bacterial infectious disease or pain caused by a viral infectious disease.
34. A process for preparing a compound represented by formula II: ##STR00198## wherein: A is phenylene, a 5-membered heteroarylene, or a 6-membered heteroarylene; wherein the 5-membered heteroarylene contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; wherein at most 1 of the heteroatoms of the 5-membered heteroarylene is O or S; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; wherein the phenylene is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, linear C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl; and wherein the 5-membered heteroarylene or 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; each R.sub.x is independently halogen, CN, C(O)OR.sub.1, OH, OC(O)R.sub.1, ORI, or R.sub.1; R.sub.1 is C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl, wherein the C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; Y is NY.sub.1Y.sub.2, NHNY.sub.3Y.sub.4, or OH; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, and S(O).sub.2C.sub.1-6 alkyl; Y.sub.2 is H, C.sub.1-6 alkyl, NH.sub.2, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2NH.sub.2, cycloalkyl, heterocycloalkyl, or heteroaryl; heteroaryl; wherein the C.sub.1-6 alkyl, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylene-C(O)OH, C.sub.1-6 alkylene-C(O)OC.sub.1-4 alkyl, C.sub.1-6 alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, acyl, NHC.sub.1-6 alkyl, NHacyl, N(C.sub.1-6 alkyl).sub.2, NO.sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, S(O).sub.2C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein each C.sub.3-6 cycloalkyl substituent is optionally and independently substituted by 1 or more OH substituents; wherein each 4-membered heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; and wherein each C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of halogen, CH.sub.3, and OCH.sub.3; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a 4- to 7-membered heterocycloalkenyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 or more additional heteroatoms independently selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; Y.sub.3 is H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; and Y.sub.4 is H, C.sub.1-4 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; or Y.sup.3 and Y.sup.4, taken together with the N atom to which they are attached, form a heterocyclyl, wherein the heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; with the proviso that if A is pyridinylene, then the pyridinylene is optionally an N-oxide thereof; wherein the process comprises the following steps: 1) reacting a compound represented by formula B: ##STR00199## wherein: G is Cl, Br, I, OH, OMs, OTf, or OTs; with a compound represented by formula IV: ##STR00200## wherein: A is phenylene, a 5-membered heteroarylene, or a 6-membered heteroarylene; wherein the 5-membered heteroarylene contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; wherein at most 1 of the heteroatoms of the 5-membered heteroarylene is O or S; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; wherein the phenylene is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, linear C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl; and wherein the 5-membered heteroarylene or 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; each R.sub.x is independently halogen, CN, C(O)OR.sub.1, OH, OC(O)R.sub.1, OR.sub.1, or R.sub.1; R.sub.1 is C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl, wherein the C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; W is Cl, Br, I, OH, OMs, OTf, or OTs; and R.sub.5 is alkyl or benzyl; (a) in the presence of a base selected from the group consisting of lithium diisopropyl amide (LDA), sodium hydride, potassium tert-butoxide, or sodium tert-butoxide in a solvent selected from the group consisting of N,N-dimethylformamide, dioxane, and tetrahydrofuran, or (b) under Mitsunobu conditions comprising (i) triphenyl phosphine, (ii) diethyl azodicarboxylate (DEAD), and (iii) a phase transfer catalyst selected from the group consisting of a crown ether and tetrabutylammoniun bromide (TBAB), to provide a compound represented by formula 1-3: ##STR00201## wherein: A is phenylene, a 5-membered heteroarylene, or a 6-membered heteroarylene; wherein the 5-membered heteroarylene contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; wherein at most 1 of the heteroatoms of the 5-membered heteroarylene is O or S; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; wherein the phenylene is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, linear C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl; and wherein the 5-membered heteroarylene or 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; each R.sub.x is independently halogen, CN, C(O)OR.sub.1, OH, OC(O)R.sub.1, OR.sub.1, or R.sub.1; R.sub.1 is C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl, wherein the C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; and R.sub.5 is alkyl or benzyl; 2) reacting the compound represented by formula 1-3 above (a) with aqueous sodium hydroxide, (b) with sodium hydroxide or lithium hydroxide in a solvent selected from the group consisting of tetrahydrofuran and water, or a mixture thereof, or (c) under hydrogenation conditions, to provide a compound represented by formula 1-4: ##STR00202## wherein: A is phenylene, a 5-membered heteroarylene, or a 6-membered heteroarylene; wherein the 5-membered heteroarylene contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; wherein at most 1 of the heteroatoms of the 5-membered heteroarylene is O or S; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; wherein the phenylene is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, linear C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl; and wherein the 5-membered heteroarylene or 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; each R.sub.x is independently halogen, CN, C(O)OR.sub.1, OH, OC(O)R.sub.1, OR.sub.1, or R.sub.1; R.sub.1 is C.sub.1-6 alkylene-NHC.sub.3-6 alkyl, C.sub.3-6 alkylene-OC.sub.1-6 alkyl, C.sub.3-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl, wherein the C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; and 3) reacting the compound represented by formula 1-4 above with a compound represented by the following formula:
Y—H wherein: Y is NY.sub.1Y.sub.2, NHNY.sub.3Y.sub.4, or OH; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, and S(O).sub.2C.sub.1-6 alkyl; Y.sub.2 is H, C.sub.1-6 alkyl, NH.sub.2, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2NH.sub.2, cycloalkyl, heterocycloalkyl, or heteroaryl; heteroaryl; wherein the C.sub.1-6 alkyl, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylene-C(O)OH, C.sub.1-6 alkylene-C(O)OC.sub.1-4 alkyl, C.sub.1-6 alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, acyl, NHC.sub.1-6 alkyl, NHacyl, N(C.sub.1-6 alkyl).sub.2, NO.sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, S(O).sub.2C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein each C.sub.3-6 cycloalkyl substituent is optionally and independently substituted by 1 or more OH substituents; wherein each 4-membered heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; and wherein each C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of halogen, CH.sub.3, and OCH.sub.3; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a 4- to 7-membered heterocycloalkenyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 or more additional heteroatoms independently selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; Y.sub.3 is H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; and Y.sub.4 is H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; or Y.sup.3 and Y.sup.4 taken together with the N atom to which they are attached, form a heterocyclyl, wherein the heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; in the presence of (a) N,N-diisopropylethylamine (Hunig's base) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate in a solvent, (b) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N′-hydroxybenzotriazole, and N,N-diisopropylethylamine (Hunig's base) in a solvent, or (c) 1,1′-carbonyldiimidazole in a solvent, to provide the compound represented by formula II above.
35. A process for preparing a compound represented by formula ##STR00203## wherein: A is phenylene, a 5-membered heteroarylene, or a 6-membered heteroarylene; wherein the 5-membered heteroarylene contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; wherein at most 1 of the heteroatoms of the 5-membered heteroarylene is O or S; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; wherein the phenylene is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, linear C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl; and wherein the 5-membered heteroarylene or 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; each R.sub.x is independently halogen, CN, C(O)OR.sub.1, OH, OC(O)R.sub.1, OR.sub.1, or R.sub.1; R.sub.1 is C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl, wherein the C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl is optionally substituted by 0.1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; Y is NY.sub.1Y.sub.2, NHNY.sub.3Y.sub.4, or OH; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, and S(O).sub.2C.sub.1-6 alkyl; Y.sub.2 is H, C.sub.1-6 alkyl, NH.sub.2, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2NH.sub.2, cycloalkyl, heterocycloalkyl, or heteroaryl; heteroaryl; wherein the C.sub.1-6 alkyl, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylene-C(O)OH, C.sub.1-6 alkylene-C(O)OC.sub.1-4 alkyl, C.sub.1-6 alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, acyl, NHC.sub.1-6 alkyl, NHacyl, N(C.sub.1-6 alkyl).sub.2, NO.sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, S(O).sub.2C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein each C.sub.3-6 cycloalkyl substituent is optionally and independently substituted by 1 or more OH substituents; wherein each 4-membered heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; and wherein each C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of halogen, CH.sub.3, and OCH.sub.3; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a 4- to 7-membered heterocycloalkenyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 or more additional heteroatoms independently selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; Y.sub.3 is H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; and Y.sub.4 is H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; or Y.sup.3 and Y.sup.4, taken together with the N atom to which they are attached, form a heterocyclyl, wherein the heterocyclyl is optionally substituted by 1, 2, 3; or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; with the proviso that if A is pyridinylene, then the pyridinylene is optionally an N-oxide thereof; wherein the process comprises the following steps: 1) reacting a compound represented by formula B: ##STR00204## wherein: G is Cl, Br, I, OH, OMs, OTf, or OTs; with a compound represented by formula IV: ##STR00205## wherein: A is phenylene, a 5-membered heteroarylene, or a 6-membered heteroarylene; wherein the 5-membered heteroarylene contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; wherein at most 1 of the heteroatoms of the 5-membered heteroarylene is O or S; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; wherein the phenylene is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, linear C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl; and wherein the 5-membered heteroarylene or 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; each R.sub.x is independently halogen, CN, C(O)OR.sub.1, OH, OC(O)R.sub.1, OR.sub.1, or R.sub.1; R.sub.1 is C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl, wherein the C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; W is Cl, Br, I, OH, OMs, OTf, or OTs; and R.sub.5 is alkyl or benzyl; (a) in the presence of a base selected from the group consisting of lithium diisopropyl amide (LDA), sodium hydride, potassium tert-butoxide, or sodium tert-butoxide in a solvent selected from the group consisting of N,N-dimethylformamide, dioxane, and tetrahydrofuran, or (b) under Mitsunobu conditions comprising (i) biphenyl phosphine, (ii) diethyl azodicarboxylate (DEAD), and (iii) a phase transfer catalyst selected from the group consisting of a crown ether and tetrabutylammoniun bromide (TBAB), to provide a compound represented by formula 1-3: ##STR00206## wherein: A is phenylene, a 5-membered heteroarylene, or a 6-membered heteroarylene; wherein the 5-membered heteroarylene contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; wherein at most 1 of the heteroatoms of the 5-membered heteroarylene is O or S; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; wherein the phenylene is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, linear C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl; and wherein the 5-membered heteroarylene or 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; each R.sub.x is independently halogen, CN, C(O)OR.sub.1, OH, OC(O)R.sub.1, OR.sub.1, or R.sub.1; R.sub.1 is C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl, wherein the C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; and R.sub.5 is alkyl or benzyl; and 2) reacting the compound represented by formula 1-3 above (a) with aqueous sodium hydroxide, (b) with sodium hydroxide or lithium hydroxide in a solvent selected from the group consisting of tetrahydrofuran and water, or a mixture thereof, or (c) under hydrogenation conditions, to provide the compound represented by formula II above.
