HETEROAROMATIC DERIVATIVES FOR USE AS REGULATOR, PREPARATION METHOD THEREFOR AND USE THEREOF
20230043863 · 2023-02-09
Inventors
- Mi ZENG (Shanghai, CN)
- Peng GAO (Shanghai, CN)
- Peng XU (Shanghai, CN)
- Yu Cheng (Shanghai, CN)
- Jian Li (Shanghai, CN)
- Jiaqiang CAI (Shanghai, CN)
- Rudi BAO (Shanghai, CN)
Cpc classification
A61P29/00
HUMAN NECESSITIES
Y02P20/55
GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
C07D451/04
CHEMISTRY; METALLURGY
C07D451/14
CHEMISTRY; METALLURGY
C07D519/00
CHEMISTRY; METALLURGY
International classification
C07D519/00
CHEMISTRY; METALLURGY
C07D451/04
CHEMISTRY; METALLURGY
Abstract
The present invention relates to heteroaromatic derivatives for use as a regulator, a preparation method therefor and a use thereof. In particular, disclosed are compounds represented by general formula (I), preparation methods therefor, pharmaceutical compositions comprising said compounds, and a use thereof as Janus kinase inhibitors in treating inflammatory diseases and tumor-related diseases.
##STR00001##
Claims
1. A compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ##STR00807## wherein: L.sub.1 is selected from bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —NR.sub.aa(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1S(O).sub.m1—, or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; L.sub.2 is selected from bond, oxygen atom, sulfur atom, —CR.sub.aaR.sub.bb—, —(CH.sub.2).sub.n1C(O)—, —NR.sub.4— or —(CH.sub.2).sub.n1S(O).sub.m1—; L.sub.3 is selected from bond, —NR.sub.aa—, or —C(O)NR.sub.aa—; ring A is 6-14 membered heteroaryl, wherein the 6-14 membered heteroaryl is selected from 6-14 membered fused heteroaryl; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered bridged heterocyclyl, 6-14 membered fused heterocyclyl or 6-14 membered spiro heterocyclyl; ring C is heteroaryl; R.sub.1 is selected from hydrogen atom, deuterium atom, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1 NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.2 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1O(CH.sub.2).sub.m1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1NR.sub.aa(CH.sub.2).sub.m1R.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S—, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.3 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1 NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1 NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd, or (CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.4 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, or alkynyl; R.sub.aa, R.sub.bb, R.sub.cc, and R.sub.dd are identical or different and are each independently selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; x is an integer of 0, 1, 2 or 3; y is an integer of 0, 1, 2, 3, 4 or 5; m.sub.1 is an integer of 0, 1 or 2; m.sub.2 is an integer of 0, 1 or 2; and n.sub.1 is an integer of 0, 1, 2, 3, 4 or 5.
2. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein, L.sub.1 is selected from bond, alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; and/or, L.sub.2 is selected from bond, oxygen atom, or —NR.sub.4—; and/or, R.sub.4 is selected from hydrogen atom, or alkyl; and/or, L.sub.3 is —NR.sub.aa—; and/or, ring A is 6-14 membered fused heteroaryl; and/or, ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered bridged heterocyclyl, or 6-14 membered fused heterocyclyl; and/or, ring C is heteroaryl; and/or, R.sub.1 is selected from hydrogen atom, alkyl, haloalkyl, amino, heterocyclyl, or heteroaryl; wherein the alkyl, amino, heterocyclyl, or heteroaryl is optionally further substituted with one or more substituents selected from halogen, cyano, alkyl, or alkoxy; and/or, R.sub.2 is selected from hydrogen atom, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, or heteroaryl; wherein the heteroaryl is optionally further substituted with one or more substituents selected from unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl; and/or, R.sub.3 is selected from hydrogen atom, alkyl, hydroxyalkyl, halogen, cyano, cycloalkyl, —(CH.sub.2).sub.n1C(O)R.sub.aa, or —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb; wherein the alkyl is optionally further substituted with hydroxyl; and/or, R.sub.aa and R.sub.bb are identical or different, and are each independently selected from hydrogen atom, alkyl, or amino; and/or, x is 0, 1, 2 or 3; and/or, y is 0, 1, 2 or 3; and/or, m.sub.1 is 0, 1 or 2; and/or, m.sub.2 is 0, 1 or 2; and/or, n.sub.1 is 0, 1 or 2.
3. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the compound of formula (I) is a compound of formula (I-1), ##STR00808## wherein, ring D is heterocycloalkenyl, aryl, or heteroaryl; and/or, the compound of formula (I) is a compound of formula (I-1), ##STR00809## wherein, X.sub.1, X.sub.2 and X.sub.3 are independently CH or N; and/or, L.sub.1 is selected from alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, (CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; and/or, R.sub.1 is selected from halogen, cyano, alkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen or alkoxy; wherein the heterocyclyl is optionally further substituted with cyano; wherein the heteroaryl is optionally further substituted with alkyl; and/or, when L.sub.1 is —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, R.sub.1 is alkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen; wherein the heterocyclyl or heteroaryl is optionally further substituted with alkyl; and/or, L.sub.2 is selected from oxygen atom, or —NR.sub.4—; and/or, R.sub.4 is selected from hydrogen atom, or alkyl; and/or, L.sub.3 is —NH—; and/or, ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered fused heterocyclyl, or 6-14 membered bridged heterocyclyl; and/or, ring C is heteroaryl; and/or, R.sub.2 is selected from hydrogen atom, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heteroaryl is optionally further substituted with unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl; and/or, R.sub.aa is selected from hydrogen atom, or alkyl; and/or, R.sub.3 is selected from hydrogen atom, alkyl, or hydroxyalkyl.
4. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the compound of formula (I) is as defined in any one of the following schemes: scheme 1: the compound of formula (I) is a compound of formula (I-1), ##STR00810## wherein, ring D is heterocycloalkenyl, aryl, or heteroaryl; X.sub.1, X.sub.2 and X.sub.3 are independently CH or N; L.sub.1 is selected from alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.1 is selected from halogen, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen or alkoxy; wherein the heterocyclyl is optionally further substituted with cyano; wherein the heteroaryl is optionally further substituted with alkyl; when L.sub.1 is —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, R.sub.1 is alkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen; wherein the heterocyclyl or heteroaryl is optionally further substituted with alkyl; scheme 2: the compound of formula (I) is a compound of formula (I-2), ##STR00811## wherein, x is 0, 1 or 2; scheme 3: the compound of formula (I) is a compound of formula (I-3), ##STR00812## wherein, x is 0, 1 or 2; scheme 4: the compound of formula (I) is a compound of formula (I-4), ##STR00813## wherein, L.sub.1 is selected from alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.1 is selected from halogen, cyano, alkyl, alkoxy, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen or alkoxy; wherein the heterocyclyl is optionally further substituted with cyano; when L.sub.1 is —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, R.sub.1 is alkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen; wherein the heterocyclyl or heteroaryl is optionally further substituted with alkyl.
5. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the compound of formula (I) is as defined in any one of the following schemes: scheme 1: L.sub.1 is selected from bond, alkylene, cycloalkyl, heterocyclyl, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —NR.sub.aa(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1S(O).sub.m1—, or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; L.sub.2 is selected from bond, oxygen atom, —CR.sub.aaR.sub.bb—, —(CH.sub.2).sub.n1C(O)—, —NR.sub.4—, or —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.4 is selected from hydrogen atom, or alkyl; L.sub.3 is selected from bond, —NR.sub.aa—, or —C(O)NR.sub.aa—; ring A is 6-14 membered fused heteroaryl; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered bridged heterocyclyl, 6-14 membered fused heterocyclyl, or 6-14 membered spiro heterocyclyl; ring C is heteroaryl; R.sub.1 is selected from hydrogen atom, alkyl, haloalkyl, alkoxy, halogen, amino, hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the alkyl, amino, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from halogen, cyano, alkyl, or alkoxy; R.sub.2 is selected from hydrogen atom, alkyl, alkoxy, halogen, amino, hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1SR.sub.aa, or —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb; wherein the alkyl, alkoxy, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from substituted or unsubstituted alkyl, unsubstituted alkoxy, unsubstituted cycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted heterocyclyl, or unsubstituted heteroaryl; wherein “substituted” refers to be substituted with alkyl, or halogen; R.sub.cc is heterocyclyl; wherein the heterocyclyl is optionally substituted with unsubstituted alkyl; R.sub.3 is selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, alkoxy, halogen, hydroxyl, cyano, cycloalkyl, heterocyclyl, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb; wherein the alkyl, alkoxy, cycloalkyl, or heterocyclyl is optionally further substituted with one or more substituents selected from halogen, hydroxyl, unsubstituted alkyl, or unsubstituted alkoxy; R.sub.aa and R.sub.bb are identical or different and are each independently selected from hydrogen atom, alkyl, amino, or heteroaryl; wherein the alkyl and amino are optionally further substituted with one or more substituents selected from unsubstituted alkyl, substituted or unsubstituted heterocyclyl, unsubstituted heteroaryl; wherein “substituted” refers to be substituted with alkyl, or halogen; x is 0, 1, 2 or 3; y is 0, 1, 2 or 3; m.sub.1 is 0, 1 or 2; m.sub.2 is 0, 1 or 2; and n.sub.1 is 0, 1 or 2; scheme 2: L.sub.1 is selected from bond, alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; L.sub.2 is selected from bond, oxygen atom, or —NR.sub.4—; R.sub.4 is selected from hydrogen atom, or alkyl; L.sub.3 is —NR.sub.aa—; ring A is 6-14 membered fused heteroaryl; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered bridged heterocyclyl, or 6-14 membered fused heterocyclyl; ring C is heteroaryl; R.sub.1 is selected from hydrogen atom, alkyl, haloalkyl, amino, heterocyclyl, or heteroaryl; wherein the alkyl, amino, heterocyclyl, or heteroaryl is optionally further substituted with one or more substituents selected from halogen, cyano, alkyl, or alkoxy; R.sub.2 is selected from hydrogen atom, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, or heteroaryl; wherein the heteroaryl is optionally further substituted with one or more substituents selected from unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl; R.sub.3 is selected from hydrogen atom, alkyl, hydroxyalkyl, halogen, cyano, cycloalkyl, —(CH.sub.2).sub.n1C(O)R.sub.aa, or —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb; wherein the alkyl is optionally further substituted with hydroxyl; R.sub.aa and R.sub.bb are identical or different and are each independently selected from hydrogen atom, alkyl, or amino; x is 0, 1, 2 or 3; y is 0, 1, 2 or 3; m.sub.1 is 0, 1 or 2; m.sub.2 is 0, 1 or 2; and n.sub.1 is 0, 1 or 2.
6. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the compound of formula (I) is as defined in any one of the following schemes: scheme 1: the compound of formula (I) is a compound of formula (I-1), ##STR00814## wherein, ring D is heterocycloalkenyl, aryl, or heteroaryl; X.sub.1, X.sub.2 and X.sub.3 are independently CH or N; L.sub.1 is selected from alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.1 is selected from halogen, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen or alkoxy; wherein the heterocyclyl is optionally further substituted with cyano; wherein the heteroaryl is optionally further substituted with alkyl; when L.sub.1 is —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, R.sub.1 is alkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen; wherein the heterocyclyl or heteroaryl is optionally further substituted with alkyl; L.sub.2 is selected from oxygen atom, or —NR.sub.4—; R.sub.4 is selected from hydrogen atom, or alkyl; L.sub.3 is —NH—; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered fused heterocyclyl, or 6-14 membered bridged heterocyclyl; ring C is heteroaryl; R.sub.2 is selected from hydrogen atom, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1OR.sub.cc, or —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb; wherein the alkyl is optionally further substituted with heterocyclyl unsubstituted or substituted with alkyl; wherein the alkoxy is optionally further substituted with unsubstituted alkoxy, heterocyclyl unsubstituted or substituted with alkyl, or unsubstituted heteroaryl; wherein the heterocyclyl is optionally further substituted with unsubstituted alkyl, unsubstituted alkoxy, or amino substituted with alkyl; wherein the heteroaryl is optionally further substituted with alkyl unsubstituted or substituted with halogen, unsubstituted alkoxy, or unsubstituted cycloalkyl; R.sub.aa and R.sub.bb are identical or different and are each independently selected from hydrogen atom, or alkyl; wherein the alkyl is optionally further substituted with heterocyclyl unsubstituted or substituted with alkyl, or unsubstituted heteroaryl; R.sub.cc is heterocyclyl; wherein the heterocyclyl is optionally further substituted with unsubstituted alkyl; R.sub.3 is selected from hydrogen atom, alkyl, or hydroxyalkyl; scheme 2: the compound of formula (I) is a compound of formula (I-1), ##STR00815## wherein, ring D is heterocycloalkenyl, aryl, or heteroaryl; X.sub.1, X.sub.2 and X.sub.3 are independently CH or N; L.sub.1 is selected from alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.1 is selected from halogen, cyano, alkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen or alkoxy; wherein the heterocyclyl is optionally further substituted with cyano; wherein the heteroaryl is optionally further substituted with alkyl; when L.sub.1 is —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, R.sub.1 is alkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen; wherein the heterocyclyl or heteroaryl is optionally further substituted with alkyl; L.sub.2 is selected from oxygen atom, or —NR.sub.4—; R.sub.4 is selected from hydrogen atom, or alkyl; L.sub.3 is —NH—; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered fused heterocyclyl, or 6-14 membered bridged heterocyclyl; ring C is heteroaryl; R.sub.2 is selected from hydrogen atom, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heteroaryl is optionally further substituted with unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl; R.sub.aa is selected from hydrogen atom, or alkyl; R.sub.3 is selected from hydrogen atom, alkyl, or hydroxyalkyl; or, scheme 3: the compound of formula (I) is a compound of formula (I-2), ##STR00816## wherein, L.sub.1 is alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.aa is selected from hydrogen atom, or alkyl; L.sub.2 is —NH—; L.sub.3 is —NH—; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered bridged heterocyclyl, or 6-14 membered fused heterocyclyl; ring C is heteroaryl; R.sub.1 is alkyl, cyano, heterocyclyl, or heteroaryl; wherein the heterocyclyl is optionally further substituted with cyano; R.sub.2 is selected from hydrogen atom, or alkyl; R.sub.3 is selected from hydrogen atom, alkyl, or hydroxyalkyl; x is 0, 1 or 2; scheme 4: the compound of formula (I) is a compound of formula (I-2), ##STR00817## wherein, L.sub.1 is alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.aa is selected from hydrogen atom, or alkyl; L.sub.2 is —NH—; L.sub.3 is —NH—; ring B is selected from 6-14 membered bridged heterocyclyl, or 6-14 membered fused heterocyclyl; ring C is heteroaryl; R.sub.1 is alkyl, cyano, or heterocyclyl; R.sub.2 is selected from hydrogen atom, or alkyl; R.sub.3 is selected from hydrogen atom, alkyl, or hydroxyalkyl; x is 0, 1 or 2; scheme 5: the compound of formula (I) is a compound of formula (I-2), ##STR00818## wherein, L.sub.1 is C.sub.1-C.sub.4 alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.aa is selected from hydrogen atom, or C.sub.1-C.sub.3 alkyl; L.sub.2 is —NH—; L.sub.3 is —NH—; ring B is selected from 7-10 membered bridged heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S, or 7-10 membered fused heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; ring C is 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; R.sub.1 is C.sub.1-C.sub.4 alkyl, cyano, or 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; R.sub.2 is selected from hydrogen atom, or C.sub.1-C.sub.3 alkyl; R.sub.3 is selected from hydrogen atom, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 hydroxyalkyl; x is 0, 1 or 2; or, scheme 6: the compound of formula (I) is a compound of formula (I-3), ##STR00819## wherein, L.sub.1 is alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; L.sub.2 is oxygen atom, or —NR.sub.4—; R.sub.4 is selected from hydrogen atom, or alkyl; L.sub.3 is —NH—; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered bridged heterocyclyl, or 6-14 membered fused heterocyclyl; ring C is heteroaryl; R.sub.1 is hydrogen atom, alkyl, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heterocyclyl, or heteroaryl is optionally further substituted with unsubstituted alkyl, or cyano; wherein the aryl is optionally further substituted with unsubstituted alkoxy; R.sub.2 is selected from hydrogen atom, alkyl, heterocyclyl, or —(CH.sub.2).sub.n1SR.sub.aa; wherein the alkyl is optionally further substituted with unsubstituted alkoxy, or heterocyclyl unsubstituted or substituted with alkyl; wherein the heterocyclyl is optionally further substituted with alkyl; R.sub.3 is selected from hydrogen atom, alkyl, or hydroxyalkyl; R.sub.aa is selected from hydrogen atom, or alkyl; x is 0, 1 or 2; scheme 7: the compound of formula (I) is a compound of formula (I-3), ##STR00820## wherein, L.sub.1 is alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; L.sub.2 is oxygen atom, or —NR.sub.4—; R.sub.4 is selected from hydrogen atom, or alkyl; L.sub.3 is —NH—; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered bridged heterocyclyl, or 6-14 membered fused heterocyclyl; ring C is heteroaryl; R.sub.1 is hydrogen atom, alkyl, cyano, heterocyclyl, or heteroaryl; wherein the heterocyclyl, or heteroaryl is optionally further substituted with unsubstituted alkyl, or cyano; R.sub.2 is selected from hydrogen atom, or alkyl; R.sub.3 is selected from hydrogen atom, alkyl, or hydroxyalkyl; R.sub.aa is selected from hydrogen atom, or alkyl; x is 0, 1 or 2; scheme 8: the compound of formula (I) is a compound of formula (I-3), ##STR00821## wherein, L.sub.1 is C.sub.1-C.sub.4 alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; L.sub.2 is oxygen atom, or —NR.sub.4—; R.sub.4 is selected from hydrogen atom, or C.sub.1-C.sub.3 alkyl; L.sub.3 is —NH—; ring B is selected from 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S, 7-10 membered bridged heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; or 7-10 membered fused heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; ring C is 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; R.sub.1 is hydrogen atom, C.sub.1-C.sub.3 alkyl, cyano, 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S, or 5-6 membered heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; wherein the monocyclic heterocyclyl, or heteroaryl is optionally further substituted with C.sub.1-C.sub.3 alkyl, or cyano; R.sub.2 is selected from hydrogen atom, or C.sub.1-C.sub.3 alkyl; R.sub.3 is selected from hydrogen atom, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 hydroxyalkyl; R.sub.aa is selected from hydrogen atom, or C.sub.1-C.sub.3 alkyl; x is 0, 1 or 2; scheme 9: the compound of formula (I) is a compound of formula (I-3), ##STR00822## wherein, L.sub.1 is alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, or —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—; R.sub.1 is alkyl, cyano, heterocyclyl or heteroaryl; wherein the heterocyclyl is optionally further substituted with alkyl; L.sub.2 is oxygen atom, or —NR.sub.4—; R.sub.4 is selected from hydrogen atom, or alkyl; L.sub.3 is —NH—; ring B is 6-14 membered bridged heterocyclyl; ring C is heteroaryl; R.sub.2 is selected from hydrogen atom, or alkyl; R.sub.3 is selected from hydrogen atom, or alkyl; R.sub.aa is selected from hydrogen atom, or alkyl; or, scheme 10: the compound of general formula (I) is a compound of formula (I-4) shown below, ##STR00823## wherein, L.sub.1 is selected from alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.1 is selected from halogen, cyano, alkyl, alkoxy, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen or alkoxy; wherein the heterocyclyl is optionally further substituted with cyano; when L.sub.1 is —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, R.sub.1 is alkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen; wherein the heterocyclyl or heteroaryl is optionally further substituted with alkyl; L.sub.2 is —NR.sub.4—; R.sub.4 is selected from hydrogen atom, or alkyl; L.sub.3 is —NH—; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered bridged heterocyclyl, or 6-14 membered fused heterocyclyl; ring C is heteroaryl; R.sub.2 is selected from hydrogen atom, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1OR.sub.cc, or —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb; wherein the alkyl is optionally further substituted with heterocyclyl unsubstituted or substituted with alkyl; wherein the alkoxy is optionally further substituted with unsubstituted alkoxy, heterocyclyl unsubstituted or substituted with alkyl, or unsubstituted heteroaryl; wherein the heterocyclyl is optionally further substituted with unsubstituted alkyl, unsubstituted alkoxy, or amino substituted with alkyl; wherein the heteroaryl is optionally further substituted with alkyl unsubstituted or substituted with halogen, unsubstituted alkoxy, or unsubstituted cycloalkyl; R.sub.aa and R.sub.bb are identical or different and are each independently selected from hydrogen atom, or alkyl; wherein the alkyl is optionally further substituted with heterocyclyl unsubstituted or substituted with alkyl, or unsubstituted heteroaryl; R.sub.cc is heterocyclyl; wherein the heterocyclyl is optionally further substituted with unsubstituted alkyl; R.sub.3 is selected from hydrogen atom, alkyl, or hydroxyalkyl; scheme 11: the compound of general formula (I) is a compound of formula (I-4) shown below, ##STR00824## wherein, L.sub.1 is selected from alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.1 is selected from halogen, cyano, alkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen or alkoxy; wherein the heterocyclyl is optionally further substituted with cyano; wherein the heteroaryl is optionally further substituted with alkyl; when L.sub.1 is —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, R.sub.1 is alkyl, heterocyclyl, or heteroaryl; wherein the alkyl is optionally further substituted with halogen; wherein the heterocyclyl or heteroaryl is optionally further substituted with alkyl; L.sub.2 is —NR.sub.4—; R.sub.4 is selected from hydrogen atom, or alkyl; L.sub.3 is —NH—; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered bridged heterocyclyl, or 6-14 membered fused heterocyclyl; ring C is heteroaryl; R.sub.2 is selected from hydrogen atom, alkyl, alkoxy, halogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the heteroaryl is optionally further substituted with unsubstituted alkyl, unsubstituted alkoxy, or unsubstituted cycloalkyl; R.sub.3 is selected from hydrogen atom, alkyl, or hydroxyalkyl; scheme 12: the compound of general formula (I) is a compound of formula (I-4) shown below, ##STR00825## wherein, L.sub.1 is selected from C.sub.1-C.sub.4 alkylene, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, or —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.1 is selected from halogen, cyano, C.sub.1-C.sub.3 alkyl, 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S, or 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; the C.sub.1-C.sub.3 alkyl is optionally further substituted with halogen or C.sub.1-C.sub.3 alkoxy; wherein the heterocyclyl is optionally further substituted with cyano; wherein the heteroaryl is optionally further substituted with C.sub.1-C.sub.3 alkyl; when L.sub.1 is —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, then R.sub.1 is C.sub.1-C.sub.3 alkyl, 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S, or 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; wherein the C.sub.1-C.sub.3 alkyl is optionally further substituted with halogen; wherein the heterocyclyl or heteroaryl is optionally further substituted with C.sub.1-C.sub.3 alkyl; L.sub.2 is —NR.sub.4—; R.sub.4 is selected from hydrogen atom, or C.sub.1-C.sub.3 alkyl; L.sub.3 is —NH—; ring B is selected from 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S, 7-10 membered bridged heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S, or 7-10 membered fused heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; ring C is 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; R.sub.2 is selected from hydrogen atom, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, halogen, cycloalkyl, 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S, 6-10 membered aryl, or 5-6 membered heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; wherein the heteroaryl is optionally further substituted with unsubstituted C.sub.1-C.sub.3 alkyl, unsubstituted C.sub.1-C.sub.3 alkoxy, or unsubstituted 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; R.sub.3 is selected from hydrogen atom, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 hydroxyalkyl; scheme 13: the compound of general formula (I) is a compound of formula (I-4) shown below, ##STR00826## wherein, L.sub.1 is alkylene, or —(CH.sub.2).sub.n1S(O).sub.m1—; R.sub.1 is cyano, or heterocyclyl; wherein the heterocyclyl is optionally further substituted with cyano; L.sub.2 is —NH—; L.sub.3 is —NH—; R.sub.2 is selected from hydrogen atom, halogen, or alkoxy; R.sub.3 is selected from hydrogen atom, or alkyl.
7. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein, when L.sub.1 is alkylene, the alkylene is C.sub.1-C.sub.4 alkylene; and/or, when L.sub.1 is cycloalkyl, the cycloalkyl is C.sub.3-C.sub.8 cycloalkyl; and/or, when L.sub.1 is heterocyclyl, the heterocyclyl is 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when L.sub.1 is —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, the —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1— is —C(O)—, —C(O)CH.sub.2—, or —CH.sub.2C(O)—; and/or, when L.sub.1 is —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, the —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2— is —C(O)CH.sub.2NH—, —C(O)CH.sub.2N(CH.sub.3)—, —C(O)CH.sub.2NHCH.sub.2—, —C(O)CH.sub.2NH(CH.sub.2).sub.2—, or —CH.sub.2C(O)N(CH.sub.3)—; and/or, when L.sub.1 is —NR.sub.aa(CH.sub.2).sub.n1—, the —NR.sub.aa(CH.sub.2).sub.n1— is —NH(CH.sub.2).sub.2—; and/or, when L.sub.1 is —(CH.sub.2).sub.n1S(O).sub.m1—, the —(CH.sub.2).sub.n1S(O).sub.m1— is —S(O).sub.2—; and/or, when L.sub.1 is —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—, the —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa— is —S(O).sub.2NH—; and/or, the left end of L.sub.1 is connected with ring B, and the right end of L.sub.1 is connected with R.sub.1; and/or, when L.sub.2 is —CR.sub.aaR.sub.bb—, the —CR.sub.aaR.sub.bb— is —CH.sub.2— or —CH(OH)—; and/or, when L.sub.2 is —(CH.sub.2).sub.n1C(O)—, the —(CH.sub.2).sub.n1C(O)— is —C(O)—; and/or, when L.sub.2 is —NR.sub.4—, the —NR.sub.4— is —NH— or —N(CH.sub.3); and/or, when L.sub.2 is —(CH.sub.2).sub.n1S(O).sub.m1—, the —(CH.sub.2).sub.n1S(O).sub.m1— is —S(O).sub.2—; and/or, the left end of L.sub.2 is connected with ring A, and the right end of L.sub.2 is connected with ring B; and/or, when R.sub.4 is alkyl, the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when L.sub.3 is —NR.sub.aa—, the —NR.sub.aa— is —NH—; and/or, when L.sub.3 is —C(O)NR.sub.aa—, the —C(O)NR.sub.aa— is —C(O)NH—; and/or, the left end of L.sub.3 is connected with ring C, and the right end of L.sub.3 is connected with ring B; and/or, when the ring A is 6-14 membered fused heteroaryl, the 6-14 membered fused heteroaryl is 6-14 membered fused heteroaryl having 1-4 heteroatoms selected from one or more of N, O or S; the left end of ring A is connected with L.sub.3, and the right end of ring A is connected with L.sub.2; and/or, when the ring B is 3-10 membered monocyclic heterocyclyl, the 3-10 membered monocyclic heterocyclyl is 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when the ring B is 6-14 membered bridged heterocyclyl, the 6-14 membered bridged heterocyclyl is 6-14 membered bridged heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when the ring B is 6-14 membered fused heterocyclyl, the 6-14 membered fused heterocyclyl is 6-14 membered fused heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when the ring B is 6-14 membered spiro heterocyclyl, the 6-14 membered spiro heterocyclyl is 6-14 membered spiro heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, the upper end of ring B is connected with L.sub.1, and the lower end of ring B is connected with L.sub.2; and/or, when the ring C is heteroaryl, the heteroaryl is 6-14 membered heteroaryl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.1 is alkyl, the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.1 is haloalkyl, the haloalkyl is C.sub.1-C.sub.8 haloalkyl; and/or, when R.sub.1 is alkoxy, the alkoxy is C.sub.1-C.sub.8 alkoxy; and/or, when R.sub.1 is halogen, the halogen is fluorine; and/or, when R.sub.1 is cycloalkyl, the cycloalkyl is C.sub.3-C.sub.8 cycloalkyl; and/or, when R.sub.1 is heterocyclyl, the heterocyclyl is 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.1 is aryl, the aryl is 6-10 membered aryl; and/or, when R.sub.1 is heteroaryl, the heteroaryl is 5-10 membered heteroaryl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.1 is alkyl, amino, heterocyclyl, aryl or heteroaryl, wherein the alkyl, amino, heterocyclyl, aryl or heteroaryl is optionally further substituted with halogen, then the halogen is fluorine; and/or, when R.sub.1 is amino, heterocyclyl, aryl or heteroaryl, wherein the amino, heterocyclyl, aryl or heteroaryl is optionally further substituted with alkyl, then the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.1 is alkyl, amino, heterocyclyl, aryl or heteroaryl, wherein the alkyl, amino, heterocyclyl, aryl or heteroaryl is optionally further substituted with alkoxy, then the alkoxy is C.sub.1-C.sub.8 alkoxy; and/or, when R.sub.2 is alkyl, the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.2 is alkoxy, the alkoxy is C.sub.1-C.sub.8 alkoxy; and/or, when R.sub.2 is halogen, the halogen is fluorine, chlorine or bromine; and/or, when R.sub.2 is cycloalkyl, the cycloalkyl is C.sub.3-C.sub.8 cycloalkyl; and/or, when R.sub.2 is heterocyclyl, the heterocyclyl is 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.2 is aryl, the aryl is 6-10 membered aryl; and/or, when R.sub.2 is heteroaryl, the heteroaryl is 5-10 membered heteroaryl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.2 is —(CH.sub.2).sub.n1SR.sub.aa, the —(CH.sub.2).sub.n1SR.sub.aa is ##STR00827## and/or, when R.sub.2 is —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, the —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb is ##STR00828## and/or, when R.sub.2 is alkyl, and the alkyl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.8 alkoxy; and/or, when R.sub.2 is alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.2 is alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, wherein the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with unsubstituted alkoxy, then the unsubstituted alkoxy is C.sub.1-C.sub.8 alkoxy; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, wherein the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with unsubstituted heteroaryl, then the heteroaryl is 5-10 membered heteroaryl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.2 is amino, and the amino is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.8 alkoxy; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with substituted or unsubstituted amino, then the amino is substituted with alkyl, wherein the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with substituted or unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with substituted or unsubstituted alkyl, then the alkyl is substituted with halogen, wherein the halogen is fluorine; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.8 alkoxy; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with unsubstituted cycloalkyl, then the cycloalkyl is C.sub.3-C.sub.8 cycloalkyl; and/or, when R.sub.cc is heterocyclyl, the heterocyclyl is 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.cc is heterocyclyl, and the heterocyclyl is optionally substituted with unsubstituted alkyl then the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.3 is alkyl, the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.3 is hydroxyalkyl, the hydroxyalkyl is C.sub.1-C.sub.8 hydroxyalkyl; and/or, when R.sub.3 is haloalkyl, the haloalkyl is C.sub.1-C.sub.8 haloalkyl; and/or, when R.sub.3 is alkoxy, the alkoxy is C.sub.1-C.sub.8 alkoxy; and/or, when R.sub.3 is halogen, the halogen is fluorine; and/or, when R.sub.3 is cycloalkyl, the cycloalkyl is C.sub.3-C.sub.8 cycloalkyl; and/or, when R.sub.3 is heterocyclyl, the heterocyclyl is 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.3 is alkyl, and the alkyl is optionally further substituted with halogen, then the halogen is fluorine; and/or, when R.sub.3 is alkyl, and the alkyl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.8 alkoxy; and/or, when R.sub.3 is alkoxy, and the alkoxy is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.3 is cycloalkyl, the cycloalkyl is substituted with hydroxyl; and/or, when R.sub.3 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.3 is —(CH.sub.2).sub.n1C(O)R.sub.aa, the —(CH.sub.2).sub.n1C(O)R.sub.aa is ##STR00829## and/or, when R.sub.3 is —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, the —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb is ##STR00830## and/or, when R.sub.3 is —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, the —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa is ##STR00831## and/or, when R.sub.3 is —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, the —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb is ##STR00832## and/or, when R.sub.aa and R.sub.bb are independently alkyl, the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.aa and R.sub.bb are independently heteroaryl, the heteroaryl is 5-10 membered heteroaryl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.aa and R.sub.bb are independently alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is 3-8 membered monocyclic heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.aa and R.sub.bb are independently alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, the alkyl is C.sub.1-C.sub.8 alkyl; and/or, when R.sub.aa and R.sub.bb are independently alkyl, and the alkyl is optionally further substituted with unsubstituted heteroaryl, then the heteroaryl is 5-10 membered heteroaryl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.aa and R.sub.bb are independently amino, and the amino is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.8 alkyl.
8. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 7, wherein, -L.sub.1- is bond, —CH.sub.2—, —(CH.sub.2).sub.2—, ##STR00833## —C(O)—, —C(O)CH.sub.2—, —CH.sub.2C(O)—, —C(O)CH.sub.2NH—, —C(O)CH.sub.2N(CH.sub.3)—, —C(O)CH.sub.2NHCH.sub.2—, —C(O)CH.sub.2NH(CH.sub.2).sub.2—, —CH.sub.2C(O)N(CH.sub.3)—, —NH(CH.sub.2).sub.2—, —S(O).sub.2—, or —S(O).sub.2NH—; the left end of L.sub.1 is connected with ring B, and the right end of L.sub.1 is connected with R.sub.1; and/or, L.sub.2 is bond, oxygen atom, —CH.sub.2—, —CH(OH)—, —C(O)—, —NH—, —N(CH.sub.3)— or —S(O).sub.2—; the left end of L.sub.2 is connected with ring A, and the right end of L.sub.2 is connected with ring B; and/or, L.sub.3 is bond, —NH— or —C(O)NH—; the left end of L.sub.3 is connected with ring C, and the right end of L.sub.3 is connected with ring B; and/or, the ring A is the following group, ##STR00834## ##STR00835## ##STR00836## ##STR00837## the left end of ring A is connected with L.sub.3, and the right end of ring A is connected with L.sub.2; and/or, the ring B is the following group, ##STR00838## the upper end of ring B is connected with L.sub.1, and the lower end of ring B is connected with L.sub.2; and/or, the ring C is the following group, ##STR00839## and/or, R.sub.1 is hydrogen atom, methyl, ethyl, fluorine, methoxy, ethoxy, phenyl, cyano, —CHF.sub.2, —CH.sub.2CH.sub.2CN, —CH.sub.2CH.sub.2F, —NHCH.sub.2CH.sub.2CN, ##STR00840## and/or, R.sub.2 is hydrogen atom, fluorine, chlorine, bromine, amino, hydroxyl, cyano, methyl, methoxy, ##STR00841## ##STR00842## and/or, R.sub.3 is hydrogen atom, methyl, ethyl, fluorine, cyano, —CHF.sub.2, CF.sub.3, ##STR00843## and/or, structure -L.sub.1-R.sub.1 is ##STR00844## ##STR00845##
9. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein, L.sub.1 is selected from bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —NR.sub.aa(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1S(O).sub.m1— or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; L.sub.2 is selected from bond, oxygen atom, sulfur atom, —CR.sub.aaR.sub.bb—, —(CH.sub.2).sub.n1C(O)—, —NR.sub.4— or —(CH.sub.2).sub.n1S(O).sub.m1—; L.sub.3 is selected from bond, —NR.sub.aa— or —C(O)NR.sub.aa—; ring A is selected from 6-14 membered heteroaryl, wherein the 6-14 membered heteroaryl is selected from 6-14 membered fused heteroaryl; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered bridged heterocyclyl or 6-14 membered fused heterocyclyl; ring C is selected from heteroaryl; R.sub.1 is selected from hydrogen atom, deuterium atom, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.2 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1O(CH.sub.2).sub.m1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1NR.sub.aa(CH.sub.2).sub.m1R.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1 SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S—, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted, unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2)n.sub.n1S(O).sub.m1 NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.3 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.4 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, or alkynyl; R.sub.aa, R.sub.bb, R.sub.cc, and R.sub.dd are identical or different, and are each independently selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; x is an integer of 0, 1, 2 or 3; y is an integer of 0, 1, 2, 3, 4 or 5; m.sub.1 is an integer of 0, 1 or 2; m.sub.2 is an integer of 0, 1 or 2; and n.sub.1 is an integer of 0, 1, 2, 3, 4 or 5.
10. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 9, wherein, L.sub.1 is selected from bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, —NR.sub.aa(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1S(O).sub.m1— or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; L.sub.2 is selected from bond, oxygen atom, sulfur atom, —CR.sub.aaR.sub.bb—, —(CH.sub.2).sub.n1C(O)—, —NR.sub.4— or —(CH.sub.2).sub.n1S(O).sub.m1—; L.sub.3 is selected from bond, —NR.sub.aa— or —C(O)NR.sub.aa—; ring A is selected from 6-14 membered heteroaryl, wherein the 6-14 membered heteroaryl is selected from 6-14 membered fused heteroaryl; ring B is selected from 6-14 membered bridged heterocyclyl or 6-14 membered fused heterocyclyl; ring C is selected from heteroaryl; R.sub.1 is selected from hydrogen atom, deuterium atom, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.2 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, oxo, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl or alkynyl; R.sub.3 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1 NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.4 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl or alkynyl; R.sub.aa, R.sub.bb, R.sub.cc and R.sub.dd are identical or different and are each independently selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; x is an integer of 0, 1, 2 or 3; y is an integer of 0, 1, 2, 3, 4 or 5; m.sub.1 is an integer of 0, 1 or 2; m.sub.2 is an integer of 0, 1 or 2; and n.sub.1 is an integer of 0, 1, 2, 3, 4 or 5.
11. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 9, which is a compound of general formula (II), a compound of general formula (IIA), a compound of general formula (IIIA), a compound of general formula (III) and a compound of general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ##STR00846## wherein: W is independently selected from nitrogen atom or alkylene; R.sub.4 is selected from hydrogen atom, halogen, cyano, alkyl, alkenyl, alkynyl or alkoxy; —R.sub.5 is selected from hydrogen atom, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.6 is selected from hydrogen atom, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl or —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb; R.sub.7 is selected from hydrogen atom, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, oxo or thioxo: R.sub.10 and R.sub.11 are identical or different and are each independently selected from hydrogen atom, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb—, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; ring D is selected from heterocyclyl, aryl or heteroaryl; E.sub.1, E.sub.2 and E.sub.3 are identical or different and are each independently selected from nitrogen atom or —CR.sub.aa—; n is an integer of 0, 1, 2, or 3; z is an integer of 0, 1, 2 or 3; and L.sub.1, L.sub.2, L.sub.3, ring A, ring B, ring C, R.sub.1-R.sub.3, R.sub.aa, x and y are as previously defined.
12.-21. (canceled)
22. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 9, which is a compound of general formula (XII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ##STR00847## wherein: L.sub.1 is selected from bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —(CH.sub.2).sub.n1S(O).sub.m1— or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered spiro heterocyclyl, 6-14 membered bridged heterocyclyl or 6-14 membered fused heterocyclyl; ring T is selected from aryl or heteroaryl; R.sub.1 is selected from hydrogen atom, deuterium atom, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1 OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.3 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.4 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl or alkynyl; R.sub.13 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1O(CH.sub.2).sub.m1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1NR.sub.aa(CH.sub.2).sub.m1R.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S—, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, (CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.aa, R.sub.bb, R.sub.cc and R.sub.dd are identical or different and are each independently selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; y is an integer of 0, 1, 2, 3, 4 or 5; q is an integer of 0, 1, 2, 3, 4 or 5; m.sub.1 is an integer of 0, 1 or 2; m.sub.2 is an integer of 0, 1 or 2; and n.sub.1 is an integer of 0, 1, 2, 3, 4 or 5.
23. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 9, which is a compound of general formula (XIII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ##STR00848## wherein: L.sub.1 is selected from bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —(CH.sub.2).sub.n1S(O).sub.m1— or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; ring T is selected from aryl or heteroaryl; R.sub.1 is selected from hydrogen atom, deuterium atom, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.3 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.4 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl or alkynyl; R.sub.5 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl or heteroaryl; R.sub.6 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl or heteroaryl; R.sub.13 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1O(CH.sub.2).sub.m1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1NR.sub.aa(CH.sub.2).sub.m1R.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S—, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; q is an integer of 0, 1, 2, 3, 4 or 5; and n is an integer of 0, 1 or 2.
24. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 9, which is a compound of the general formula (XIV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ##STR00849## wherein: L.sub.1 is selected from bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —(CH.sub.2).sub.n1S(O).sub.m1— or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; R.sub.1 is selected from hydrogen atom, deuterium atom, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.4 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl or alkynyl; R.sub.5 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl or heteroaryl, R.sub.6 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl or heteroaryl; R.sub.13 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1O(CH.sub.2).sub.m1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1NR.sub.aa(CH.sub.2).sub.m1R.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S—, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.m1NR.sub.ccS(O).sub.m1R.sub.dd; q is an integer of 0, 1, 2, 3, 4 or 5; and n is an integer of 0, 1 or 2.
25. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 9, which is a compound of the general formula (XV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ##STR00850## wherein: L.sub.1 is selected from bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —(CH.sub.2).sub.n1S(O).sub.m1— or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; J.sub.1, J.sub.2 and J.sub.3 are identical or different and are each independently selected from nitrogen atom, sulfur atom, oxygen atom, NR.sub.aa or CR.sub.14; R.sub.1 is selected from hydrogen atom, deuterium atom, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.4 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl or alkynyl; R.sub.5 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl or heteroaryl; R.sub.6 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl or heteroaryl; R.sub.14 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1O(CH.sub.2).sub.m1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1NR.sub.aa(CH.sub.2).sub.m1R.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S—, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.aa, R.sub.bb, R.sub.cc and R.sub.dd are identical or different and are each independently selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer of 0, 1 or 2; m.sub.1 is an integer of 0, 1 or 2; m.sub.2 is an integer of 0, 1 or 2; and n.sub.1 is an integer of 0, 1, 2, 3, 4 or 5.
26. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 9, which is a compound of the general formula (XVI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ##STR00851## wherein: L.sub.1 is selected from bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —(CH.sub.2).sub.n1S(O).sub.m1— or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; R.sub.1 is selected from hydrogen atom, deuterium atom, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.5 is selected from hydrogen atom, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.6 is selected from hydrogen atom, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl or —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb; R.sub.15 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1O(CH.sub.2).sub.m1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1NR.sub.aa(CH.sub.2).sub.m1R.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S—, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.aa, R.sub.bb, R.sub.cc and R.sub.dd are identical or different and are each independently selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and n is an integer of 0, 1, 2 or 3.
27. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 9, which is a compound of general formula (XVII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ##STR00852## wherein: L.sub.1 is selected from bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.n1NR.sub.aa(CH.sub.2).sub.m2—, —(CH.sub.2).sub.n1S(O).sub.m1— or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; R.sub.1 is selected from hydrogen atom, deuterium atom, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.4 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl or alkynyl; R.sub.5 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl or heteroaryl; R.sub.6 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl or heteroaryl, R.sub.16 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1O(CH.sub.2).sub.m1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1NR.sub.aa(CH.sub.2).sub.m1R.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S—, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.aa, R.sub.bb, R.sub.cc and R.sub.dd are identical or different and are each independently selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; r is an integer of 0, 1 or 2; n is an integer of 0, 1 or 2; m.sub.1 is an integer of 0, 1 or 2; m.sub.2 is an integer of 0, 1 or 2; and n.sub.1 is an integer of 0, 1, 2, 3, 4 or 5.
28. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 9, wherein: ring A is selected from the following group: ##STR00853## ##STR00854## ##STR00855## ##STR00856## ring B is selected from the following group: ##STR00857## ring C is selected from the following group: ##STR00858##
29. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 10, wherein, L.sub.1 is C.sub.3-8 cycloalkyl, C.sub.3-8 heterocycloalkyl, —(CH.sub.2).sub.n1—, —NR.sub.aa(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1S(O).sub.m1— or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; L.sub.2 is selected from bond, oxygen atom, —CR.sub.aaR.sub.bb—, —(CH.sub.2).sub.n1C(O)—, —NR.sub.4— or —(CH.sub.2).sub.n1S(O).sub.m1—; L.sub.3 is selected from bond, —NR.sub.aa— or —C(O)NR.sub.aa—; R.sub.1 is selected from cyano, —(CH.sub.2).sub.n1R.sub.aa, C.sub.3-8 cycloalkyl or 3-10 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally further substituted with one or more substituents selected from hydrogen atom or cyano; R.sub.2 is selected from hydrogen atom, halogen, cyano, hydroxyl, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or 3-10 membered heterocyclyl; preferably hydrogen atom, halogen, cyano, hydroxyl, oxo, C.sub.1-3 alkoxy, C.sub.1-3 alkyl or 3-8 membered heterocyclyl; more preferably hydrogen atom, fluorine, cyano, hydroxyl, oxo, methoxy, methyl or morpholinyl; R.sub.3 is selected from hydrogen atom, cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.3-8 cycloalkyl, 3-10 membered heterocyclyl, —(CH.sub.2).sub.n1OR.sub.aa, —C(O)NR.sub.aaR.sub.bb or —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, wherein the cycloalkyl and heterocyclyl are optionally further substituted with one or more substituents selected from hydrogen atom, C.sub.1-6 alkyl or hydroxyl; R.sub.4 is selected from hydrogen atom or methyl; R.sub.aa, R.sub.bb, R.sub.cc and R.sub.dd are identical or different and are each independently selected from hydrogen atom, C.sub.1-6 alkyl, cyano, hydroxyl, amino or 3-10 membered heterocyclyl; wherein the C.sub.1-6 alkyl, amino and 3-10 membered heterocyclyl are optionally further substituted with hydrogen atom, cyano, hydroxyl or 5-10 membered heteroaryl.
30. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to any one of claim 9, wherein, L.sub.1 is C.sub.3-8 cycloalkyl, 3-10 membered heterocyclyl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —NR.sub.aa(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1S(O).sub.m1— or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; L.sub.2 is selected from bond, oxygen atom, —CR.sub.aaR.sub.bb—, —(CH.sub.2).sub.n1C(O)—, —NR.sub.4— or —(CH.sub.2).sub.n1S(O).sub.m1—; L.sub.3 is selected from bond, —NR.sub.aa— or —C(O)NR.sub.aa—; R.sub.1 is selected from cyano, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, C.sub.3-8 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl or 5-10 membered heteroaryl, wherein the C.sub.3-8 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl and 5-14 membered heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, cyano, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; R.sub.2 is selected from hydrogen atom, halogen, cyano, hydroxyl, oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-12 aryl, 5-10 membered heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —O(CH.sub.2).sub.n1R.sub.aa, —S(CH.sub.2).sub.n1R.sub.aa or —NR.sub.aa(CH.sub.2).sub.n1R.sub.bb, wherein the C.sub.3-8 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl and 5-10 membered heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl or —NR.sub.ccR.sub.dd; R.sub.3 is selected from hydrogen atom, cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.3-8 cycloalkyl, 3-10 membered heterocyclyl, —(CH.sub.2).sub.n1OR.sub.aa, —C(O)NR.sub.aaR.sub.bb or —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, wherein the cycloalkyl and heterocyclyl are optionally further substituted with one or more substituents selected from hydrogen atom, C.sub.1-6 alkyl or hydroxyl; R.sub.4 is selected from hydrogen atom or methyl; R.sub.aa, R.sub.bb, R.sub.cc and R.sub.dd are identical or different and are each independently selected from hydrogen atom, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, cyano, hydroxyl, amino, C.sub.3-8 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl or 5-10 membered heteroaryl; wherein the C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, amino, C.sub.3-8 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-12 aryl and 5-10 membered heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, cyano, hydroxyl, amino, aminoalkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-8 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl or 5-10 membered heteroaryl.
31. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to any one of claim 1, wherein, the compound of the general formula (I) is selected from the following compounds: ##STR00859## ##STR00860## ##STR00861## ##STR00862## ##STR00863## ##STR00864## ##STR00865## ##STR00866## ##STR00867## ##STR00868## ##STR00869## ##STR00870## ##STR00871## ##STR00872## ##STR00873## ##STR00874## ##STR00875## ##STR00876## ##STR00877## ##STR00878## ##STR00879## ##STR00880## ##STR00881## ##STR00882## ##STR00883## ##STR00884## ##STR00885## ##STR00886## ##STR00887## ##STR00888## ##STR00889## ##STR00890## ##STR00891## ##STR00892## ##STR00893## ##STR00894## ##STR00895## ##STR00896## ##STR00897## ##STR00898## ##STR00899## ##STR00900## ##STR00901## ##STR00902## ##STR00903## ##STR00904## ##STR00905## ##STR00906## ##STR00907## ##STR00908## ##STR00909## ##STR00910## ##STR00911## ##STR00912## ##STR00913## ##STR00914## ##STR00915## ##STR00916## ##STR00917## ##STR00918## ##STR00919## ##STR00920## ##STR00921## ##STR00922## ##STR00923## ##STR00924## ##STR00925## ##STR00926## ##STR00927## ##STR00928## ##STR00929## ##STR00930## ##STR00931## ##STR00932## ##STR00933## ##STR00934## ##STR00935## ##STR00936## ##STR00937## ##STR00938## ##STR00939## ##STR00940## ##STR00941## ##STR00942## ##STR00943## ##STR00944## ##STR00945## ##STR00946##
32. A pharmaceutical composition, comprising a therapeutically effective dose of the compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 8 and one or more pharmaceutically acceptable carriers, diluents or excipients.
33.-34. (canceled)
35. A pharmaceutical composition, comprising the compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 and one or more pharmaceutically acceptable carriers, diluents or excipients, wherein the compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is present in a therapeutically effective amount.
36.-38. (canceled)
39. A method for the treatment of an inflammatory disease or a neoplastic disease, comprising administering to a patient a therapeutically effective dose of the compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1.
40. A method for the prevention and/or treatment of a condition mediated by JAK kinase, comprising administering to a patient a therapeutically effective dose of the compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1.
41. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein, ring A is 5,5 fused heteroaryl, 5,6 fused heteroaryl or 6,6 fused heteroaryl.
42. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 7, wherein, when L.sub.1 is alkylene, the alkylene is —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3— or —(CH.sub.2).sub.4—; and/or, when L.sub.1 is cycloalkyl, the cycloalkyl is C.sub.3-C.sub.6 cycloalkyl; and/or, when L.sub.1 is heterocyclyl, the heterocyclyl is 4-6 membered monocyclic heterocyclyl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.4 is alkyl, the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when the ring A is 6-14 membered fused heteroaryl, the 6-14 membered fused heteroaryl is 5,6 fused heteroaryl having 1-4 heteroatoms selected from one or more of N, O or S or 6,6 fused heteroaryl having 1-4 heteroatoms selected from one or more of N, O or S; and/or, when the ring B is 3-10 membered monocyclic heterocyclyl, the 3-10 membered monocyclic heterocyclyl is 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when the ring B is 6-14 membered bridged heterocyclyl, the 6-14 membered bridged heterocyclyl is 7-10 membered bridged heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when the ring B is 6-14 membered fused heterocyclyl, the 6-14 membered fused heterocyclyl is 7-10 membered fused heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when the ring B is 6-14 membered spiro heterocyclyl, the 6-14 membered spiro heterocyclyl is 7-10 membered spiro heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when the ring C is heteroaryl, the heteroaryl is 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S, or 8-10 membered fused heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.1 is alkyl, the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.1 is haloalkyl, the haloalkyl is C.sub.1-C.sub.6 haloalkyl; and/or, when R.sub.1 is alkoxy, the alkoxy is C.sub.1-C.sub.6 alkoxy; and/or, when R.sub.1 is cycloalkyl, the cycloalkyl is C.sub.3-C.sub.6 cycloalkyl; and/or, when R.sub.1 is heterocyclyl, the heterocyclyl is 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.1 is aryl, the aryl is phenyl; and/or, when R.sub.1 is heteroaryl, the heteroaryl is 5-6 membered heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.1 is amino, heterocyclyl, aryl or heteroaryl, wherein the amino, heterocyclyl, aryl or heteroaryl is optionally further substituted with alkyl, then the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.1 is alkyl, amino, heterocyclyl, aryl or heteroaryl, wherein the alkyl, amino, heterocyclyl, aryl or heteroaryl is optionally further substituted with alkoxy, then the alkoxy is C.sub.1-C.sub.6 alkoxy; and/or, when R.sub.2 is alkyl, the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.2 is alkoxy, the alkoxy is C.sub.1-C.sub.6 alkoxy; and/or, when R.sub.2 is cycloalkyl, the cycloalkyl is C.sub.3-C.sub.6 cycloalkyl; and/or, when R.sub.2 is heterocyclyl, the heterocyclyl is 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.2 is aryl, the aryl is phenyl; and/or, when R.sub.2 is heteroaryl, the heteroaryl is 5-6 membered heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.2 is alkyl, and the alkyl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.6 alkoxy; and/or, when R.sub.2 is alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.2 is alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, wherein the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with unsubstituted alkoxy, then the unsubstituted alkoxy is C.sub.1-C.sub.6 alkoxy; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, wherein the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with unsubstituted heteroaryl, then the heteroaryl is 5-6 membered heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.2 is amino, and the amino is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.6 alkoxy; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with substituted or unsubstituted amino, then the amino is substituted with alkyl, wherein the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with substituted or unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.6 alkoxy; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with unsubstituted cycloalkyl, then the cycloalkyl is C.sub.3-C.sub.6 cycloalkyl; and/or, when R.sub.cc is heterocyclyl, the heterocyclyl is 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.cc is heterocyclyl, and the heterocyclyl is optionally substituted with unsubstituted alkyl then the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.3 is alkyl, the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.3 is hydroxyalkyl, the hydroxyalkyl is C.sub.1-C.sub.6 hydroxyalkyl; and/or, when R.sub.3 is haloalkyl, the haloalkyl is C.sub.1-C.sub.6 haloalkyl; and/or, when R.sub.3 is alkoxy, the alkoxy is C.sub.1-C.sub.6 alkoxy; and/or, when R.sub.3 is cycloalkyl, the cycloalkyl is C.sub.3-C.sub.6 cycloalkyl; and/or, when R.sub.3 is heterocyclyl, the heterocyclyl is 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.3 is alkyl, and the alkyl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.6 alkoxy; and/or, when R.sub.3 is alkoxy, and the alkoxy is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.3 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.aa and R.sub.bb are independently alkyl, the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.aa and R.sub.bb are independently heteroaryl, the heteroaryl is 5-6 membered heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.aa and R.sub.bb are independently alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is 4-6 membered monocyclic heterocyclyl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.aa and R.sub.bb are independently alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, the alkyl is C.sub.1-C.sub.6 alkyl; and/or, when R.sub.aa and R.sub.bb are independently alkyl, and the alkyl is optionally further substituted with unsubstituted heteroaryl, then the heteroaryl is 5-6 membered heteroaryl having 1-3 heteroatoms selected from one or more of N, O or S; and/or, when R.sub.aa and R.sub.bb are independently amino, and the amino is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.6 alkyl.
43. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 7, wherein, when L.sub.1 is alkylene, the alkylene is —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3— or —(CH.sub.2).sub.4; and/or, when L.sub.1 is cycloalkyl, the cycloalkyl is ##STR00947## and/or, when L.sub.1 is heterocyclyl, the heterocyclyl is ##STR00948## and/or, when R.sub.4 is alkyl, the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when the ring A is 6-14 membered fused heteroaryl, the 5,6 fused heteroaryl is thienopyrimidinyl or pyrazolopyrimidinyl, benzopyrrolyl, pyrrolopyridyl, imidazolopyridyl, triazolopyridyl, imidazolopyridazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazolopyrimidinyl, triazolopyrimidinyl, thienopyrimidinyl, thiazolopyrimidinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazolopyrazinyl, triazolopyrazinyl, pyrrolotriazinyl, imidazolotriazinyl or imidazolopyrazinonyl; the 6,6 fused heteroaryl is isoquinolinyl, naphthyridinyl, pyridopyrazinyl, pyridopyrimidinyl, quinazolinyl, pteridinyl, quinoxalinyl, dihydropyranopyrimidinyl, dihydrodioxinopyrimidinyl, ##STR00949## and/or, when the ring B is 3-10 membered monocyclic heterocyclyl, the 3-10 membered monocyclic heterocyclyl is ##STR00950## and/or, when the ring B is 6-14 membered bridged heterocyclyl, the 6-14 membered bridged heterocyclyl is ##STR00951## and/or, when the ring B is 6-14 membered fused heterocyclyl, the 6-14 membered fused heterocyclyl is ##STR00952## and/or, when the ring B is 6-14 membered spiro heterocyclyl, the 6-14 membered spiro heterocyclyl is ##STR00953## and/or, when the ring C is heteroaryl, the 5-6 membered monocyclic heteroaryl is pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridazinyl, pyrimidinyl or pyrazinyl, the 8-10 membered fused heteroaryl is indazolyl, or pyrazolopyridyl; and/or, when R.sub.1 is alkyl, the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.1 is haloalkyl, the haloalkyl is C.sub.1-C.sub.3 haloalkyl; and/or, when R.sub.1 is alkoxy, the alkoxy is C.sub.1-C.sub.3 alkoxy; and/or, when R.sub.1 is cycloalkyl, the cycloalkyl is ##STR00954## and/or, when R.sub.1 is heterocyclyl, the heterocyclyl is ##STR00955## and/or, when R.sub.1 is heteroaryl, the heteroaryl is ##STR00956## and/or, when R.sub.1 is amino, heterocyclyl, aryl or heteroaryl, wherein the amino, heterocyclyl, aryl or heteroaryl is optionally further substituted with alkyl, then the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.1 is alkyl, amino, heterocyclyl, aryl or heteroaryl, wherein the alkyl, amino, heterocyclyl, aryl or heteroaryl is optionally further substituted with alkoxy, then the alkoxy is C.sub.1-C.sub.3 alkoxy; and/or, when R.sub.2 is alkyl, the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.2 is alkoxy, the alkoxy is C.sub.1-C.sub.3 alkoxy; and/or, when R.sub.2 is cycloalkyl, the cycloalkyl is ##STR00957## and/or, when R.sub.2 is heterocyclyl, the heterocyclyl is ##STR00958## and/or, when R.sub.2 is heteroaryl, the heteroaryl is ##STR00959## and/or, when R.sub.2 is alkyl, and the alkyl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.3 alkoxy; and/or, when R.sub.2 is alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is ##STR00960## and/or, when R.sub.2 is alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, wherein the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with unsubstituted alkoxy, then the unsubstituted alkoxy is C.sub.1-C.sub.3 alkoxy; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is ##STR00961## and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, wherein the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with unsubstituted heteroaryl, then the heteroaryl is ##STR00962## and/or, when R.sub.2 is amino, and the amino is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.3 alkoxy; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with substituted or unsubstituted amino, then the amino is substituted with alkyl, wherein the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with substituted or unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.3 alkoxy; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with unsubstituted cycloalkyl, then the cycloalkyl is ##STR00963## and/or, when R.sub.cc is heterocyclyl, the heterocyclyl is ##STR00964## and/or, when R.sub.cc is heterocyclyl, and the heterocyclyl is optionally substituted with unsubstituted alkyl then the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.3 is alkyl, the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.3 is hydroxyalkyl, the hydroxyalkyl is C.sub.1-C.sub.3 hydroxyalkyl; and/or, when R.sub.3 is haloalkyl, the haloalkyl is C.sub.1-C.sub.3 haloalkyl; and/or, when R.sub.3 is alkoxy, the alkoxy is C.sub.1-C.sub.3 alkoxy; and/or, when R.sub.3 is cycloalkyl, the cycloalkyl is ##STR00965## and/or, when R.sub.3 is heterocyclyl, the heterocyclyl is ##STR00966## and/or, when R.sub.3 is alkyl, and the alkyl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is C.sub.1-C.sub.3 alkoxy; and/or, when R.sub.3 is alkoxy, and the alkoxy is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.3 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.aa and R.sub.bb are independently alkyl, the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.aa and R.sub.bb are independently heteroaryl, the heteroaryl is ##STR00967## and/or, when R.sub.aa and R.sub.bb are independently alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is ##STR00968## and/or, when R.sub.aa and R.sub.bb are independently alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, the alkyl is C.sub.1-C.sub.3 alkyl; and/or, when R.sub.aa and R.sub.bb are independently alkyl, and the alkyl is optionally further substituted with unsubstituted heteroaryl, then the heteroaryl is ##STR00969## and/or, when R.sub.aa and R.sub.bb are independently amino, and the amino is optionally further substituted with unsubstituted alkyl, then the alkyl is C.sub.1-C.sub.3 alkyl.
44. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 7, wherein, when R.sub.4 is alkyl, the alkyl is methyl; and/or, when the ring A is 6-14 membered fused heteroaryl, the 5,6 fused heteroaryl is ##STR00970## ##STR00971## ##STR00972## ##STR00973## the 6,6 fused heteroaryl is ##STR00974## ##STR00975## and/or, when the ring B is 6-14 membered bridged heterocyclyl, the 6-14 membered bridged heterocyclyl is ##STR00976## and/or, when the ring C is heteroaryl, wherein the 5-6 membered monocyclic heteroaryl is ##STR00977## the 8-10 membered fused heteroaryl is ##STR00978## and/or, when R.sub.1 is alkyl, the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.1 is haloalkyl, the haloalkyl is —CHF.sub.2 or CF.sub.3; and/or, when R.sub.1 is alkoxy, the alkoxy is methoxy, ethoxy, propoxy or isopropoxy; and/or, when R.sub.1 is amino, heterocyclyl, aryl or heteroaryl, wherein the amino, heterocyclyl, aryl or heteroaryl is optionally further substituted with alkyl, then the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.1 is alkyl, amino, heterocyclyl, aryl or heteroaryl, wherein the alkyl, amino, heterocyclyl, aryl or heteroaryl is optionally further substituted with alkoxy, then the alkoxy is methoxy, ethoxy, propoxy or isopropoxy; and/or, when R.sub.2 is alkyl, the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.2 is alkoxy, the alkoxy is methoxy, ethoxy, propoxy or isopropoxy; and/or, when R.sub.2 is alkyl, and the alkyl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is methoxy, ethoxy, propoxy or isopropoxy; and/or, when R.sub.2 is alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, wherein the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with unsubstituted alkoxy, then the unsubstituted alkoxy is methoxy, ethoxy, propoxy or isopropoxy; and/or, when R.sub.2 is alkoxy, and the alkoxy is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, wherein the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.2 is amino, and the amino is optionally further substituted with unsubstituted alkyl, then the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkyl, then the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is methoxy, ethoxy, propoxy or isopropoxy; and/or, when R.sub.2 is heterocyclyl, and the heterocyclyl is optionally further substituted with substituted or unsubstituted amino, then the amino is substituted with alkyl, wherein the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with substituted or unsubstituted alkyl, then the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.2 is heteroaryl, and the heteroaryl is optionally further substituted with unsubstituted alkoxy, then the alkoxy is methoxy, ethoxy, propoxy or isopropoxy; and/or, when R.sub.cc is heterocyclyl, the heterocyclyl is ##STR00979## and/or, when R.sub.cc is heterocyclyl, and the heterocyclyl is optionally substituted with unsubstituted alkyl, then the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.3 is alkyl, the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.3 is hydroxyalkyl, the hydroxyalkyl is hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxyisopropyl; and/or, when R.sub.3 is haloalkyl, the haloalkyl is —CHF.sub.2 or CF.sub.3; and/or, when R.sub.3 is alkoxy, the alkoxy is methoxy, ethoxy, propoxy or isopropoxy; and/or, when R.sub.3 is heterocyclyl, and the heterocyclyl is optionally further substituted with unsubstituted alkyl, then the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.aa and R.sub.bb are independently alkyl, the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.aa and R.sub.bb are independently alkyl, and the alkyl is optionally further substituted with substituted or unsubstituted heterocyclyl, then the heterocyclyl is substituted with alkyl, the alkyl is methyl, ethyl, propyl or isopropyl; and/or, when R.sub.aa and R.sub.bb are independently amino, and the amino is optionally further substituted with unsubstituted alkyl, then the alkyl is methyl, ethyl, propyl or isopropyl.
45. A method for the prevention and/or treatment of a condition mediated by JAK kinase, comprising administering to a patient a therapeutically effective dose of the compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 40, wherein the condition mediated by JAK kinase is an inflammatory disease or a neoplastic disease; the inflammatory disease is selected from rheumatoid arthritis, dermatitis, psoriasis, or inflammatory bowel disease; wherein gastrointestinal inflammatory disease is chronic inflammatory disease of the intestine; the neoplastic disease is selected from myelofibrosis, polycythemia vera and essential thrombocythemia, acute myelomonocytic leukemia, acute lymphocytic leukemia, ductal carcinoma of the breast or non-small cell lung cancer.
46. A method for the prevention and/or treatment of a condition mediated by JAK kinase, comprising administering to a patient a therapeutically effective dose of the compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 45, wherein gastrointestinal inflammatory disease is ulcerative colitis and Crohn's disease.