36. A process for preparing a compound represented by formula II: ##STR00207## wherein: A is phenylene, a 5-membered heteroarylene, or a 6-membered heteroarylene; wherein the 5-membered heteroarylene contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; wherein at most 1 of the heteroatoms of the 5-membered heteroarylene is O or S; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; wherein the phenylene is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, linear C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl; and wherein the 5-membered heteroarylene or 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; each R.sub.x is independently halogen, CN, C(O)OR.sub.1, OH, OC(O)R.sub.1, OR.sub.1, or R.sub.1; R.sub.1 is C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl, wherein the C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; Y is NY.sub.1Y.sub.2, NHNY.sub.3Y.sub.4, or OH; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, and S(O).sub.2C.sub.1-6 alkyl; Y.sub.2 is H, C.sub.1-6 alkyl, NH.sub.2, OC.sub.1-6alkyl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2NH.sub.2, cycloalkyl, heterocycloalkyl, or heteroaryl; heteroaryl; wherein the C.sub.1-6 alkyl, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylene-C(O)OH, C.sub.1-6 alkylene-C(O)OC.sub.1-4 alkyl, C.sub.1-6 alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, acyl, NHC.sub.1-6 alkyl, NHacyl, N(C.sub.1-6 alkyl).sub.2, NO.sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, S(O).sub.2C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein each C.sub.3-6 cycloalkyl substituent is optionally and independently substituted by 1 or more OH substituents; wherein each 4-membered heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; and wherein each 04.6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of halogen, CH.sub.3, and OCH.sub.3; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a 4- to 7-membered heterocycloalkenyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 or more additional heteroatoms independently selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; Y.sub.3 is H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; and Y.sub.4 is H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; or Y.sup.3 and Y.sup.4, taken together with the N atom to which they are attached, form a heterocyclyl, wherein the heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; with the proviso that if A is pyridinylene, then the pyridinylene is optionally an N-oxide thereof; wherein the process comprises the following step: 1) reacting a compound represented by formula B: ##STR00208## wherein: G is Cl, Br, I, OH, OMs, OTf, or OTs; with a compound represented by formula V: ##STR00209## wherein: A is phenylene, a 5-membered heteroarylene, or a 6-membered heteroarylene; wherein the 5-membered heteroarylene contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; wherein at most 1 of the heteroatoms of the 5-membered heteroarylene is O or S; wherein the 6-membered heteroarylene contains 1, 2, or 3 N heteroatoms; wherein the phenylene is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, linear C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.3-6 cycloalkyl; and wherein the 5-membered heteroarylene or 6-membered heteroarylene is optionally substituted by 1 or more independently selected R.sub.x substituents; each R.sub.x is independently halogen, CN, C(O)OR.sub.1, OH, OC(O)R.sub.1, OR.sub.1, or R.sub.1; R.sub.1 is C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl, wherein the C.sub.1-6 alkylene-NHC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-6 alkylene-OC.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, C.sub.1-6 alkylene-C.sub.3-6 heterocycloalkyl, OC.sub.1-6 haloalkyl, OC.sub.1-6 alkylene-C.sub.3-6 cycloalkyl, or C.sub.3-6 heterocycloalkyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and ═O; W is Cl, Br, I, OH, OMs, OTf, or OTs; and Y is NY.sub.1Y.sub.2, NHNY.sub.3Y.sub.4, or OH; Y.sub.1 is H or C.sub.1-6 alkyl, wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, and S(O).sub.2C.sub.1-6 alkyl; Y.sub.2 is H, C.sub.1-6 alkyl, NH.sub.2, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, S(O).sub.2NH.sub.2, cycloalkyl, heterocycloalkyl, or heteroaryl; heteroaryl; wherein the C.sub.1-6 alkyl, OC.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylene-C(O)OH, C.sub.1-6 alkylene-C(O)OC.sub.1-4 alkyl, C.sub.1-6 alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6 alkyl, acyl, NHC.sub.1-6 alkyl, NHacyl, N(C.sub.1-6 alkyl).sub.2, NO.sub.2, OH, OC.sub.1-6 alkyl, OC.sub.1-6 haloalkyl, S(O).sub.2C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 4-membered heterocycloalkyl, and C.sub.4-6 heterocycloalkyl; wherein each 4-membered heterocycloalkyl and C.sub.4-6 heterocycloalkyl substituent independently contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; wherein each C.sub.3-6 cycloalkyl substituent is optionally and independently substituted by 1 or more OH substituents; wherein each 4-membered heterocycloalkyl substituent is optionally and independently substituted by 1 or more CH.sub.3 substituents; and wherein each C.sub.4-6 heterocycloalkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of halogen, CH.sub.3, and OCH.sub.3; or Y.sup.1 and Y.sup.2, taken together with the N atom to which they are attached, form a 4- to 7-membered heterocycloalkyl, a 4- to 7-membered heterocycloalkenyl, a spirocyclic 6- to 9-membered heterocyclyl, or a bridged 6- to 9-membered heterocyclyl; wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl optionally contains 1 or more additional heteroatoms independently selected from the group consisting of N and O; and wherein the 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, spirocyclic 6- to 9-membered heterocyclyl, or bridged 6- to 9-membered heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; Y.sub.3 is H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; and Y.sub.4 is H, C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl, wherein the C.sub.1-6 alkyl, S(O).sub.2C.sub.1-6 alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, and OC.sub.1-6 alkyl; or Y.sup.3 and Y.sup.4, taken together with the N atom to which they are attached, form a heterocyclyl, wherein the heterocyclyl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, C.sub.1-6 alkyl, OH, OC.sub.1-6 alkyl, and ═O; (a) in the presence of a base selected from the group consisting of lithium diisopropyl amide (LDA), sodium hydride, potassium tert-butoxide, or sodium tert-butoxide in a solvent selected from the group consisting of N,N-dimethylformamide, dioxane, and tetrahydrofuran, or (b) under Mitsunobu conditions comprising (i) triphenyl phosphine, (ii) diethyl azodicarboxylate (DEAD), and (iii) a phase transfer catalyst selected from the group consisting of a crown ether and tetrabutylammonium bromide (TBAB), optionally in the presence of a base or, catalyst, to provide the compound represented by formula II above.
Description
DETAILED DESCRIPTION
Preparation Example 1
(1) ##STR00094##
3-(6-chloro-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)-5-(methoxymethyl)isoxazole (B-2)
(2) B-1 (0.8 g, 4 mmol) (CAS: 4752-10-7) and A-1 (0.75 g, CAS: 625120-12-9) were mixed in DMF (10 mL) and stirred at 90° C. for 1 hour. TLC showed the complete consumption of the starting materials, and the mixture was cooled to room temperature and poured into ice water (100 mL). The resulting precipitate was collected by filtration, washed with water for 3 times, and dried to give product B-2 (1 g crude) as a light yellow solid.
Preparation Example 2
methyl 6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinate (B-3)
(3) B-2 (1 g crude), A-2 (CAS: 56026-36-9) (0.53 g, 3.2 mmol) and cesium carbonate (2.1 g, 6.4 mmol) were mixed in DMF (20 mL) and stirred at room temperature for 16 hours. TLC showed that the complete consumption of the starting materials, and the mixture was poured into ice water (200 mL). The resulting precipitate was collected by filtration, washed with water for 3 times, and dried to give product B-3 (0.93 g crude) as a light brown solid.
Example 1
6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinic acid (01)
(4) Lithium hydroxide (4.96 g, 95.29 mmol) was dissolved in 60 mL of water, and then added into a suspension of B-3 (8.5 g, 19.06 mmol) in methanol (150 mL) and stirred for 3 hours. The reaction solution was poured into water, and the pH value was adjusted to 4. The mixture was filtered by suction to give a yellow solid. The obtained yellow solid was slurried with ethanol, then slurried with methyl tert-butyl ether, and dried under suction with an oil pump to give a pale yellow powder (5.3 g, 64%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 13.42 (s, 1H), 9.10 (s, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.34-8.32 (m, 1H), 8.15-8.11 (m, 1H), 8.00-7.98 (m, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.15 (s, 1H), 5.80 (s, 2H), 4.71 (s, 2H), 3.39 (s, 3H). LCMS: Rt=3.059 min, [M+H].sup.+=432.
Example 2
N-ethyl-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinamide (02)
(5) ##STR00095##
(6) The experimental operation was as described in Preparation Example 2: compound B-2 and A-3 (refer to patent application WO2013/120438A) were reacted to give 81 mg of the target compound as an off-white solid with a yield of 46%.
(7) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.03 (d, J=1.71 Hz, 1H), 8.69 (t, J=5.35 Hz, 1H), 8.60 (d, J=7.86 Hz, 1H), 8.38 (d, J=7.99 Hz, 1H), 8.25 (dd, J=8.15, 2.17 Hz, 1H), 8.14 (m, 1H), 8.01 (m, 1H), 7.84 (d, J=8.15 Hz, 1H), 7.19 (s, 1H), 5.78 (s, 2H), 4.71 (s, 2H), 3.31-3.29 (m, 5H), 1.13 (t, J=7.20 Hz, 3H); LC-MS: m/z (ES+) for C.sub.23H.sub.21N.sub.7O.sub.4 460 [M+1].sup.+.
Example 3
N-(3,3-difluoro-cyclobutyl)-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinamide (03)
(8) ##STR00096##
(9) Compound 01 (50 mg crude), HOBt (24 mg, 0.18 mmol) and EDCI (34 mg, 0.18 mmol) were sequentially added into 2 mL of DMF, and 3,3-difluorocyclobutylamine hydrochloride (CAS: 637031-93-7) and then N,N-diisopropylethylamine (0.063 mL, 0.36 mmol) were sequentially added to the mixture. The resulting mixture was stirred at room temperature overnight. TLC (dichloromethane:methanol=20:1) showed the complete consumption of the raw materials. The mixture was poured into ice water (10 mL) and extracted 3 times with ethyl acetate/methanol (20:1, 15 mL). The combined organic layer was washed 3 times with water (20 mL), and 1 time with brine (20 mL), dried (anhydrous sodium sulfate) and evaporated. The residue was purified by preparative TLC (dichloromethane/methanol=20/1) to give the target compound as a pale yellow solid, 33.7 mg, yield 54%, the appearance was pale yellow solid.
(10) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.02 (s, 1H), 8.54 (d, J=6.70 Hz, 1H), 8.23 (dd, J=24.11, 6.77 Hz, 2H), 7.91 (s, 1H), 7.84-7.65 (m, 2H), 7.48 (s, 1H), 6.93 (s, 1H), 5.72 (s, 2H), 4.60 (s, 2H), 4.47 (s, 1H), 3.47 (s, 3H), 3.06 (s, 2H), 2.69 (d, J=5.72 Hz, 2H); LC-MS: m/z (ES+) for C.sub.25H.sub.21F.sub.2N.sub.7O.sub.4 522 [M+1].sup.+.
Example 4
6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-N-(tetrahydro-pyran-4-yl)-nicotinamide (04)
(11) ##STR00097##
(12) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 4-aminotetrahydropyran hydrochloride (CAS: 33024-60-1) gave 24 mg of the target compound as a yellow solid with a yield of 39%.
(13) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.95 (s, 1H), 8.63 (d, J=7.89 Hz, 1H), 8.30 (d, J=8.04 Hz, 1H), 8.24-8.13 (m, 1H), 7.97 (t, J=7.55 Hz, 1H), 7.83 (dd, J=18.12, 7.97 Hz, 2H), 7.18 (d, J=7.47 Hz, 1H), 7.04 (s, 1H), 5.77 (s, 2H), 4.67 (s, 2H), 4.24-4.09 (m, 1H), 3.97 (d, J=9.68 Hz, 2H), 3.59-3.40 (m, 5H), 1.94 (d, J=11.39 Hz, 2H), 1.59 (dq, J=12.16, 4.16 Hz, 2H); LC-MS: m/z (ES+) for C.sub.26H.sub.25N.sub.7O.sub.5 516 [M+1].sup.+.
Example 5
(S)—N-(2-methoxy-1-methyl-ethyl)-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinamide (05)
(14) ##STR00098##
(15) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and (S)-(+)-1-methoxy-2-propylamine (CAS: 99636-32-5) gave 18.3 mg of the target compound as a light yellow solid with a yield of 30%.