47. The compound of general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 9, which is a compound of general formula (V), a compound of general formula (VI), a compound of general formula (VII), a compound of general formula (VIII), a compound of general formula (IX), a compound of general formula (X), and a compound of general formula (IX), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ##STR00980## ##STR00981## wherein: L.sub.1 is independently selected from bond, alkylene, alkenylene, alkynyl, cycloalkyl, heterocyclyl, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1—, —(CH.sub.2).sub.n1C(O)(CH.sub.2).sub.m1NR.sub.aa(CH.sub.2).sub.m2—, —NR.sub.aa(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1S(O).sub.m1— or —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aa—; L.sub.2 is independently selected from bond, oxygen atom, sulfur atom, —CR.sub.aaR.sub.bb—, —(CH.sub.2).sub.n1C(O)—, —NR.sub.4— or —(CH.sub.2).sub.n1S(O).sub.m1—; M.sub.1 is selected from nitrogen atom or —CR.sub.aa—; E.sub.1, E.sub.2 and E.sub.3 are identical or different and are each independently selected from nitrogen atom or —CR.sub.aa—; ring A is selected from 6-14 membered heteroaryl, wherein the 6-14 membered heteroaryl is selected from 6-14 membered fused heteroaryl; ring B is selected from 3-10 membered monocyclic heterocyclyl, 6-14 membered bridged heterocyclyl or 6-14 membered fused heterocyclyl; ring C is selected from heteroaryl; ring G is selected from heterocyclyl, aryl or heteroaryl; ring K is selected from heterocyclyl, aryl or heteroaryl; preferably 5-6 membered heterocyclyl, 6-10 membered aryl, or 5-6 membered heteroaryl; R.sub.1 is independently selected from hydrogen atom, deuterium atom, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccC(O)R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.2 is independently selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioxoheterocyclyl, aryl, heteroaryl, —(CH.sub.2).sub.n1R.sub.aa, —(CH.sub.2).sub.n1O(CH.sub.2).sub.m1R.sub.aa, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1NR.sub.aa(CH.sub.2).sub.m1R.sub.aa, —NR.sub.aaC(O)(CH.sub.2).sub.n1OR.sub.aa, —NR.sub.aaC(═S)(CH.sub.2).sub.n1OR.sub.bb, —(CH.sub.2).sub.n1SR.sub.aa, —(CH.sub.2).sub.n1C(O)R.sub.aa, —(CH.sub.2).sub.n1C(O)OR.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.aa, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1P(O).sub.m2R.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1S—, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, —(CH.sub.2).sub.n1NR.sub.aaC(O)R.sub.bb or —(CH.sub.2).sub.n1NR.sub.aaS(O).sub.m1R.sub.bb, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted, unsubstituted heteroaryl, —(CH.sub.2).sub.n1—, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.4 is selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, or alkynyl; R.sub.5 is independently selected from hydrogen atom, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, —(CH.sub.2).sub.n1OR.sub.aa, —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH.sub.2).sub.n1R.sub.cc, —(CH.sub.2).sub.n1OR.sub.cc, —(CH.sub.2).sub.n1SR.sub.cc, —(CH.sub.2).sub.n1C(O)R.sub.cc, —(CH.sub.2).sub.n1C(O)OR.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1R.sub.cc, —(CH.sub.2).sub.n1S(O).sub.m1 NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccR.sub.dd, —(CH.sub.2).sub.n1C(O)NR.sub.ccS(O).sub.m1R.sub.dd, —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd or —(CH.sub.2).sub.n1NR.sub.ccS(O).sub.m1R.sub.dd; R.sub.6 is independently selected from hydrogen atom, halogen, cyano, alkyl, alkoxy, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl or —(CH.sub.2).sub.n1C(O)NR.sub.aaR.sub.bb; R.sub.7 is independently selected from hydrogen atom, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, oxo or thioxo; R.sub.8 is independently selected from hydrogen atom, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, oxo or thioxo; R.sub.9 is independently selected from hydrogen atom, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, oxo or thioxo; R.sub.12 is independently selected from hydrogen atom, cyano, halogen, alkyl or alkoxy; R.sub.aa is independently selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; x is an integer of 0, 1, 2 or 3; y is an integer of 0, 1, 2, 3, 4 or 5; z is an integer of 0, 1 or 2; p is an integer 0, 1, 2 or 3; q is an integer of 0, 1, 2 or 3; and n is an integer of 0, 1, 2 or 3.
Description
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0979] The present disclosure will be further described by the embodiments below, but the present disclosure is not limited to the scope of the described embodiments. In the following embodiments, the experimental methods without specific conditions are selected according to conventional methods and conditions, or according to the product specification.
EMBODIMENT
[0980] The structure of the compound of the present embodiment is determined by nuclear magnetic resonance (NMR) or/and liquid-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated methanol (CD.sub.3OD) and deuterated chloroform (CDCl.sub.3), and the internal standard was tetramethylsilane (TMS).
[0981] The liquid mass spectrometry LC-MS was measured with an Agilent 1200 Infinity Series mass spectrometer. HPLC was determined by Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gi minutes i C18 150×4.6 mm column).
[0982] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used as the thin layer chromatography silica gel plate, the specification of TLC is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation used for product purification is 0.4 mm-0.5 mm. 200-300 mesh silica gel of Yantai Huanghai silica gel was generally used as the carrier of the column chromatography.
[0983] The starting materials in the embodiment of the present disclosure are known and can be purchased on the market, or can be synthesized by adopting or following methods known in the art.
[0984] Unless otherwise specified, all reactions of the present embodiment were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, the solvent was dry solvent, and the reaction temperature unit was degrees Celsius.
Embodiment 1
3-((3-exo)-3-((7-((5-methylthioazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[0985] ##STR00347##
Step 1: preparation of tert-butyl (3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[0986] ##STR00348##
[0987] The compound 5,7-dichloro-1,6-diazanaphthalene (100 mg, 0.502 mmol), Tert-butyl (3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (119 mg, 0.527 mmol) and diisopropylethylamine (195 mg, 1.51 mmol) were dissolved in dimethyl sulfoxide (4 mL), and the reaction mixture was heated to 110° C. and stirred for 22 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated sodium chloride aqueous solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. The resulting residue was separated and purified by silica gel column chromatography to obtain the title compound as a yellow-white solid (173 mg, 92%).
[0988] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.89 (dd, J=4.2, 1.3 Hz, 1H), 8.72 (d, J=8.3 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.48 (dd, J=8.4, 4.3 Hz, 1H), 6.96 (s, 1H), 4.70-4.56 (m, 1H), 4.16 (s, 2H), 2.05-1.87 (m, 4H), 1.81-1.57 (m, 4H), 1.44 (s, 9H).
[0989] MS m/z (ESI): 389.2 [M+H].sup.+.
Step 2: preparation of 3-((3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl) propionitrile
[0990] ##STR00349##
[0991] Tert-butyl (3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.257 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added with stirring at room temperature. The resulting reaction mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure to remove the solvent. The mixture was dissolved by anhydrous methanol, and diisopropylethylamine (332 mg, 2.57 mmol) and acrylonitrile (16 mg, 0.31 mmol) were added successively. The reaction mixture was stirred at room temperature for 26.5 hours, and concentrated under reduced pressure to remove the solvent. The residue was separated and purified by silica gel column chromatography to obtain the title compound as a white powder (81 mg, 92%).
[0992] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.90-8.87 (m, 1H), 8.72 (d, J=8.3 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.47 (dd, J=8.4, 4.3 Hz, 1H), 6.94 (s, 1H), 4.51-4.35 (m, 1H), 3.34 (s, 2H), 2.69-2.58 (m, 4H), 1.98-1.88 (m, 2H), 1.84-1.62 (m, 6H).
[0993] MS m/z (ESI): 342.1 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((7-((5-methylthioazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[0994] ##STR00350##
[0995] 3-((3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (50 mg, 0.146 mmol), 5-methylthioazol-2-amine (25 mg, 0.219 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (7 mg, 0.009 mmol) and cesium carbonate (86 mg, 0.263 mmol) were added to ultra-dry 1,4-dioxane (5 mL). The reaction mixture was filled with dry nitrogen. The reaction mixture was then sealed, heated to 110° C. and stirred for 24 hours, then cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative TLC to obtain the title compound as a yellow-green solid (14 mg, 23%).
[0996] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.77 (s, 1H), 8.71-8.63 (m, 1H), 8.55 (d, J=8.3 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.10 (dd, J=8.3, 4.3 Hz, 1H), 7.02 (d, J=1.1 Hz, 1H), 6.46 (s, 1H), 4.96-4.77 (m, 1H), 3.36 (s, 2H), 2.65 (s, 4H), 2.32 (s, 3H), 2.04-1.72 (m, 8H).
[0997] MS m/z (ESI): 420.2 [M+H].sup.+.
Embodiment 2
3-(3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazadiazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[0998] ##STR00351##
[0999] 3-((3-exo)-3-((7-Chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (50 mg, 0.146 mmol), (2-aminothiazol-5-yl)methanol (38 mg, 0.292 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (58 mg, 0.073 mmol) and cesium carbonate (143 mg, 0.438 mmol) were added to ultra-dry 1,4-dioxane (5 mL). The reaction mixture was filled with dry nitrogen to remove oxygen, heated to 140° C. with a microwave reactor, stirred for 2.5 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography and reverse phase HPLC to obtain the title compound (8.6 mg, 14%).
[1000] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.85 (s, 1H), 8.70-8.65 (m, 1H), 8.60-8.53 (m, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.18 (s, 1H), 7.11 (dd, J=8.3, 4.3 Hz, 1H), 6.50 (s, 1H), 5.16 (t, J=5.2 Hz, 1H), 4.86 (dd, J=16.7, 8.2 Hz, 1H), 4.56 (d, J=5.2 Hz, 2H), 3.33 (s, 2H), 2.65 (s, 4H), 1.99-1.86 (m, 4H), 1.81 (d, J=7.4 Hz, 4H).
[1001] MS m/z (ESI): 436.1 [M+H].sup.+.
Embodiment 3
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1002] ##STR00352##
Step 1: Preparation of 2,4-dichloro-5-tosyl-7H-pyrrolo[2,3-d]pyrimidine
[1003] ##STR00353##
[1004] TsCl (242 mg, 1.27 mmol) and DIPEA (273 mg, 2.12 mmol) were added successively into the solution of 2,4-dichloropyrrole[3,2-d]pyrimidine (200 mg, 1.06 mmol) in dichloromethane (5 mL), and stirred overnight at room temperature. When the reaction was complete, the reaction mixture was extracted with DCM (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. The resulting product was purified by silica gel column chromatography (PE: DCM from 0 to 70:30) to obtain the title compound as a white solid (360 mg, 99%).
[1005] MS m/z (ESI): 343.0 [M+H].sup.+.
Step 2: preparation of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine
[1006] ##STR00354##
[1007] 3-Amino-5-methylpyrazol (53 mg, 0.55 mmol) and DIPEA (129 mg, 1 mmol) were added successively into the solution of 2,4-dichloro-5-tosyl-7H-pyrrolo[2,3-d]pyrimidine (171 mg, 0.5 mmol) in MeCN (10 mL), then the mixture was stirred under microwave conditions at 100° C. for 2 hours. When the reaction was completed, the reaction mixture was extracted with EA (15 mL×3) and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (DCM: MeOH from 0 to 95:5) to obtain the title compound as a pale yellow solid (185 mg, 92%).
[1008] MS m/z (ESI): 402.1 [M+H].sup.+.
Step 3: preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1009] ##STR00355##
[1010] N-Boc-exo-3-aminotropane (85 mg, 0.375 mmol) and DIPEA (64.5 mg, 0.5 mmol) were added successively into the solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.25 mmol) in n-BuOH (5 mL), then heated to 150° C. under microwave condition and stirred for 12 hours. When the reaction was completed, the reaction mixture was extracted with EA (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to remove the organic solvent to obtain the title compound as a pale yellow solid (100 mg, 68%).
[1011] MS m/z (ESI): 593.1 [M+H].sup.+.
Step 4: preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1012] ##STR00356##
[1013] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.17 mmol) was dissolved in ethyl acetate hydrochloride (4.0 N, 2 mL). The mixture was stirred at room temperature for 30 minutes, then evaporated to dryness and dissolved with MeOH (10 mL), followed by dropwise addition of DIPEA (88 mg, 0.68 mmol). The mixture was stirred at room temperature for 10 minutes, and acrylonitrile (14 mg, 0.26 mmol) was added and stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, then purified by silica gel chromatography (DCM:MeOH=10:1) to obtain the title compound as a yellow solid (52.6 mg, 57%).
[1014] MS m/z (ESI): 546.1 [M+H].sup.+.
Step 5: preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1015] ##STR00357##
[1016] Sodium hydroxide (36 mg, 0.9 mmol) aqueous solution (0.2 mL) was added to the mixed solution of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (50 mg, 0.09 mmol) in 1,4-dioxane (10 mL) and methanol (5 mL). The mixture was then heated to 55° C. and stirred overnight. When the reaction was completed, the reaction mixture was concentrated under reduced pressure, then purified by prep-HPLC to obtain the title compound as a white solid (10 mg, 29%).
[1017] .sup.1H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 10.72 (s, 1H), 9.38 (s, 1H), 6.67 (s, 3H), 5.92 (s, 1H), 4.11 (s, 1H), 3.29 (s, 2H), 2.62 (s, 4H), 2.20 (s, 3H), 1.90 (s, 2H), 1.82-1.47 (m, 6H).
[1018] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 4
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1019] ##STR00358##
Step 1: preparation of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine
[1020] ##STR00359##
[1021] 2,4-Dichloroquinazoline (199 mg, 1.0 mmol), 5-methyl-1H-pyrazol-3-amine (99 mg, 1.02 mmol) and triethylamine (213 mg, 2.1 mmol) were added to anhydrous ethanol (5 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was suspended in water-ethanol (v\v=9:1, 20 mL) and then filtered. The resulting solid was washed with petroleum ether, and then dried to obtain the title compound (240 mg, 92%).
[1022] MS m/z (ESI): 260.1, 262.1 [M+H].sup.+.
Step 2: preparation of Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1023] ##STR00360##
[1024] 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (40 mg, 0.154 mmol) and tert-butyl (3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (70 mg, 0.308 mmol) were added to n-butanol (3 mL). The mixture was stirred evenly under room temperature, then heated to 150° C. with microwave and reacted for 4 hours. The mixture was concentrated under reduced pressure to remove the solvent, and the resulting product was purified by silica gel chromatography to obtain the crude title compound (120 mg), which was used directly in the next step.
[1025] MS m/z (ESI): 450.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1026] ##STR00361##
[1027] The crude product of Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (120 mg, 0.154 mmol) was dissolved in methanol (3 mL). The mixture was stirred at room temperature and 4M HCl in 1,4-dioxane (10 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in anhydrous methanol (10 mL), stirred at room temperature, followed by successive addition of diisopropylethylamine (0.51 mL, 3.08 mmol) and acrylonitrile (10 mg, 0.154 mmol). The resulting reaction mixture was stirred at room temperature for 2.5 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified successively by silica gel chromatography and reverse phase HPLC to obtain the title compound (6.0 mg, 10%).