(16) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.00 (s, 1H), 8.69 (d, J=7.41 Hz, 1H), 8.32 (d, J=7.45 Hz, 1H), 8.15 (d, J=7.22 Hz, 1H), 7.97 (t, J=7.12 Hz, 1H), 7.89-7.73 (m, 2H), 7.05 (s, 1H), 6.49 (d, J=6.21 Hz, 1H), 5.80 (s, 2H), 4.70 (s, 2H), 4.51-4.25 (m, 1H), 3.68-3.50 (m, 3H), 3.50-3.42 (m, 2H), 3.38 (s, 3H), 1.36-1.28 (m, 3H); LC-MS: m/z (ES+) for C.sub.25H.sub.25N.sub.7O.sub.5 504 [M+1].sup.+.
Example 6
(S)-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-N-(tetrahydro-furan-2-ylmethyl)-nicotinamide (06)
(17) ##STR00099##
(18) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and (S)-(+)-tetrahydrofurfurylamino (CAS: 7175-81-7) gave 17.7 mg of the target compound as a light yellow solid with a yield of 29%.
(19) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.02 (s, 1H), 8.69 (d, J=6.06 Hz, 1H), 8.33 (d, J=5.78 Hz, 1H), 8.25-8.07 (m, 1H), 8.06-7.92 (m, 1H), 7.90-7.70 (m, 2H), 7.06 (s, 1H), 6.65 (s, 1H), 5.80 (s, 2H), 4.70 (s, 2H), 4.22-3.96 (m, 1H), 3.94-3.70 (m, 3H), 3.52 (s, 3H), 3.40-3.20 (m, 1H), 2.13-1.83 (m, 3H), 1.64-1.51 (m, 1H);
(20) LC-MS: m/z (ES+) for C.sub.26H.sub.25N.sub.7O.sub.5 516 [M+1].sup.+.
Example 7
N-(2-methoxy-ethyl)-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinamide (07)
(21) ##STR00100##
(22) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 2-methoxyethylamine (CAS: 109-85-3) gave 17.2 mg of the target compound as a light yellow solid with a yield of 29%.
(23) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.02 (s, 1H), 8.70 (d, J=7.79 Hz, 1H), 8.34 (d, J=7.68 Hz, 1H), 8.17 (d, J=7.14 Hz, 1H), 7.99 (t, J=7.48 Hz, 1H), 7.85 (t, J=7.65 Hz, 2H), 7.06 (s, 1H), 6.61 (s, 1H), 5.81 (s, 2H), 4.71 (s, 2H), 3.77-3.62 (m, 2H), 3.62-3.54 (m, 2H), 3.52 (s, 3H), 3.39 (s, 3H); LC-MS: m/z (ES+) for C.sub.24H.sub.23N.sub.7O.sub.5 490 [M+1].sup.+.
Example 8
6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-N-(3-methoxy-propyl)-nicotinamide (08)
(24) ##STR00101##
(25) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 3-methoxypropylamine (CAS: 5332-73-0) gave 9.2 mg of the target compound as an off-white solid with a yield of 13%.
(26) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.97 (d, J=1.66 Hz, 1H), 8.70 (d, J=7.93 Hz, 1H), 8.34 (d, J=8.03 Hz, 1H), 8.18 (dd, J=8.08, 2.07 Hz, 1H), 7.99 (t, J=7.52 Hz, 1H), 7.86 (m, 2H), 7.21-7.12 (m, 1H), 7.07 (s, 1H), 5.81 (s, 2H), 4.70 (s, 2H), 3.60 (td, J=8.60, 5.54 Hz, 4H), 3.39 (s, 3H), 3.52 (s, 3H), 1.96-1.82 (m, 2H); LC-MS: m/z (ES+) for C.sub.25H.sub.25N.sub.7O.sub.5 504 [M+1].sup.+.
Example 9
(R)—N-(2-methoxy-1-methyl-ethyl)-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinamide (09)
(27) ##STR00102##
(28) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and (R)-(−)-1-methoxy-2-propylamine (CAS: 99636-38-1) gave 29.6 mg of the target compound as an off-white solid with a yield of 42%.
(29) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.00 (d, J=1.04 Hz, 1H), 8.67 (d, J=7.90 Hz, 1H), 8.31 (d, J=8.03 Hz, 1H), 8.16 (dd, J=8.05, 1.91 Hz, 1H), 7.96 (t, J=7.48 Hz, 1H), 7.83 (t, J=8.13 Hz, 2H), 7.04 (s, 1H), 6.54 (d, J=7.68 Hz, 1H), 5.79 (s, 2H), 4.69 (s, 2H), 4.49-4.27 (m, 1H), 3.51 (s, 3H), 3.49 (d, J=3.91 Hz, 1H), 3.43 (dd, J=9.47, 4.03 Hz, 1H), 3.39 (s, 3H), 1.32-1.27 (m, 3H); LC-MS: m/z (ES+) for C.sub.25H.sub.25N.sub.7O.sub.5 504 [M+1].sup.+.
Example 10
N-(2-methoxy-1-methyl-ethyl)-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinamide (10)
(30) ##STR00103##
(31) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 1-methoxy-2-propylamine (CAS: 37143-54-7) gave 27.4 mg of the target compound as an off-white solid with a yield of 39%.
(32) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.00 (s, 1H), 8.68 (d, J=7.86 Hz, 1H), 8.32 (d, J=7.99 Hz, 1H), 8.21-8.10 (m, 1H), 7.97 (t, J=7.48 Hz, 1H), 7.84 (t, J=8.11 Hz, 2H), 7.05 (s, 1H), 6.52 (d, J=7.39 Hz, 1H), 5.79 (s, 2H), 4.69 (s, 2H), 4.38 (m, 1H), 3.52 (s, 3H), 3.38 (s, 3H), 3.43 (dd, J=9.46, 3.96 Hz, 1H), 3.51-3.48 (m, 1H), 1.30 (d, J=6.72 Hz, 3H); LC-MS: m/z (ES+) for C.sub.25H.sub.25N.sub.7O.sub.5 504 [M+1].sup.+.
Example 11
N-isopropyl-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinamide (11)
(33) ##STR00104##
(34) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and isopropylamine (CAS: 75-31-0) gave 13.3 mg of the target compound as a light yellow solid with a yield of 15%.
(35) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.97 (d, J=1.5 Hz, 1H), 8.68 (d, J=8.3 Hz, 1H), 8.32 (d, J=7.8 Hz, 1H), 8.16 (dd, J=2.2, 8.1 Hz, 1H), 7.98 (t, J=7.8 Hz, 1H), 7.90-7.76 (m, 2H), 7.04 (s, 1H), 6.16 (d, J=6.8 Hz, 1H), 5.79 (s, 2H), 4.70 (s, 2H), 4.30 (qd, J=6.7, 13.8 Hz, 1H), 3.57-3.45 (m, 3H), 1.28 (d, J=6.4 Hz, 6H); LC-MS: m/z (ES+) for C.sub.24H.sub.23N.sub.7O.sub.4 474 [M+1].sup.+.
Example 12
N-cyclopropyl-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinamide (12)
(36) ##STR00105##
(37) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and cyclopropylamine (CAS: 765-30-0) gave 29.0 mg of the target compound as a light yellow solid with a yield of 33%.
(38) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.94 (d, J=2.0 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.18-8.11 (m, 1H), 7.99 (t, J=7.8 Hz, 1H), 7.91-7.77 (m, 2H), 7.03 (s, 1H), 6.46 (br. s., 1H), 5.80 (s, 2H), 4.71 (s, 2H), 3.53 (s, 3H), 2.97-2.87 (m, 1H), 0.95-0.85 (m, 2H), 0.70-0.62 (m, 2H); LC-MS: m/z (ES+) for C.sub.24H.sub.21N.sub.7O.sub.4 472 [M+1].sup.+.
Example 13
6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-N-(2-trifluoromethoxy-ethyl)-nicotinamide (13)
(39) ##STR00106##
(40) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 2-(trifluoromethoxy)ethylamine hydrochloride (CAS: 886050-51-7) gave 34.7 mg of the target compound as a light yellow solid with a yield of 34.5%.
(41) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.01 (s, 1H), 8.68 (d, J=7.8 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.20 (dd, J=2.0, 8.3 Hz, 1H), 7.99 (t, J=7.3 Hz, 1H), 7.92-7.78 (m, 2H), 7.04 (s, 1H), 5.80 (s, 2H), 4.69 (s, 2H), 4.17 (t, J=5.1 Hz, 2H), 3.76 (q, J=4.9 Hz, 2H), 3.52 (s, 3H); LC-MS: m/z (ES+) for C.sub.24H.sub.20F.sub.3N.sub.7O.sub.5 544 [M+1].sup.+.
Example 14
N-(2-methoxy-1,1-dimethyl-ethyl)-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin 6-yloxymethyl]-nicotinamide (14)
(42) ##STR00107##
(43) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 1-methoxy-2-methyl-2-propylamine (CAS: 20719-68-0) gave 28.3 mg of the target compound as a light yellow solid with a yield of 30%.
(44) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.96 (s, 1H), 8.67 (d, J=7.8 Hz, 1H), 8.31 (d, J=8.3 Hz, 1H), 8.18-8.08 (m, 1H), 7.97 (t, J=7.6 Hz, 1H), 7.89-7.74 (m, 2H), 7.06 (s, 1H), 6.46 (br. s., 1H), 5.79 (s, 2H), 4.69 (s, 2H), 3.51 (s, 3H), 3.47-3.42 (m, 2H), 3.40 (s, 3H), 1.47 (s, 6H); LC-MS: m/z (ES+) for C.sub.27H.sub.27N.sub.7O.sub.5 530 [M+1].sup.+.
Example 15
6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylhydroxymethyl]-N-(2,2,2-trifluoroethyl)-nicotinamide (15)
(45) ##STR00108##
(46) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and trifluoroethylamine hydrochloride (CAS: 373-88-6) gave 16 mg of the target compound as a light yellow solid.
(47) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.35 (s, 1H), 9.08 (s, 1H), 8.58 (d, J=7.3 Hz, 1H), 8.37 (s, 1H), 8.30 (d, J=5.4 Hz, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.17 (s, 1H), 5.79 (s, 2H), 4.70 (s, 2H), 4.12 (s, 2H), 3.52 (s, 3H); LC-MS: m/z (ES+) for C.sub.23H.sub.18F.sub.3N.sub.7O.sub.4 514 [M+1].sup.+.
Example 16
N-(2-hydroxy-ethyl)-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinamide (16)
(48) ##STR00109##
(49) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and ethanolamine (CAS: 141-43-5) gave 11.4 mg of the target compound as a light yellow solid with a yield of 10%.
(50) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.03 (s, 1H), 8.67 (d, J=7.3 Hz, 1H), 8.33 (d, J=7.8 Hz, 1H), 8.23 (d, J=8.3 Hz, 1H), 7.99 (t, J=7.8 Hz, 1H), 7.90-7.78 (m, 2H), 7.06 (s, 1H), 5.79 (s, 2H), 4.69 (s, 2H), 3.80 (t, J=4.9 Hz, 2H), 3.61 (m, 2H), 3.51 (s, 3H); LC-MS: m/z (ES+) for C.sub.23H.sub.21N.sub.7O.sub.5 476 [M+1].sup.+.
Example 17
6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-N-oxetan-3-yl-nicotinamide (17)
(51) ##STR00110##
(52) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and oxetane-3-amine hydrochloride (CAS: 491588-41-1) gave 22.3 mg of the target compound as a light yellow solid with a yield of 25%.
(53) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.99 (s, 1H), 8.60 (d, J=7.8 Hz, 1H), 8.30 (d, J=7.8 Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), 8.03-7.91 (m, 1H), 7.89-7.75 (m, 2H), 7.04 (s, 1H), 5.75 (s, 2H), 5.20-5.06 (m, 1H), 4.93 (t, J=6.6 Hz, 2H), 4.65 (s, 2H), 4.64-4.52 (m, 2H), 3.46 (s, 3H); LC-MS: m/z (ES+) for C.sub.24H.sub.21N.sub.7O.sub.5 488 [M+1].sup.+.
Example 18
N-(oxetan-3-methyl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (18)
(54) ##STR00111##
(55) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 3-aminomethyloxetane (CAS: 6246-05-5) gave 22.3 mg of the target compound as a light yellow solid with a yield of 25%.
(56) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.03 (s, 1H), 8.83 (s, 1H), 8.568 (d, J=8 Hz, 1H), 8.35 (d, J=8 Hz, 1H), 8.254 (d, J=6 Hz, 1H), 8.12-8.10 (m, 1H), 8.00-7.98 (m, 1H), 7.855 (d, J=8 Hz, 1H), 7.185 (s, 1H), 5.76 (s, 2H), 4.71 (s, 2H), 4.638 (t, J=6.3 Hz, 2H), 4.347 (t, J=6.2 Hz, 2H), 3.569 (t, J=6.4 Hz, 2H), 3.39 (s, 3H), 3.18-3.15 (m, 1H); LC-MS: Rt=3.263 min, [M+H].sup.+=502.
Example 19
N-(1-cyanocyclopropyl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazole[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (19)
(57) ##STR00112##
(58) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 1-amino-1-cyclopropylnitrile hydrochloride (CAS: 127946-77-4) gave the product (54 mg, 36.2%) as a white solid.
(59) .sup.1H NMR (400 MHz, CDCl.sub.3) (400 MHz, DMSO-d.sub.6): 9.57 (s, 1H), 9.036 (s, 1H), 8.58 (d, J=7.6 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.37 (dd, J=8.4 Hz, 2.0 Hz, 1H), 8.15-8.12 (m, 1H), 8.02-7.99 (m, 1H), 7.89-7.87 (m, 1H), 7.18 (s, 1H), 5.79 (s, 2H), 4.71 (s, 2H), 3.39-3.34 (m, 3H), 1.61-1.58 (m, 2H), 1.33-1.29 (m, 2H). LC-MS: Rt=2.911 min, [M+H].sup.+=497.
Example 20
N-((3-methyl(oxetanyl)-methyl)-6-{3-[5(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazole[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (20)
(60) ##STR00113##
(61) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 3-methyl-3-aminomethyl-1-oxetane (CAS: 153209-97-3) gave the product (30.7 mg, 26%) as a white solid.
(62) .sup.1H NMR (400 MHz, CDCl.sub.3) (400 MHz, DMSO-d.sub.6): δ 9.06 (s, 1H), 8.88-8.84 (m, 1H), 8.60 (d, J=7.2 Hz, 1H), 8.38 (d, J=8.0 Hz, 1H), 8.27 (d, J=6.4 Hz, 1H), 8.16-8.13 (m, 1H), 8.03-7.99 (m, 1H), 7.88-7.86 (d, J=8.0 Hz, 1H), 7.21 (s, 1H), 5.79 (s, 2H), 4.72 (s, 2H), 4.46 (d, J=6.0 Hz, 2H), 4.21 (d, J=5.6 Hz, 2H), 3.50-3.49 (m, 2H), 3.39 (s, 3H), 1.26 (s, 3H). LC-MS: Rt=2.840 min, [M+H].sup.+=516.0.
Example 21
N-(3-fluorocyclobutyl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazole[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (21)
(63) ##STR00114##
(64) The experimental operation was as described in Example 3: the condensation reaction was carried out with compound 01 and 3-fluorocyclobutylamine (CAS: 234616-60-4), the reaction mixture obtained was separated and purified by prep-HPLC to give the product (48.2 mg, 41%) as a white solid.
(65) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.05 (d, J=2.0 Hz, 1H), 8.92 (d, J=7.2 Hz, 1H), 8.59 (d, J=7.6 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.28-8.26 (m, 1H), 8.16-8.12 (m, 1H), 8.03-7.99 (m, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 5.78 (s, 2H), 5.37-4.81 (m, 1H), 4.72 (s, 2H), 4.54-3.97 (m, 2H), 3.39 (s, 3H), 2.78-2.70 (m, 2H), 2.33-2.23 (m, 2H). LC-MS: Rt=3.830 min, [M+H].sup.+=504.0.
Example 22
N-2-difluoroethyl-6-(((3-(5-(methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]peptidazin-6-yl)oxy)methyl)nicotinamide (22)
(66) ##STR00115##
(67) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 2-fluoroethylamine hydrochloride (CAS: 460-08-2) gave 29.8 mg of the target compound as an off-white solid with a yield of 39.0%.
(68) 1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.10-8.94 (m, 2H), 8.59 (d, J=7.8 Hz, 1H), 8.39 (d, J=7.8 Hz, 1H), 8.32-8.26 (m, 1H), 8.14 (t, J=7.6 Hz, 1H), 8.06-7.97 (m, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.19 (s, 1H), 5.78 (s, 2H), 4.71 (s, 2H), 4.61 (t, J=5.1 Hz, 1H), 4.49 (t, J=4.9 Hz, 1H), 3.70-3.52 (m, 3H), 2.06-1.90 (m, 2H); LC-MS: m/z (ES+) for C23H20FN7O4 478 [M+1].sup.+.
Example 23
N-cyclobutyl-6-(((3-(5-(methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]peptidazin-6-yl)oxy)methyl)nicotinamide (23)
(69) ##STR00116##
(70) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and cyclobutylamine (CAS: 2516-34-9) gave 42.3 mg of the target compound as an off-white solid with a yield of 54.5%.
(71) 1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.03 (s, 1H), 8.87 (d, J=7.3 Hz, 1H), 8.60 (d, J=7.8 Hz, 1H), 8.38 (d, J=7.8 Hz, 1H), 8.26 (d, J=6.4 Hz, 1H), 8.20-8.09 (m, 1H), 8.07-7.94 (m, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.27-7.11 (m, 2H), 5.86-5.69 (m, 2H), 5.32 (s, 1H), 4.71 (s, 2H), 4.42 (dd, J=8.3, 16.1 Hz, 2H), 2.21 (s, 1H), 2.12-1.90 (m, 3H), 1.75-1.60 (m, 2H); LC-MS: m/z (ES+) for C25H23N7O4 486 [M+1].sup.+.
Example 24
N-2,2-difluoroethyl-6-(((3-(5-(methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]peptidazin-6-yl)oxy)methyl)nicotinamide (24)
(72) ##STR00117##
(73) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 2,2-difluoroethylamine (CAS: 430-67-1) gave 13.7 mg of the target compound as an off-white solid with a yield of 14.5%.
(74) _H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.14-9.02 (m, 2H), 8.58 (d, J=7.8 Hz, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.27 (dd, J=2.0, 8.3 Hz, 1H), 8.16-8.06 (m, 1H), 8.02-7.93 (m, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.17 (s, 1H), 6.26 (d, J=3.9 Hz, 1H), 6.14-6.08 (m, 1H), 5.97 (d, J=3.9 Hz, 1H), 5.77 (s, 2H), 4.69 (s, 2H), 3.76-3.60 (m, 3H); LC-MS: m/z (ES+) for C23H.sub.19F.sub.2N7O4 496 [M+1].sup.+.
Example 25
N-(2,2-difluoro-1-propyl-3-yl)-6-(((3-(5-(methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]peptidazin-6-yl)oxy)methyl)nicotinamide (25)
(75) ##STR00118##
(76) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 3-amino-2,2-difluoropropan-1-ol (CAS: 155310-11-5) gave 70.1 mg of the target compound as an off-white solid with a yield of 83.4%.
(77) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.11-8.95 (m, 1H), 8.58 (d, J=7.8 Hz, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.28 (dd, J=2.0, 8.3 Hz, 1H), 8.12 (t, J=7.6 Hz, 1H), 7.99 (t, J=7.6 Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.17 (s, 1H), 5.77 (s, 2H), 5.55 (t, J=6.1 Hz, 1H), 4.69 (s, 2H), 3.87-3.74 (m, 1H), 3.70-3.58 (m, 2H); LC-MS: m/z (ES+) for C24H21F2N7O5 526 [M+1].sup.+.
Example 26
6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-N-(tetrahydrofuran-3-yl)-nicotinamide (26)
(78) ##STR00119##
(79) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 3-aminotetrahydrofuran hydrochloride (CAS: 204512-94-7) gave 17.7 mg of the target compound as an off-white solid with a yield of 19%.
(80) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.00 (s, 1H), 8.63 (d, J=7.8 Hz, 1H), 8.30 (d, J=7.8 Hz, 1H), 8.17 (dd, J=1.7, 8.1 Hz, 1H), 7.95 (t, J=7.6 Hz, 1H), 7.88-7.76 (m, 2H), 7.01 (s, 1H), 6.85 (d, J=7.3 Hz, 1H), 5.76 (s, 2H), 4.80-4.70 (m, 1H), 4.68 (s, 2H), 3.99 (q, J=7.8 Hz, 1H), 3.94-3.87 (m, 1H), 3.87-3.77 (m, 2H), 3.51 (s, 3H), 2.45-2.31 (m, 1H), 2.03-1.96 (m, 1H); LC-MS: m/z (ES+) for C.sub.25H.sub.23N.sub.7O.sub.5 502 [M+1].sup.+.
Example 27
6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylhydroxymethyl]-N-(2,2,2-trifluoro-1-methyl-ethyl)-nicotinamide (27)
(81) ##STR00120##
(82) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 1,1,1-trifluoroisopropylamine hydrochloride (CAS: 2968-32-3) gave 77.6 mg of the target compound as an off-white solid with a yield of 80%.
(83) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.11 (d, J=8.8 Hz, 1H), 9.07 (d, J=2.0 Hz, 1H), 8.60 (d, J=7.8 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.30 (dd, J=2.0, 8.3 Hz, 1H), 8.14 (t, J=7.6 Hz, 1H), 8.06-7.97 (m, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.19 (s, 1H), 5.80 (s, 2H), 4.95-4.80 (m, 1H), 4.71 (s, 2H), 1.37 (d, J=7.3 Hz, 3H); LC-MS: m/z (ES+) for C.sub.24H.sub.20F.sub.3N.sub.7O.sub.4 528 [M+1].sup.+.
Example 28
N-(2-cyano-ethyl)-6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-nicotinamide (28)
(84) ##STR00121##
(85) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 3-aminopropionitrile (CAS: 151-18-8) gave 38.5 mg of the target compound as an off-white solid with a yield of 43%.
(86) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.19-8.95 (m, 2H), 8.57 (s, 1H), 8.43-8.19 (m, 2H), 8.17-7.77 (m, 3H), 7.17 (s, 1H), 5.76 (s, 2H), 4.69 (s, 2H), 3.64-3.50 (m, 5H), 2.88-2.69 (m, 2H). LC-MS: m/z (ES+) for C.sub.24H.sub.20N.sub.8O.sub.4 485 [M+1].sup.+.