[1028] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.04 (d, J=8.1 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.39 (s, 1H), 7.16 (t, J=7.5 Hz, 1H), 6.62 (s, 1H), 4.35 (s, 1H), 3.37 (s, 2H), 2.76 (t, J=6.9 Hz, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.31 (s, 3H), 2.16-1.74 (m, 6H), 1.67 (t, J=11.7 Hz, 2H).
[1029] MS m/z (ESI): 403.2 [M+H].sup.+.
Embodiment 5
3-(cis-5-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile
[1030] ##STR00362##
Step 1: Preparation of tert-butyl(3aR,5r,6aS)-5-((7-chloro-1,6-diazanaphthalen-5-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate
[1031] ##STR00363##
[1032] Tert-butyl cis-5-aminohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate (100 mg, 0.442 mmol), 5,7-dichloro-1,6-diazanaphthalen (83 mg, 0.42 mmol) and diisopropylethylamine (0.208 mL, 1.26 mmol) were dissolved in DMSO (2 mL). The mixture then heated to 110° C. and stirred for 15 hours. The reaction mixture was then diluted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. The resulting product was purified by silica gel chromatography to obtain the title compound (142 mg, 87%).
[1033] MS m/z (ESI): 389.4 [M+H].sup.+.
Step 2: Preparation of 3-(cis-5-((7-chloro-1,6-diazanaphthalen-5-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile
[1034] ##STR00364##
[1035] Tert-butyl cis-5-((7-chloro-1,6-diazanaphthalen-5-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate (142 mg, 0.365 mmol) was dissolved in methanol (2 mL). The mixture was stirred at room temperature then 4M HCl in 1,4-dioxane (10 mL) was added. The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (10 mL), diisopropylethylamine (1.2 mL, 7.3 mmol) and acrylonitrile (0.03 mL, 0.438 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to remove the solvent. The residue was successively purified by silica gel chromatography to obtain the title compound (123 mg, 98%).
[1036] MS m/z (ESI): 342.1 [M+H].sup.+.
Step 3: preparation of 3-(cis-5-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile
[1037] ##STR00365##
[1038] 3-(cis-5-((7-chloro-1,6-diazanaphthalen-5-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile (50 mg, 0.146 mmol), tert-butyl 3-amino-5-methyl-1H-pyrazol-1-carboxylate (44 mg, 0.219 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (7 mg, 0.009 mmol) and cesium carbonate(86 mg, 0.263 mmol) were added to ultra-dry 1,4-dioxane(5 mL). The reaction mixture was filled with dry nitrogen. The reaction mixture was then sealed, heated to 100° C. and stirred for 17 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure. The mixture was dissolved in 4M HCl in 1,4-dioxane(10 mL), and stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC to obtain the title compound (2.6 mg, 4%).
[1039] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.54 (dd, J=9.0, 5.7 Hz, 1H), 8.43-8.24 (m, 1H), 7.06 (d, J=5.8 Hz, 1H), 6.66 (d, J=5.2 Hz, 1H), 6.12 (s, 1H), 4.63-4.48 (m, 1H), 3.06-2.56 (m, 8H), 2.55-2.34 (m, 4H), 2.28 (s, 3H), 1.57 (s, 2H).
[1040] MS m/z (ESI): 403.2 [M+H].sup.+.
Embodiment 6
3-((3-exo)-3-((7-((1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1041] ##STR00366##
[1042] 3-((3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (50 mg, 0.146 mmol), tert-butyl 3-(12-azaalkyl)-1H-pyrazol-1-carboxylate (40 mg, 0.219 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)e (7 mg, 0.009 mmol) and cesium carbonate (86 mg, 0.263 mmol) were added to ultra-dry 1,4-dioxane (5 mL), the reaction mixture was filled with dry nitrogen to remove the oxygen. The reaction mixture was then sealed, heated to 110° C. and stirred for 16 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure. The mixture was dissolved in dichloromethane (2 mL), followed by addition of trifluoroacetate acid (1 mL). The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the title compound (17 mg, 31%).
[1043] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.07 (s, 1H), 8.81 (s, 1H), 8.58 (d, J=3.3 Hz, 1H), 8.42 (d, J=8.6 Hz, 1H), 7.58 (s, 1H), 7.14 (dd, J=6.2, 2.8 Hz, 1H), 6.97 (dd, J=7.9, 4.2 Hz, 1H), 6.75 (s, 1H), 6.34 (s, 1H), 4.59-4.42 (m, 1H), 3.33 (s, 2H), 2.63 (s, 4H), 1.97-1.86 (m, 2H), 1.78 (ddt, J=24.7, 23.4, 7.2 Hz, 6H).
[1044] MS m/z (ESI): 389.2 [M+H].sup.+.
Embodiment 7
3-((3-exo)-3-((7-((5-(difluoromethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1045] ##STR00367##
[1046] The preparation of 3-((3-exo)-3-((7-((5-(difluoromethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 1.
[1047] MS m/z (ESI): 439.2 [M+H].sup.+.
Embodiment 8
3-((3-exo)-3-((7-((5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1048] ##STR00368##
[1049] The preparation of 3-((3-exo)-3-((7-((5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 1.
[1050] MS m/z (ESI): 457.2 [M+H].sup.+.
Embodiment 9
3-((3-exo)-3-((7-((5-fluoro-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1051] ##STR00369##
[1052] The preparation of 3-((3-exo)-3-((7-((5-fluoro-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 1.
[1053] .sup.1H NMR (400 MHz, DMSO-d6) δ 11.61 (d, J=1.5 Hz, 1H), 9.35 (s, 1H), 8.65 (dd, J=4.3, 1.2 Hz, 1H), 8.49 (d, J=8.8 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.07 (dd, J=8.4, 4.3 Hz, 1H), 6.25 (s, 1H), 5.77 (dd, J=6.0, 2.1 Hz, 1H), 4.47-4.39 (m, 1H), 3.32 (s, 2H), 2.62 (t, J=4.2 Hz, 4H), 1.95-1.86 (m, 2H), 1.83-1.70 (m, 6H).
[1054] MS m/z (ESI): 407.2 [M+H].sup.+.
Embodiment 10
3-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)-1H-pyrazol-5-formonitrile
[1055] ##STR00370##
[1056] The preparation of 3-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)-1H-pyrazol-5-formonitrile was carried out with the reference to Embodiment 1.
[1057] MS m/z (ESI): 414.2 [M+H].sup.+.
Embodiment 11
3-((3-exo)-3-((7-((5-ethyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1058] ##STR00371##
[1059] 3-((3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (100 mg, 0.292 mmol), 5-ethyl-1H-pyrazol-3-amine (65 mg, 0.584 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (115 mg, 0.146 mmol) and cesium carbonate (286 mg, 0.876 mmol) were added to ultra-dry 1,4-dioxane (10 mL). The reaction mixture was filled with dry nitrogen, heated to 150° C. with a microwave reactor and reacted for 8 hours. Then the mixture was cooled down to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and successively purified by silica gel chromatography and reverse phase HPLC to obtain the title compound (2.2 mg, 2%).
[1060] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.77 (s, 1H), 8.71 (s, 1H), 8.57 (dd, J=4.1, 1.4 Hz, 1H), 8.40 (d, J=7.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.95 (dd, J=8.1, 4.4 Hz, 1H), 6.68 (s, 1H), 6.16 (s, 1H), 4.53 (dd, J=12.8, 5.6 Hz, 1H), 3.33 (s, 2H), 2.63 (ddd, J=24.2, 9.2, 4.8 Hz, 6H), 1.92 (dd, J=8.1, 4.4 Hz, 2H), 1.85-1.66 (m, 6H), 1.20 (t, J=7.6 Hz, 3H).
[1061] MS m/z (ESI): 417.2 [M+H].sup.+.
Embodiment 12
3-((3-exo)-3-((7-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1062] ##STR00372##
[1063] 3-((3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (100 mg, 0.292 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (72 mg, 0.585 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (115 mg, 0.146 mmol) and cesium carbonate (285 mg, 0.876 mmol) were added to ultra-dry 1,4-dioxane (5 mL). The reaction mixture was filled with dry nitrogen, heated to 150° C. with microwave, stirred for 3 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and successively purified by silica gel chromatography and reverse phase HPLC to obtain the title compound (20 mg, 16%).
[1064] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.75 (s, 1H), 8.67 (s, 1H), 8.57 (d, J=3.2 Hz, 1H), 8.44-8.36 (m, 1H), 7.12 (ddd, J=12.4, 9.6, 3.9 Hz, 1H), 6.96 (dd, J=8.0, 3.9 Hz, 1H), 6.70 (s, 1H), 6.06 (s, 1H), 4.53 (d, J=4.9 Hz, 1H), 3.33 (s, 2H), 2.63 (s, 4H), 2.01-1.63 (m, 9H), 0.91 (d, J=7.5 Hz, 2H), 0.70 (d, J=4.3 Hz, 2H).
[1065] MS m/z (ESI): 429.2 [M+H].sup.+.
Embodiment 13
3-((3-exo)-3-((7-((5-(oxetan-3-yl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1066] ##STR00373##
[1067] The preparation of 3-((3-exo)-3-((7-((5-(oxetan-3-yl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 12.
[1068] MS m/z (ESI): 445.2 [M+H].sup.+.
Embodiment 14
3-((3-exo)-3-((7-((5-(1-methylazetindin-3-yl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1069] ##STR00374##
[1070] The preparation of 3-((3-exo)-3-((7-((5-(1-methylazetindin-3-yl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 12.
[1071] MS m/z (ESI): 458.3 [M+H].sup.+.
Embodiment 15
3-((3-exo)-3-((7-((4,5-dimethyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1072] ##STR00375##
[1073] The preparation of 3-((3-exo)-3-((7-((4,5-dimethyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 12.
[1074] .sup.1H NMR (400 MHz, DMSO-d6) δ 8.76 (dd, J=4.2, 1.3 Hz, 1H), 8.60 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.24 (dd, J=8.3, 4.4 Hz, 1H), 7.10 (s, 1H), 4.97 (s, 2H), 4.52 (dd, J=16.9, 8.1 Hz, 1H), 3.33 (s, 2H), 2.66 (dd, J=10.4, 2.9 Hz, 7H), 1.92 (ddd, J=5.9, 3.4, 1.8 Hz, 2H), 1.85 (s, 3H), 1.72 (ddd, J=20.9, 11.4, 4.3 Hz, 6H).
[1075] MS m/z (ESI): 417.1 [M+H].sup.+.
Embodiment 16
3-((3-exo)-3-((7-((4-fluoro-5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1076] ##STR00376##
[1077] The preparation of 3-((3-exo)-3-((7-((4-fluoro-5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 12.
[1078] MS m/z (ESI): 421.2 [M+H].sup.+.
Embodiment 17
3-((3-exo)-3-((7-((5-methoxyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1079] ##STR00377##
[1080] The preparation of 3-((3-exo)-3-((7-((5-methoxyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 12.
[1081] MS m/z (ESI): 419.2 [M+H].sup.+.
Embodiment 18
3-((3-exo)-3-((7-((5-(methoxylmethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1082] ##STR00378##
[1083] 3-((3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (72 mg, 0.21 mmol), 2-(2-aminothiazol-5-yl)propan-2-ol (54 mg, 0.42 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (83 mg, 0.105 mmol) and cesium carbonate (205 mg, 0.63 mmol) were added to ultra-dry 1,4-dioxane (10 mL). The reaction mixture was filled with dry nitrogen, heated to 150° C. with a microwave reactor and stirred for 7 hours. Then the mixture was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and purified by prep-HPLC to obtain the title compound (22.4 mg, 25%).
[1084] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.57 (d, J=3.5 Hz, 1H), 8.50 (d, J=8.6 Hz, 1H), 7.07 (dd, J=8.0, 4.7 Hz, 1H), 6.74 (s, 1H), 6.35 (s, 1H), 4.63 (td, J=10.8, 6.1 Hz, 1H), 4.43 (s, 2H), 3.71-3.48 (m, 2H), 3.35 (s, 3H), 2.93 (s, 2H), 2.75 (s, 2H), 2.23-1.75 (m, 8H).
[1085] MS m/z (ESI): 433.2 [M+H].sup.+.
Embodiment 19
3-((3-exo)-3-((7-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1086] ##STR00379##
[1087] 3-((3-exo)-3-((7-Chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (100 mg, 0.292 mmol), (3-amino-1H-pyrazol-5-yl)methanol (66 mg, 0.584 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (115 mg, 0.146 mmol) and cesium carbonate (286 mg, 0.877 mmol) were added to ultra-dry 1,4-dioxane (15 mL), the reaction mixture was filled with dry nitrogen, heated to 150° C. with a microwave reactor and stirred for 6 hours. Then the mixture was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and purified by prep-HPLC to obtain the title compound (15.7 mg, 13%).
[1088] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.94 (s, 1H), 8.77 (s, 1H), 8.58 (d, J=3.3 Hz, 1H), 8.41 (d, J=8.1 Hz, 1H), 7.13 (s, 1H), 6.97 (dd, J=7.9, 4.4 Hz, 1H), 6.72 (s, 1H), 6.24 (s, 1H), 5.20 (d, J=1.8 Hz, 1H), 4.53 (dd, J=6.8, 4.2 Hz, 1H), 4.45 (d, J=5.2 Hz, 2H), 3.33 (s, 2H), 2.63 (s, 4H), 1.95-1.87 (m, 2H), 1.80 (dd, J=13.3, 7.7 Hz, 4H), 1.75-1.67 (m, 2H).