Example 29
N-(3,3,3-trifluoropropyl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazole[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (29)
(87) ##STR00122##
(88) The experimental operation was as described in Example 3: the condensation reaction was carried out with compound 01 and 3,3,3-trifluoropropylamine (CAS: 460-39-9), the reaction mixture obtained was separated and purified by prep-HPLC to give a white solid (30 mg, 20%).
(89) .sup.1H NMR (400 MHz DMSO-d.sub.6): δ 9.036 (s, 1H) 8.953-8.925 (m, 1H) 8.614-8.593 (d, J=8.4 Hz, 1H) 8.405-8.384 (d, J=8.4 Hz, 1H) 8.241-8.236 (m, 1H) 8.166-8.125 (t, J=5.4 Hz, 1H) 8.035-7.993 (t, J=5.6 Hz, 1H) 7.886-7.866 (d, J=8 Hz, 1H) 7.202 (s, 1H) 5.790 (s, 2H) 4.715 (s, 2H) 3.529-3.515 (m, 2H) 3.389 (s, 3H) 2.553-2.524 (m, 2H); LC-MS: Rt=3.697 min, [M+H].sup.+=528.
Example 30
N-(1,3-dimethoxyprop-2-yl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazole[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (30)
(90) ##STR00123##
(91) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 2-amino-1,3-dimethoxypropane (CAS: 78531-29-0) gave a white solid (46 mg, 31%).
(92) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.048 (s, 1H) 8.601-8.591 (m, 2H) 8.386-8.367 (d, J=7.6 Hz, 1H) 8.289-8.263 (m, 1H) 8.157-8.119 (t, J=7.6 Hz, 1H) 8.026-7.988 (t, J=7.6 Hz, 1H) 7.864-7.843 (d, J=8.4 Hz, 1H) 7.191 (s, 1H) 5.782 (s, 2H) 4.715 (s, 2H) 4.326-4.307 (m, 1H) 3.491-3.428 (m, 4H) 3.391 (s, 3H) 3.262 (s, 6H); LC-MS: Rt=3.311 min, [M+H].sup.+=534.
Example 31
N-(bicyclo[1.1.1]pentan-1-yl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (31)
(93) ##STR00124##
(94) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and bicyclo[1.1.1]-1-pentylamine (CAS: 22287-35-0) gave a white solid (38 mg, 28%).
(95) .sup.1H NMR (400 Mhz, DMSO-d.sub.6): δ 9.216 (s, 1H), 9.024 (s, 1H), 8.603-8.583 (d, J=8 Hz, 1H), 8.393-8.373 (d, J=8 Hz, 1H), 8.254-8.234 (d, J=8 Hz, 1H), 8.157-8.120 (t, J=7.4 Hz, 1H), 8.026-7.988 (t, J=7.6 Hz, 1H), 7.851-7.831 (d, J=8 Hz, 1H), 7.179 (s, 1H), 5.773 (s, 2H), 4.712 (s, 2H), 3.389 (s, 3H), 2.479 (s, 1H), 2.100 (s, 6H); LC-MS: Rt=3.693 min, [M+H].sup.+=498.
Example 32
N-(1-acetyl-azetidin-3-yl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (32)
(96) ##STR00125##
(97) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 1-acetyl-azetidinylamine hydrochloride (CAS: 1462921-50-1) gave a white solid (23 mg, 15%).
(98) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.258-9.241 (d, J=6.8 Hz, 1H), 9.075 (s, 1H), 8.605-8.587 (d, J=7.2 Hz, 1H), 8.395-8.375 (d, J=8 Hz, 1H), 8.304-8.277 (m, 1H), 8.160-8.121 (t, J=5.2 Hz, 1H), 8.031-7.993 (t, J=5.1 Hz, 1H), 7.893-7.873 (d, J=8 Hz, 1H) 7.199 (s, 1H) 5.790 (s, 2H) 4.716 (s, 2H) 4.690-4.673 (m, 1H) 4.451-4.409 (t, J=5.6 Hz, 1H), 4.158-4.052 (m, 2H), 3.879-3.841 (m, 1H), 3.391 (s, 3H), 1.774 (s 3H); LC-MS: Rt=2.514 min, [M+H].sup.+=529.
Example 33
N-(4,4-difluorocyclohexyl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (33)
(99) ##STR00126##
(100) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 4,4-difluorocyclohexylamine hydrochloride (CAS: 675112-70-6) gave a white solid (36 mg, 23%).
(101) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.03 (s, 1H), 8.551 (t, J=8.2 Hz, 2H), 8.339 (d, J=8 Hz, 1H), 8.27-8.24 (m, 1H), 8.116 (t, J=7.2 Hz, 1H), 7.985 (t, J=7.4 Hz, 1H), 7.867 (d, J=8 Hz, 1H), 7.18 (s, 1H), 5.76 (s, 2H), 4.72-4.71 (m, 2H), 4.02-4.00 (m, 1H), 3.395 (s, 3H), 2.08-1.88 (m, 6H), 1.69-1.62 (m, 2H). LCMS: Rt=3.715 min, [M+H].sup.+=550.
Example 34
(4,4-difluoropiperidin-1-yl)(6-(((3-(5-methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methylene)pyridin-3-yl)methanone (34)
(102) ##STR00127##
(103) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 4,4-difluoropiperidine hydrochloride (CAS: 144230-52-4) gave 48 mg of the target compound as a white solid with a yield of 55.3%.
(104) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.71 (d, J=1.5 Hz, 1H), 8.59 (d, J=7.8 Hz, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.16-8.10 (m, 1H), 8.02-7.94 (m, 2H), 7.83 (d, J=8.3 Hz, 1H), 7.22 (s, 1H), 5.76 (s, 2H), 4.72 (s, 2H), 3.74 (m, 2H), 3.51 (m, 2H), 3.43 (s, 3H), 2.12-1.99 (m, 4H); LC-MS: m/z (ES+) for C.sub.26H.sub.23F.sub.2N.sub.7O.sub.4 536 [M+1].sup.+.
Example 35
N-(3,3-difluoro-1-cyclopentylamino)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (35)
(105) ##STR00128##
(106) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 3,3-difluoro-1-cyclopentylamine (CAS: 1462921-50-1) gave a white solid (19 mg, 13%).
(107) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.044 (s, 1H), 8.809-8.791 (d, J=7.2 Hz, 1H), 8.615-8.594 (d, J=8.4 Hz, 1H), 8.393-8.373 (d, J=8 Hz, 1H), 8.276-8.250 (m, 1H), 8.164-8.127 (t, J=4.9 Hz, 1H), 8.035-7.995 (t, J=5.3 Hz, 1H), 7.876-7.855 (d, J=8.4 Hz, 1H), 7.200 (s, 1H), 5.790 (s, 2H), 4.716 (s, 2H), 4.466-4.407 (m, 1H), 3.442-3.356 (br, 3H), 2.161-2.117 (m, 6H); LC-MS: Rt=3.650 min, [M+H].sup.+=536.
Example 36
6-(((3-(5-(methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]peptidazine-6-yl)oxo)methyl)nicotinamide (36)
(108) ##STR00129##
(109) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and ammonium chloride (CAS: 12125-02-9) gave 8.8 mg of the target compound as an off-white solid with a yield of 12.7%.
(110) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.07 (s, 1H), 8.57 (d, J=7.8 Hz, 1H), 8.45-8.22 (m, 2H), 8.17-7.91 (m, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.63 (s, 1H), 7.23-7.06 (m, 1H), 5.76 (br. s., 2H), 5.29 (s, 1H), 4.69 (s, 2H), 1.64 (s, 3H); LC-MS: m/z (ES+) for C21H17N7O4 432 [M+1].sup.+.
Example 37
6-[3-(5-Methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylhydroxymethyl]-N,N-dimethyl-nicotinamide (37)
(111) ##STR00130##
(112) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and dimethylamine (CAS: 124-40-3) gave 9.4 mg of the target compound as a white solid with a yield of 18%.
(113) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.71 (d, J=8.71 Hz, 2H), 8.33 (d, J=7.70 Hz, 1H), 7.99 (t, J=7.13 Hz, 1H), 7.89-7.78 (m, 3H), 7.10 (s, 1H), 5.80 (s, 2H), 4.70 (s, 2H), 3.52 (s, 3H), 3.13 (s, 3H), 3.01 (s, 3H); LC-MS: m/z (ES+) for C.sub.23H.sub.21N.sub.7O.sub.4 460 [M+1].sup.+.
Example 38
{6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-pyridin-3-yl}-morpholin-4-methanone (38)
(114) ##STR00131##
(115) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and morpholine (CAS: 110-91-8) gave the target compound (14.9 mg) as a pale yellow solid with a yield of 12%, and the appearance was white solid.
(116) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.71 (s, 2H), 8.33 (d, J=7.78 Hz, 1H), 7.98 (t, J=6.74 Hz, 1H), 7.81-7.84 (m, 3H), 7.10 (s, 1H), 5.79 (s, 2H), 4.69 (s, 2H), 3.97-3.55 (m, 6H), 3.54-3.35 (m, 5H); LC-MS: m/z (ES+) for C.sub.25H.sub.23N.sub.7O.sub.5 502 [M+1].sup.+.
Example 39
(2-oxa-6-azaspiro[3,3]heptanyl)(6-(((3-(5-methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methylene)pyridin-3-yl)methanone (39)
(117) ##STR00132##
(118) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 2-oxa-6-azaspiro[3,3]heptane (CAS: 174-78-7) gave a white solid (50 mg, 9.6%) after preparative liquid phase chromatography.
(119) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.827 (d, J=2 Hz, 1H), 8.585 (d, J=8 Hz, 1H), 8.364 (d, J=8 Hz, 1H), 8.14-8.11 (m, 1H), 8.08-8.05 (m, 1H), 8.02-7.98 (m, 1H), 7.828 (d, J=8 Hz, 1H), 5.76 (s, 2H), 4.72 (s, 2H), 4.70-4.65 (m, 2H), 4.49 (s, 2H), 4.24 (s, 2H), 3.40 (s, 3H). LCMS: Rt=2.883 min, [M+H].sup.+=514.
Example 40
N-methyl-N-(cyclopropylmethyl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (40)
(120) ##STR00133##
(121) The experimental operation was as described in Example 3: the condensation reaction was carried out with compound 01 and 1-cyclopropyl-N-methylmethylamine (CAS: 18977-45-2), the reaction mixture obtained was purified by RP-HPLC to give a white solid (40 mg, 29%).
(122) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.671-8.641 (m, 1H), 8.607-8.587 (d, J=8 Hz, 1H), 8.394-8.374 (d, J=8 Hz, 1H), 8.159-8.122 (t, J=7.4 Hz, 1H), 8.027-7.988 (t, J=7.8 Hz, 1H), 7.919 (s, 1H), 7.817-7.798 (d, J=7.6 Hz, 1H), 7.233-7.218 (m, 1H), 5.773 (s, 2H), 4.725 (s, 2H), 3.401 (s, 3H), 3.385 (m, 1H), 3.064-2.996 (m, 4H), 1.075-0.910 (m, 1H), 0.520-0.298 (m, 3H), 0.001 (m, 1H);
(123) LC-MS: Rt=3.256 min, [M+H].sup.+=500.
Example 41
(3-hydroxyazetidinyl)(6-(((3-(5-methoxymethyl)isoxazol-3-yl)-[1,2,4]triazole[3,4-a]phthalazin-6-yl)oxy)methylene)pyridin-3-yl)methanone (41)
(124) ##STR00134##
(125) The experimental operation was as described in Example 3: the condensation reaction was carried out with compound 01 and azetidine-3-ol (CAS: 45347-82-8), the reaction mixture obtained was purified by RP-HPLC to give a white solid (40 mg, 16%).
(126) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.844 (d, J=1.6 Hz, 1H), 8.594 (d, J=8 Hz, 1H), 8.377 (d, J=7.6 Hz, 1H), 8.15-8.07 (m, 2H), 8.006 (t, J=7.8 Hz, 1H), 7.818 (d, J=8.4 Hz, 1H), 7.20 (s, 1H), 5.76 (s, 2H), 5.80-5.77 (m, 3H), 4.72 (s, 2H), 4.51-4.45 (m, 2H), 4.29-4.25 (m, 1H), 4.08-4.07 (m, 1H), 3.82-3.78 (m, 1H), 3.40 (s, 3H). LCMS: Rt=2.749 min, [M+H].sup.+=488.
Example 42
(3-methoxyazetidinyl)(6-(((3-(5-methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methylene)pyridin-3-yl)methanone (42)
(127) ##STR00135##
(128) The experimental operation was as described in Example 3: the condensation reaction was carried out with compound 01 and 3-methoxyazetidine (CAS: 110925-17-2), the reaction mixture obtained was purified by RP-HPLC to give a white solid. (40 mg, 16%).
(129) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.844 (d, J=1.6 Hz, 1H), 8.594 (d, J=8 Hz, 1H), 8.377 (d, J=7.6 Hz, 1H), 8.15-8.07 (m, 2H), 8.006 (t, J=7.8 Hz, 1H), 7.818 (d, J=8.4 Hz, 1H), 7.20 (s, 1H), 5.76 (s, 2H), 5.80-5.77 (m, 3H), 4.72 (s, 2H), 4.51-4.45 (m, 2H), 4.29-4.25 (m, 1H), 4.08-4.07 (m, 1H), 3.82-3.78 (m, 1H), 3.40 (s, 3H). LCMS: Rt=2.749 min, [M+H].sup.+=488.
Example 43
((1S,4S)-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)(6-(((3-(5-methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methylene)pyridin-3-yl)methanone (43)
(130) ##STR00136##
(131) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and bridged cyclic morpholine hydrochloride (CAS: 31560-06-2) gave 31.2 mg of the target compound as a light yellow solid with a yield of 33%.
(132) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.80 (d, J=13.2 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.03-7.80 (m, 4H), 7.10 (s, 1H), 5.80 (d, J=3.9 Hz, 2H), 5.06 (s, 0.5H), 4.74 (s, 0.5H), 4.70 (s, 2H), 4.61 (s, 0.5H), 4.40 (s, 0.5H), 4.09-3.94 (m, 1H), 3.92-3.78 (m, 1H), 3.72-3.57 (m, 1H), 3.52 (s, 3H), 3.47 (s, 1H), 2.05-1.89 (m, 2H); LC-MS: m/z (ES+) for C.sub.26H.sub.23N.sub.7O.sub.5 514 [M+1].sup.+.
Example 44
(2,6-dimethylmorpholinyl)(6-(((3-(5-methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methylene)pyridin-3-yl)methanone (44)
(133) ##STR00137##
(134) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 2,6-dimethylmorpholine (CAS: 141-91-3) gave 19.7 mg of the target compound as a light yellow solid with a yield of 20%.
(135) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.70 (s, 2H), 8.33 (d, J=7.8 Hz, 1H), 7.98 (t, J=7.3 Hz, 1H), 7.92-7.75 (m, 3H), 7.10 (s, 1H), 5.80 (s, 2H), 4.70 (s, 2H), 4.56 (m, 1H), 3.65 (m, 2H), 3.52 (s, 3H), 2.88 (m, 1H), 2.60 (m, 1H), 1.26 (s, 3H), 1.08 (s, 3H); LC-MS: m/z (ES+) for C.sub.27H.sub.27N.sub.7O.sub.5 530 [M+1].sup.+.
Example 45
(4-hydroxypiperidin-1-yl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene}pyridin-3-ylmethanone (45)
(136) ##STR00138##
(137) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 4-piperidinol (CAS: 5382-16-1) gave the target compound as a white solid (40 mg, 37%).
(138) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.644 (d, J=1.6 Hz, 1H), 8.589 (d, J=7.6 Hz, 1H), 8.373 (d, J=8 Hz, 1H), 8.15-8.11 (m, 1H), 8.01-7.98 (m, 1H), 7.91-7.89 (m, 1H), 7.807 (d, J=8.4 Hz, 1H), 7.22 (s, 1H), 5.76 (s, 2H), 4.82 (s, 1H), 4.72 (s, 2H), 4.01-3.98 (m, 1H), 3.74 (s, 1H), 3.53-3.46 (m, 1H), 3.40 (s, 3H), 3.26-3.25 (m, 1H), 3.15-3.12 (m, 1H), 1.83-1.66 (m, 2H), 1.43-1.32 (m, 2H). LCMS: Rt=2.788 min, [M+H].sup.+=516.
Example 46
(3,3-difluoroazetidin-1-yl)(6-(((3-(5-(methoxymethyl)isoxazol-3-yl)[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methyl)pyridin-3-yl)methanone (46)
(139) ##STR00139##
(140) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 3,3-difluoroazetidine hydrochloride (CAS: 288315-03-7) gave 35 mg of the target compound as a white solid with a yield of 42.7%.
(141) 1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.90 (d, J=2.0 Hz, 1H), 8.60 (d, J=7.8 Hz, 1H), 8.38 (d, J=7.8 Hz, 1H), 8.18-8.11 (m, 2H), 8.04-7.98 (m, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.19 (s, 1H), 5.79 (s, 2H), 4.83 (s, 2H), 4.72 (m, 2H), 4.51 (m, 2H), 3.42 (s, 3H); LC-MS: m/z (ES+) for C24H19F2N7O4 508 [M+1].sup.+.
Example 47
(6-(((3-(5-(methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methyl)pyridin-3-yl)(3-methylmorpholino)methanone (47)
(142) ##STR00140##
(143) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 3-methylmorpholine (CAS: 42185-06-8) gave 36 mg of the target compound as a white solid with a yield of 43.1%.
(144) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.67-8.63 (m, 1H), 8.57 (d, J=7.8 Hz, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.15-8.09 (m, 1H), 8.02-7.96 (m, 1H), 7.92 (dd, J=2.0, 7.8 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.21 (s, 1H), 5.75 (s, 2H), 4.71 (s, 2H), 3.78 (m, 1H), 3.61-3.53 (m, 2H), 3.49-3.41 (m, 3H), 3.33 (m, 4H), 1.25 (d, J=5.9 Hz, 3H); LC-MS: m/z (ES+) for C26H25N7O5 516 [M+1].sup.+.
Example 48
(tetrahydropyrrolyl)(6-(((3-(5-methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methylene)pyridin-3-yl)methanone (48)
(145) ##STR00141##
(146) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and pyrrolidine (CAS: 123-75-1) gave 14 mg of the target compound as a white solid with a yield of 17.8%.
(147) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.76 (d, J=1.5 Hz, 1H), 8.59 (d, J=7.8 Hz, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.17-8.10 (m, 1H), 8.04-7.97 (m, 2H), 7.80 (d, J=7.8 Hz, 1H), 7.20 (s, 1H), 5.76 (s, 2H), 4.72 (s, 2H), 3.51-3.45 (m, 4H), 3.43 (s, 3H), 1.90-1.80 (m, 4H); LC-MS: m/z (ES+) for C.sub.25H.sub.23N.sub.7O.sub.4 486 [M+1].sup.+.
Example 49
(6-(((3-(5-(methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methyl)pyridin-3-yl)(piperidin-1-yl)methanone (49)
(148) ##STR00142##
(149) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and piperidine (CAS: 110-89-4) gave 38 mg of the target compound as a white solid with a yield of 47.0%.
(150) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.66-8.53 (m, 2H), 8.36 (d, J=8.3 Hz, 1H), 8.12 (t, J=7.6 Hz, 1H), 8.02-7.96 (m, 1H), 7.89 (dd, J=2.2, 8.1 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.21 (s, 1H), 5.75 (s, 2H), 4.71 (s, 2H), 3.59 (m, 2H), 3.43 (s, 3H), 3.26 (d, J=4.9 Hz, 2H), 1.65-1.51 (m, 4H), 1.46 (m, 2H); LC-MS: m/z (ES+) for C.sub.26H.sub.25N.sub.7O.sub.4 500 [M+1].sup.+.
Example 50
N-methyl-N-(cyclopropyl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (50)
(151) ##STR00143##
(152) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and N-methylcyclopropylamine (CAS: 5163-20-2) gave a white solid (32 mg, 29%).
(153) .sup.1H NMR (400 MHz DMSO-d.sub.6): δ 8.752 (s, 1H), 8.611-8.592 (d, J=7.6 Hz, 1H), 8.399-8.380 (d, J=7.6 Hz, 1H), 8.163-8.122 (m, 1H), 8.031-7.990 (m, 2H), 7.791-7.771 (d, J=8.0 Hz, 1H), 7.231 (s, 1H), 5.779 (s 2H), 4.723 (s, 2H), 3.397 (s, 3H), 2.992-2.945 (m, 4H), 0.464-0.379 (m, 4H), 0.001 (m, 1H); LC-MS: Rt=3.141 min, [M+H].sup.+=486.
Example 51
(3,3-difluoropyrrolidinyl)(6-(((3-(5-methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methylene)pyridin-3-yl)methanone (51)
(154) ##STR00144##
(155) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 3,3-difluoropyrrolidine (CAS: 316131-01-8) gave the product (112 mg, 46.7%) as a white solid.
(156) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.81 (s, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.36 (d, J=8.0 Hz, 1H), 8.15-8.11 (m, 1H), 8.08-8.05 (m, 1H), 8.02-7.98 (m, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.20 (s, 1H), 5.77 (s, 2H), 4.72 (s, 2H), 3.98-3.89 (m, 2H), 3.76-3.68 (m, 2H), 3.40 (s, 3H), 2.47-2.41 (m, 2H). LC-MS: Rt=3.125 min, [M+H].sup.+=521.9.
Example 52
N,N-(Bis(2-methoxyethyl))-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (52)
(157) ##STR00145##
(158) The experimental operation was as described in Example 3: the condensation reaction was carried out with compound 01 and bis(2-methoxyethyl)amine (CAS: 111-95-5), the reaction mixture obtained was separated and purified by prep-HPLC to give the product (33.9 mg, 29%) as a light yellow solid.
(159) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.71 (d, J=1.6 Hz, 1H), 8.58 (d, J=7.6 Hz, 1H), 8.36 (d, J=8.0 Hz, 1H), 8.15-8.11 (m, 1H), 8.01-8.00 (m, 1H), 7.89 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.23 (s, 1H), 5.76 (s, 2H), 4.73 (s, 2H), 3.64-3.63 (m, 2H), 3.56-3.55 (m, 2H), 3.40-3.39 (m, 7H), 3.30 (s, 3H), 3.13 (s, 3H). LC-MS: Rt=3.432 min, [M+H].sup.+=548.1.
Example 53
(1-methyl-2-oxo-piperazinyl)(6-(3-(5-methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methylene)pyridin-3-yl)methanone (53)
(160) ##STR00146##
(161) The experimental operation was as described in Example 3: the condensation reaction was carried out with compound 01 and 1-methylpiperazine-2-one (CAS: 59702-07-7), the reaction mixture was purified by preparative liquid phase chromatography to give a white solid. The reaction mixture was diluted with water, filtered, and the filter cake was purified with reversed phase column to give a white solid (50 mg, 41%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.719 (d, J=1.2 Hz, 1H), 8.577 (d, J=8 Hz, 1H), 8.36 (d, J=7.6 Hz, 1H), 8.14-8.10 (m, 1H), 8.01-7.97 (m, 2H), 7.839 (d, J=8.4 Hz, 1H), 7.20 (s, 1H), 5.76 (s, 2H), 4.72 (s, 2H), 4.16-4.00 (m, 2H), 3.87-3.59 (m, 2H), 3.44-3.40 (m, 5H), 2.87 (s, 3H). LCMS: Rt=2.782 min, [M+H].sup.+=529.
Example 54
(2-methylmorpholinyl)(6-(((3-(5-methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methylene)pyridin-3-yl)methanone (54)
(162) ##STR00147##
(163) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 2-methylmorpholine (CAS: 27550-90-9) gave 30.0 mg of the target compound as an off-white solid with a yield of 31%.
(164) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.75-8.68 (m, 2H), 8.34 (d, J=8.3 Hz, 1H), 8.00 (t, J=7.8 Hz, 1H), 7.92-7.79 (m, 3H), 7.11 (s, 1H), 5.81 (s, 2H), 4.71 (s, 2H), 4.66-4.40 (m, 1H), 4.11-3.76 (m, 1H), 3.73-3.41 (m, 7H), 3.36-2.62 (m, 1H), 1.26 (m, 3H); LC-MS: m/z (ES+) for C.sub.26H.sub.25N.sub.7O.sub.5 516 [M+1].sup.+.
Example 55
(1,4-oxazepanyl)(6-(((3-(5-methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methylene)pyridin-3-yl)methanone (55)
(165) ##STR00148##
(166) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and homomorpholine (CAS: 5638-60-8) gave 14.0 mg of the target compound as an off-white solid with a yield of 15%.
(167) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.72-8.57 (m, 2H), 8.31 (d, J=7.8 Hz, 1H), 8.02-7.92 (m, 1H), 7.90-7.74 (m, 3H), 7.09 (s, 1H), 5.77 (s, 2H), 4.67 (s, 2H), 3.92-3.70 (m, 5H), 3.70-3.61 (m, 1H), 3.57-3.50 (m, 2H), 3.49 (s, 3H), 2.03 (q, J=5.6 Hz, 1H), 1.81 (q, J=5.5 Hz, 1H); LC-MS: m/z (ES+) for C.sub.26H.sub.25N.sub.7O.sub.5 516 [M+1].sup.+.
Example 56
{6-[3-(5-methoxymethyl-isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yloxymethyl]-pyridin-3-yl}-(2-oxa-7-aza-spiro[3.5]non-7-yl)-methanone (56)
(168) ##STR00149##
(169) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 2-oxa-7-azaspiro[3.5]nonane (CAS: 241820-91-7) gave 43.1 mg of the target compound as an off-white solid with a yield of 43%.
(170) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.63 (s, 1H), 8.58 (d, J=7.3 Hz, 1H), 8.36 (d, J=8.3 Hz, 1H), 8.12 (t, J=6.8 Hz, 1H), 8.06-7.95 (m, 1H), 7.89 (d, J=7.3 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 5.75 (s, 2H), 4.72 (s, 2H), 4.34 (m, 4H), 3.54 (s, 3H), 3.21 (m, 4H), 1.84 (m, 2H), 1.76 (m, 2H); LC-MS: m/z (ES+) for C.sub.28H.sub.27N.sub.7O.sub.5 542 [M+1].sup.+.
Example 57
(6-(((3-(5-(methoxymethyl)isoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)oxy)methyl)pyridin-3-yl)(4-methoxypiperidin-1-yl)methanone (57)
(171) ##STR00150##
(172) The experimental operation was as described in Example 3: the condensation reaction of compound 01 and 4-methoxypiperidine (CAS: 4045-24-3) gave 31 mg of the target compound as a white solid with a yield of 36.1%.
(173) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.67-8.62 (m, 1H), 8.56 (d, J=7.8 Hz, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.11 (t, J=7.3 Hz, 1H), 7.98 (t, J=7.6 Hz, 1H), 7.91 (dd, J=2.0, 7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.20 (s, 1H), 5.74 (s, 2H), 4.71 (s, 2H), 3.98-3.84 (m, 1H), 3.46 (s, 3H), 3.37-3.28 (m, 3H), 3.25 (s, 3H), 3.15 (m, 1H), 1.94-1.82 (m, 1H), 1.77 (m, 1H), 1.48 (m, 1H), 1.42 (m, 1H); LC-MS: m/z (ES+) for C.sub.27H.sub.27N.sub.7O.sub.5 530 [M+1].sup.+.
Example 58
N-methyl-N-(2,2,2-trifluoroethyl)-6-{3-[5-(methoxymethyl)isoxazol-3-yl]-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene}nicotinamide (58)
(174) ##STR00151##
(175) The experimental operation was as described in Example 3: the condensation reaction was carried out with compound 01 and N-methyl-2,2,2-trifluoroethylamine (CAS: 2730-67-8), the reaction mixture obtained was separated and purified by prep-HPLC to give the product (50 mg, 40%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.71 (s, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.15-8.11 (m, 1H), 8.02-8.00 (m, 2H), 7.83 (d, J=8.0 Hz, 1H), 7.20 (s, 1H), 5.78 (s, 2H), 4.72 (s, 2H), 4.40-4.18 (m, 2H), 3.40 (s, 3H), 3.05 (s, 3H). LC-MS: Rt=3.412 min, [M+H].sup.+=528.1.
Example 59
N-ethyl-6-((3-(5-methoxymethylisoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene)isonicotinamide (59)
(176) ##STR00152## ##STR00153##
(177) Experimental Process:
(178) Step 1:
(179) Raw materials B-2 (630 mg, 2.0 mmol), C-1 (CAS: 58481-17-7) (334 mg, 2.0 mmol) and Cs.sub.2CO.sub.3 (1.30 g, 4.0 mmol) were sequentially added into DMF (10 mL). The reaction was allowed to run at room temperature overnight. After the completion of the reaction, the reaction mixture was poured into ice water (100 mL), and the resulting precipitate was collected by filtration, washed with water three times to give the product A1 (760 mg, 85.2%) as a yellow solid C-2.
(180) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.83-8.82 (m, 1H), 8.71 (d, J=8.0 Hz, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.30 (s, 1H), 8.01-7.97 (m, 1H), 7.88-7.84 (m, 2H), 7.11 (s, 1H), 5.84 (s, 2H), 4.71 (s, 2H), 3.96 (s, 3H), 3.51 (s, 3H). LC-MS: Rt=1.43 min, [M+H].sup.+=447.
(181) Step 2:
(182) An aqueous solution of lithium hydroxide monohydrate (150 mg, 3.6 mmol, in 4 mL of water) was added into a suspension of C-2 (400 mg, 0.9 mmol) in ethanol (10 mL). Then, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was poured into ice water (20 mL) and the pH value was adjusted to 3-4 with 1 N HCl. The precipitated solid was filtered, collected, and washed with water for three times, then dried to give product C-3 as a white solid (360 mg, 92.6%).
(183) 1H NMR (400 MHz, DMSO-d.sub.6): δ 8.83-8.82 (m, 1H), 8.59 (d, J=7.6 Hz, 1H), 8.31 (d, J=7.6 Hz, 1H), 8.16-8.12 (m, 2H), 8.03-8.01 (m, 1H), 7.83-7.81 (m, 1H), 7.26 (s, 1H), 5.82 (s, 2H), 4.72 (s, 2H), 3.40-3.36 (m, 3H). LC-MS: Rt=1.12 min, [M+H].sup.+=433.
(184) Step 3:
N-ethyl-6-((3-(5-methoxymethylisoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene)isonicotinamide (59)
(185) The experimental operation was as described in Example 3: the condensation reaction was carried out with intermediate C-3 and ethylamine hydrochloride (CAS: 557-66-4), and the reaction mixture obtained was separated and purified by prep-HPLC to give the product (82 mg, 50.9%) as a white solid.
(186) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.83-8.80 (m, 1H), 8.77 (d, J=4.0 Hz, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.15-8.11 (m, 1H), 8.05 (s, 1H), 8.02-7.98 (m, 1H), 7.76-7.75 (m, 1H), 7.25 (s, 1H), 5.78 (s, 2H), 4.72 (s, 2H), 3.40 (s, 3H), 3.30-3.27 (m, 2H), 1.14-1.11 (m, 3H). LC-MS: Rt=3.000 min, [M+H].sup.+=460.
Example 60
N-ethyl-6-((3-(5-methoxymethylisoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene)picolinamide (60)
(187) ##STR00154## ##STR00155##
(188) Experimental Process:
(189) Step 1:
(190) The experimental operation was as described in Example 59: Intermediate B-2 and D-1 (CAS: 39977-44-1) were reacted to give the product D-2 (900 mg, crude) as a yellow solid.
(191) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.70 (d, J=8.0 Hz, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.04-7.93 (m, 3H), 7.87-7.83 (m, 1H), 7.09 (s, 1H), 5.87 (s, 2H), 4.71 (s, 2H), 4.04 (s, 3H), 3.51 (s, 3H). LC-MS: Rt=1.41 min, [M+H].sup.+=447.
(192) Step 2:
(193) The experimental operation was as described in Example 59: Intermediate D-2 was hydrolyzed with LiOH to give the product D-3 (212 mg, 54.5%) as a white solid.
(194) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.56 (d, J=8.4 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.13-8.06 (m, 1H), 8.04-7.98 (m, 2H), 7.98-7.93 (m, 2H), 7.22 (s, 1H), 5.79-5.76 (m, 2H), 3.44-3.35 (m, 3H). LC-MS: Rt=1.07 min, [M+H].sup.+=433.
(195) Step 3:
N-ethyl-6-((3-(5-methoxymethylisoxazol-3-yl)-[1,2,4]triazolo[3,4-a]phthalazin-6-oxy)methylene)picolinamide (60)
(196) The experimental operation was as described in Example 3: the condensation reaction was carried out with intermediate D-3 and ethylamine hydrochloride (CAS: 557-66-4), the reaction mixture obtained was separated and purified by prep-HPLC to give the product 60 (44 mg, 20.8%) as a white solid.
(197) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.78-8.75 (m, 1H), 8.59 (d, J=8.0 Hz, 1H), 8.36 (d, J=8.0 Hz, 1H), 8.15-7.97 (m, 5H), 7.16 (s, 1H), 5.78 (s, 2H), 4.69 (s, 2H), 3.37-3.36 (m, 3H), 3.33-3.31 (m, 2H), 1.15-1.11 (m, 3H). LC-MS: Rt=3.083 min, [M+H].sup.+=460.
Effect Embodiment 1
(198) Biological Experiment Method:
(199) Previous studies have revealed that the GABA.sub.A receptors mediate at least two modes of inhibition, the phasic inhibition and the tonic inhibition. When the GABA increases to the millimole level, the GABA.sub.A receptors will be desensitized rapidly, show low affinity for GABA and mediate phasic inhibition. When the GABA activates GABA.sub.A receptors at tens of micromole or hundreds of nano mole level, the high affinity extrasynaptic GABA.sub.A receptors will mediate tonic inhibition and regulate neuronal excitability and signal transmission (Farrant M et al. (2005) Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci 6: 215-229Y). Yeung J Y et al reported that the α5-GABA.sub.A receptor can be activated preferably by low level of GABA (Yeung J Y et al (2003). Tonically activated GABA.sub.A receptors in hippocampal neurons are high-affinity, low-conductance sensors for extracellular GABA. Mol Pharmacol; 63: 2-8). K. Y LEE et al reported that the sustainable high-affinity GABA.sub.A current induced by low level GABA is detected in dissociated cultured DRG neurons cultured for 24 hours and 20 μM of GABA can induce about 100 pA/pF high-affinity GABA.sub.A current (Lee K Y et al. Upregulation of high-affinity GABA(A) receptors in cultured rat dorsal root ganglion neurons. Neuroscience 208 (2012) 133-142). In 2013, I. Lecker et al reported that L-655,708, an α5-GABA.sub.A specific inverse agonist, inhibited the current included by low level GABA (5, 50 and 500 nM) in the concentration dependent manner. When the GABA concentration is increased to 1 μM, the inhibition efficacy of the highest dose of L-655,708 is only 15%. When the GABA concentration is higher, there is even no inhibition of L-655,708 on the current induced by GABA (I. Lecker et al (2013). Potentiation of GABA.sub.A receptor activity by volatile anaesthetics is reduced by α5-GABA.sub.A receptor-preferring inverse agonists. British Journal of Anaesthesia 110 (S1): i73-i81).
(200) Cell-Level Screening
(201) The inventors used electrophysiological methods to determine the inverse agonist efficacy of the substances to be tested. The detailed procedures are as follows:
(202) (1) Different subunits of GABA.sub.A receptors were expressed in human embryonic kidney cells 293 (HEK293). The cells were cultured in a culture medium and used as a cell model for screening potential analgesics. The α, β and γ subunits are necessary to form complete functional GABA.sub.A receptors. In this example, the inventors have established the following cell model: (a) α5 subunit (protein sequence is GenBank accession number: NM_000810.3), (33 subunit (protein sequence is GenBank accession number: NM_000814.5) and γ2 subunit (protein sequence is GenBank accession number: NM_000816.3) were expressed in HEK-293 cell line at the same time, followed by screening the monoclonal cell line. This cell line contained α5-GABA.sub.A receptor and had complete GABA.sub.A receptor function.
(203) (2) The monoclonal stably transfected HEK-293 cells expressing α5-GABA.sub.A receptor were cultured in 10 cm culture dishes. The cells were passaged after reaching 80-90% confluence. During passaging, the culture medium was removed and discarded, 3 mL of DPBS (phosphate buffered saline, Gibco™) was added to the dishes, the dishes were shaken slightly, and DPBS was removed and discarded. 1 mL of trypsin (TrypLE Express, Gibco™) was added and the cells were digested at 37° C. for 1-2 minutes. Then 3 mL of complete medium (DMEM+10% FBS (Gibco™)) was added and the cells at the bottom of the culture dishes were dispersed. The cell suspension were transferred to a 15 mL centrifugal tube (Corning™) and then centrifuged at 200 g for 3 minutes. The supernatant was discarded, 4 mL of complete medium was added, and the cells were resuspended by gently blowing. The cell suspension was diluted by 1:5 or 1:10 for subculturing. The cell suspension was diluted by 1:12 for electrophysiology experiment, and added to a 24 well plate (Corning™) with a glass slide pre-treated with poly-D-lysine placed thereon; the experiment was initiated after the cells were adhered to the slide. The cells for electrophysiology experiment were maintained in culture for no more than 48 hours before use.
(204) (3) Compound concentration: for screening, all compounds were diluted to a final concentration of 100 nM and the concentration of GABA was 0.05 μM. The compounds were at the concentration of 0.3 nM, 3 nM, 10 nM, 30 nM, 100 nM and 300 nM in dose-inverse agonism efficacy (%) experiment. The whole cell patch clamp technique was used in electrophysiology experiments, which can refer to the literature (I. Lecker, Y. Yin, D. S. Wang and B. A. Orser, (2013) Potentiation of GABA.sub.A receptor activity by volatile anaesthetics is reduced by α5-GABA.sub.A receptor-preferring inverse agonists, British Journal of Anaesthesia 110 (S1): i73-i81). The extracellular solution (ECS) contained: 150 mM NaCl, 5 mM KCl, 2.5 mM CaCl.sub.2, 1 mM MgCl.sub.2, 10 mM HEPES and 10 mM glucose (pH 7.4); Patch electrodes were filled with an intracellular solution containing: 140 mM CsCl, 11 mM EGTA, 10 mM HEPES, 2 mM CaCl.sub.2, 1 mM MgCl.sub.2, 4 mM MgATP, 2 mM TEA (pH 7.3). The currents were recorded by an EPC-10 amplifier and the PatchMaster software (HEKA). Patch electrodes with a resistance of 4-6 MΩ were pulled from borosilicate glass. The ALA-VC3-8PP™ system was used for extracellular administration. Separate cells that grew independently was selected for recording. During recording, the membrane voltage was clamped at −60 mV. During experiment, the cells were firstly perfused with ECS for 20 seconds. When the baseline reached to a stable state, the cells were then perfused with GABA solution. Then the current induced by GABA could be detected. After about 20 to 40 seconds, the current was stable. ECS was switched to compounds solution and the effects of the compounds were detected. At last, the perfusion solution was switched to ECS. The experiment was finished when the post-baseline returned to the pre-baseline before compounds perfusion. Only data whose baseline are less than −120 pA and can be recovered after drug administration will be used for analysis. GABA was diluted at a final concentration of 0.05 μM in ECS. Then, compounds were diluted at the desired concentration in GABA ECS.
(205) (4) Currents were analyzed with the PatchMaster software. The leakage currents (I.sub.leak), the GABA currents before (I.sub.pre) and after (I.sub.post) compounds perfusion were recorded respectively. The effects of compounds were calculated by the following equation: inverse agonism efficacy (%)=100−100*(I.sub.post−I.sub.leak)/(I.sub.pre−I.sub.leak). N indicates the number of the experiments.
(206) Example 7 in CN106854207A was used as the reference compound during compound screening, and the activity results were expressed as the ratio of the inverse agonism efficacy of the compound to the inverse agonism efficacy of the reference compound in the same batch of experiments. The inverse agonism efficacy of the reference compound was between 40% and 60%, with N>20.
(207) (6) The screening results of the compounds are shown in Table 1.
(208) TABLE-US-00002 TABLE 1 Inverse agonism efficacy of the compound/inverse Compound agonism efficacy of the No. reference compound (%) N 02 78.0 2 03 92.1 4 05 90.0 3 06 74.9 5 07 107.7 3 08 110.3 3 10 102.9 3 11 106.0 4 12 94.03 3 17 105.1 3 18 114.84 3 20 118.1 3 23 73.73 3 28 133.41 2 30 85.25 3 31 95.1 3 32 89.12 3 37 72.1 4 38 93.4 2 39 90.21 3 40 78.26 3 42 73.3 3 43 86.9 3 45 88.4 4 46 94.6 3 47 72.46 3 48 78.68 3 49 75.24 3 54 77.55 3 56 110.86 3
Effect Example 2: Solubility of the Compounds
(209) Experimental Materials and Instrument:
(210) 50 mM phosphate buffer pH=7.4: 0.39 g of NaH.sub.2PO.sub.4.2H.sub.2O, and 1.4025 g of Na.sub.2HPO.sub.4 were weighted and placed in an erlenmeyer flask, 240 mL of water was added. The solid was dissolved and mixed thoroughly, the pH value was adjusted to 7.4 with 10M NaOH solution, and the resulting solution was transferred to a 250 mL volumetric flask, followed by adding water to the mark.
(211) Waters e2695 HPLC high performance liquid chromatography, Mettler XSE105 analytical balance.
(212) Experimental Method:
(213) Firstly, a 10 mM stock solution with DMSO as the solvent was prepared, and was diluted with a diluent (ACN: PB buffer 50:50) into 1 μM-200 μM as standard solution.
(214) Kinetic solubility. 30 μL of the stock solution was placed in a 2 mL centrifuge tube, 1470 μL of 50 mM phosphate buffer (pH 7.4) (containing DMSO at a final concentration of 2%) was added. The mixture was shaken at room temperature (1000 rpm/min) for 24 hours, and then filtered. The filtrate was tested by high performance liquid chromatography (UV). The results are shown in Table 2.
(215) Thermodynamic solubility. About 1 mg of the sample was weighted, 1.5 mL of 50 mM phosphate buffer (pH 7.4) was added thereto, and the mixture was shaken at room temperature for 24 hours to ensure that the solution reached a state of saturation. The solution was then filtered, and the filtrate was tested with high-performance liquid chromatography (UV). The results are shown in Table 2.
(216) TABLE-US-00003 TABLE 2 Compound Kinetic solubility Thermodynamic No. μg/mL solubility μg/mL 02 8.02 3.39 04 13.13 05 25.55 06 13.63 07 23.22 09 27.69 10 18.94 11 9.23 4.40 12 10.89 9.05 13 0.57 14 35.66 15 0.77 0.84 16 49.35 18 10.75 19 1.06 20 10.14 21 1.18 22 8.92 23 9.11 24 1.39 0.74 25 2.71 26 20.34 27 5.58 28 3.68 30 6.85 31 4.19 32 29.73 33 2.99 34 4.60 4.40 35 5.62 36 0.80 37 91.90 84.73 38 17.75 8.7 39 48.45 40 31.94 41 6.57 42 5.89 6.02 43 100.27 44 74.57 45 6.93 47 97.8 48 31.71 50 3.75 51 5.62 52 51.86 53 28.03 54 97.92 55 101.72 56 12.5 57 26.49 58 1.46
(217) TABLE-US-00004 TABLE 3 Thermo- Kinetic dynamic solubility solubility Compound No. μg/mL μg/mL
(218) It can be seen from Table 3 that the kinetic and thermodynamic solubility of the methoxymethyl-containing compounds of the present disclosure is twice as much as the methyl-containing reference compound. Therefore the compounds of the present disclosure can significantly reduce the difficulty of formulation development in preclinical and clinical research and improve oral bioavailability.
Effect Example 3: Pharmacokinetic Experiment on Rats
(219) In the pharmacokinetic experiment on rats, the maximum drug concentration (C.sub.max) in the blood was determined to evaluate the absorption of the compounds in rats. All rats fasted overnight before administration; the test compounds were dissolved and administered orally (po, intragastric administration) to male SD rats, with 3 rats in each group. After administration of the test compounds, blood was collected by jugular vein puncture at 0.25, 0.5, 1.2, and 4.8 hours with 0.25 mL per sample. The plasma drug concentration was determined by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin7.0. The dose was 1 mg/kg, and the menstruum was 50% PEG400/50% water.
(220) TABLE-US-00005 TABLE 4 PO C.sub.max Compound No. ng/mL
(221) It can be seen from Table 4 that, compared with the reference compound containing methyl group, the compounds containing methoxymethyl group of the present disclosure show a higher maximum drug concentration in blood and have pharmacokinetic advantages.
(222) Although the specific examples of the present disclosure have been described above, those skilled in the art should understand that these are only for illustration, and a variety of changes and modifications can be made to these examples without departing from the principle and essence of the present disclosure. Therefore, the protection scope of the present disclosure is defined by the appended claims.