[1089] MS m/z (ESI): 419.2 [M+H].sup.+.
Embodiment 20
3-((3-exo)-3-((7-((5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1090] ##STR00380##
[1091] The preparation of 3-((3-exo)-3-((7-((5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 2.
[1092] MS m/z (ESI): 447.3 [M+H].sup.+.
Embodiment 21
3-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)-1H-pyrazol-5-formamide
[1093] ##STR00381##
[1094] The preparation of 3-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)-1H-pyrazol-5-formamide was carried out with the reference to Embodiment 2.
[1095] MS m/z (ESI): 432.2 [M+H].sup.+.
Embodiment 22
3-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)-N-methyl-1H-pyrazol-5-formamide
[1096] ##STR00382##
[1097] The preparation of 3-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)-N-methyl-1H-pyrazol-5-formamide was carried out with the reference to Embodiment 2.
[1098] MS m/z (ESI): 446.2 [M+H].sup.+.
Embodiment 23
3-((3-exo)-3-((7-((2-methyl-1H-imidazol-4-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1099] ##STR00383##
[1100] The preparation of 3-((3-exo)-3-((7-((2-methyl-1H-imidazol-4-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 6.
[1101] MS m/z (ESI): 403.2 [M+H].sup.+.
Embodiment 24
3-((3-exo)-3-((7-((5-methyl-1H-1,2,4-triazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1102] ##STR00384##
[1103] 3-((3-exo)-3-((7-Chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (100 mg, 0.292 mmol), 5-methyl-4H-1,2,4-triazol-3-amine hydrochloride (47.2 mg, 0.351 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (115 mg, 0.146 mmol) and cesium carbonate (171 mg, 0.526 mmol) were added to ultra-dry 1,4-dioxane (10 mL). The reaction mixture was filled with dry nitrogen, heated to 150° C. with a microwave reactor and stirred for 4 hours. Then the mixture was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and successively purified by silica gel chromatography and reverse phase HPLC to obtain the title compound (12.4 mg, 10.5%).
[1104] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.73 (s, 1H), 9.19 (s, 1H), 8.68-8.62 (m, 1H), 8.47 (d, J=8.3 Hz, 1H), 7.23 (dt, J=39.0, 8.1 Hz, 2H), 7.08 (dd, J=8.2, 4.2 Hz, 1H), 4.48 (td, J=12.0, 6.7 Hz, 1H), 3.31-3.30 (m, 2H), 2.63 (t, J=3.0 Hz, 4H), 2.28 (s, 3H), 1.92-1.80 (m, 6H), 1.69 (t, J=11.8 Hz, 2H).
[1105] MS m/z (ESI): 404.2 [M+H].sup.+.
Embodiment 25
3-((3-exo)-3-((7-((1-methyl-1H-imidazol-4-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1106] ##STR00385##
##STR00386##
[1107] 3-((3-exo)-3-((7-Chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (100 mg, 0.292 mmol), 1-methyl-1H-imidazol-4-amine hydrochloride (78 mg, 0.585 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (115 mg, 0.146 mmol) and cesium carbonate(477 mg, 1.46 mmol) were added to ultra-dry 1,4-dioxane(5 mL). The reaction mixture was filled with dry nitrogen, heated to 140° C. with microwave, stirred for 4 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and successively purified by silica gel chromatography and reverse phase HPLC to obtain the title compound (4.4 mg, 4%).
[1108] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.77 (s, 1H), 8.55 (dd, J=4.2, 1.3 Hz, 1H), 8.40 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.17 (d, J=7.5 Hz, 2H), 6.92 (dd, J=8.3, 4.3 Hz, 1H), 6.32 (s, 1H), 4.56 (ddd, J=17.5, 12.0, 6.1 Hz, 1H), 3.64 (s, 3H), 3.34 (s, 2H), 2.64 (s, 4H), 2.06-1.65 (m, 8H).
[1109] MS m/z (ESI): 403.2 [M+H].sup.+.
Embodiment 26
3-((3-exo)-3-((7-((1-methyl-1H-1,2,4-triazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1110] ##STR00387##
[1111] The preparation of 3-((3-exo)-3-((7-((1-methyl-1H-1,2,4-triazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 25.
[1112] MS m/z (ESI): 404.2 [M+H].sup.+.
Embodiment 27
3-((3-exo)-3-((7-((1H-indazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1113] ##STR00388##
[1114] The preparation of 3-((3-exo)-3-((7-((1H-indazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 6.
[1115] MS m/z (ESI): 439.2 [M+H].sup.+.
Embodiment 28
3-((3-exo)-3-((7-((1H-pyrazolo[3,4-c]pyridin-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1116] ##STR00389##
[1117] The preparation of 3-((3-exo)-3-((7-((1H-pyrazolo[3,4-c]pyridin-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 6.
[1118] MS m/z (ESI): 440.2 [M+H].sup.+.
Embodiment 29
3-((3-exo)-3-((7-(pyrazin-2-ylamino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1119] ##STR00390##
[1120] 3-((3-exo)-3-((7-Chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (50 mg, 0.146 mmol), pyrazin-2-amine (21 mg, 0.219 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (7 mg, 0.009 mmol) and cesium carbonate(86 mg, 0.263 mmol) were added to ultra-dry 1,4-dioxane(5 mL). The reaction mixture was filled with dry nitrogen. The mixture was then sealed, heated to 110° C., stirred for 23 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and purified by prep-HPLC to obtain the title compound (30.2 mg, 52%).
[1121] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.65 (s, 1H), 9.28 (d, J=0.4 Hz, 1H), 8.70 (d, J=3.1 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.33-8.20 (m, 3H), 8.07 (d, J=2.5 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.15 (dd, J=8.3, 4.3 Hz, 1H), 7.04 (s, 1H), 4.54 (ddd, J=16.1, 11.1, 6.6 Hz, 1H), 3.34 (d, J=0.9 Hz, 2H), 2.64 (s, 4H), 2.00-1.69 (m, 8H).
[1122] MS m/z (ESI): 401.3 [M+H].sup.+.
Embodiment 30
3-((3-exo)-3-((7-(pyrimidin-2-ylamino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1123] ##STR00391##
[1124] The preparation of 3-((3-exo)-3-((7-(pyrimidin-2-ylamino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 29.
[1125] MS m/z (ESI): 401.2 [M+H].sup.+.
Embodiment 31
3-((3-exo)-3-((7-((5-(e2-hydroxypropan-2-yl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1126] ##STR00392##
Step 1: preparation of 2-(2-aminothiazol-5-yl)propan-2-ol
[1127] ##STR00393##
[1128] Ethyl 2-aminothiazol-5-carboxylate (345 mg, 2.0 mmol) was dissolved in dry tetrahydrofuran (10 mL), and then cooled to 0° C. Under nitrogen atmosphere, methyl magnesium bromide (3M ether solution, 4 mL, 12 mmol) was added dropwise thereto, and the reaction mixture was stirred at 0° C. for 17 hours. The reaction was quenched with water, and the reaction mixture was extracted with ethyl acetate. The organic phase was successively washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (237 mg, 75%).
[1129] MS m/z (ESI): 159.2 [M+H].sup.+.
Step 2: preparation of 3-((3-exo)-3-((7-((5-(2-hydroxypropan-2-yl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1130] ##STR00394##
[1131] 3-((3-exo)-3-((7-Chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (50 mg, 0.146 mmol), 2-(2-aminothiazol-5-yl)propan-2-ol (46 mg, 0.292 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (57 mg, 0.073 mmol) and cesium carbonate (143 mg, 0.438 mmol) were added to ultra-dry 1,4-dioxane (5 mL). The reaction mixture was filled with dry nitrogen, heated to 90° C. and stirred for 4 hours. Then the mixture was cooled down to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and purified by prep-HPLC to obtain the title compound (29.8 mg, 44%).
[1132] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.71 (s, 1H), 8.67 (dd, J=4.2, 1.2 Hz, 1H), 8.56 (d, J=8.3 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.13-7.07 (m, 2H), 6.49 (s, 1H), 5.25 (s, 1H), 4.83 (dd, J=17.2, 8.5 Hz, 1H), 3.35 (s, 2H), 2.65 (s, 4H), 1.93 (dt, J=12.9, 9.8 Hz, 4H), 1.80 (dd, J=8.5, 1.5 Hz, 4H), 1.52 (s, 6H).
[1133] MS m/z (ESI): 464.2 [M+H].sup.+.
Embodiment 32
3-((3-exo)-3-((7-((5-(1-hydroxylcyclopropyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-eyl)propionitrile
[1134] ##STR00395##
[1135] The preparation of 3-((3-exo)-3-((7-((5-(1-hydroxylcyclopropyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 31.
[1136] MS m/z (ESI): 462.2 [M+H].sup.+.
Embodiment 33
3-((3-exo)-3-((7-((5-(hydroxymethyl)-4-methylthioazole-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1137] ##STR00396##
[1138] The preparation of 3-((3-exo)-3-((7-((5-(hydroxymethyl)-4-methylthioazole-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 31.
[1139] MS m/z (ESI): 450.2 [M+H].sup.+.
Embodiment 34
2-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)thiazol-5-sulfonamide
[1140] ##STR00397##
[1141] The preparation of 2-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)thiazol-5-sulfonamide was carried out with the reference to Embodiment 2.
[1142] MS m/z (ESI): 485.1 [M+H].sup.+.
Embodiment 35
2-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)thiazol-5-formamide
[1143] ##STR00398##
Step 1: preparation of Tert-butyl (3-exo)-3-((7-((5-carbamidethiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1144] ##STR00399##
[1145] Tert-butyl (3-exo)-3-((7-((5-cyanothiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (72 mg, 0.15 mmol) was dissolved in DMSO (5 mL). The mixture was stirred at room temperature, followed by successive addition of lithium hydroxide monohydrate (19 mg, 0.45 mmol) and 30% hydrogen peroxide aqueous solution (0.18 mL, 0.45 mmol). The mixture was stirred at room temperature for 21 hour, and then diluted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The crude product was used directly in the next step.
[1146] MS m/z (ESI): 496.1 [M+H].sup.+.
Step 2: preparation of 2-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)thiazol-5-formamide
[1147] ##STR00400##
[1148] Tert-butyl (3-exo)-3-((7-((5-carbamidethiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate was dissolved in 4M HCl in 1.4-dioxane (10 mL), and the mixture was stirred at room temperature for 15 minutes. Then the mixture was concentrated under reduced pressure, and the residue was dissolved in anhydrous methanol (10 mL), followed by successive addition of DIPEA (0.74 mL, 4.5 mmol) and acrylonitrile (0.2 mL, 3.0 mmol). The resulting reaction mixture was stirred at room temperature for 70 minutes, and concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC to obtain the title compound (6.1 mg, 9%).
[1149] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.23 (s, 1H), 8.71 (dd, J=4.2, 1.3 Hz, 1H), 8.61 (d, J=7.9 Hz, 1H), 7.95 (s, 1H), 7.70 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.16 (dd, J=8.4, 4.3 Hz, 1H), 7.10 (s, 1H), 6.55 (s, 1H), 4.82 (dd, J=17.6, 9.3 Hz, 1H), 3.32-3.27 (m, 2H), 2.65 (t, J=3.1 Hz, 4H), 2.00 (dd, J=14.0, 6.3 Hz, 2H), 1.91-1.74 (m, 6H).
Embodiment 36
6-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)pyridazin-3-formamide
[1150] ##STR00401##
[1151] The preparation of 6-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)pyridazin-3-formamide was carried out with the reference to Embodiment 2.
[1152] MS m/z (ESI): 444.2 [M+H].sup.+.
Embodiment 37
6-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)-N-methylpyridazin-3-formamide
[1153] ##STR00402##
[1154] The preparation of 6-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)-N-methylpyridazin-3-formamide was carried out with the reference to Embodiment 2.
[1155] MS m/z (ESI): 458.2 [M+H].sup.+.
Embodiment 38
5-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)pyrazin-2-formamide
[1156] ##STR00403##
[1157] The preparation of 54(5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)pyrazin-2-formamide was carried out with the reference to Embodiment 2.
[1158] MS m/z (ESI): 444.2 [M+H].sup.+.
Embodiment 39
3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1159] ##STR00404##
Step 1: Preparation of tert-butyl-(3-exo)-3-((2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1160] ##STR00405##
[1161] Tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (136 mg, 0.6 mmol), DIPEA (129 mg, 1 mmol) were added successively into the solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (171 mg, 0.5 mmol) in ethanol (10 mL), and stirred at 80° C. for 1 hour under reflux condition. When the reaction was completed, the mixture was extracted with dichloromethane (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane 100%) to obtain the title compound as a white solid (250 mg, 94%).
[1162] MS m/z (ESI): 532.1 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1163] ##STR00406##
[1164] Tert-butyl-(3-exo)-3 #2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (20 mg, 0.47 mmol), tert-butyl-3amino-5-methyl-1H-pyrazol-1-carboxylate (111 mg, 0.56 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (37 mg, 0.047 mmol) and cesium carbonate(306 mg, 0.94 mmol) were suspended in ultra-dry 1,4-dioxane (10 mL). The mixture was filled with nitrogen for 3 times, heated to 140° C. with microwave and stirred for 4 hours. When the reaction was completed, the mixture was extracted with dichloromethane (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound as a yellow solid (100 mg, 48%).
[1165] MS m/z (ESI): 439.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1166] ##STR00407##
[1167] Tert-butyl-(3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.23 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then dissolved in methanol (10 mL). DIPEA (118 mg, 0.91 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (18 mg, 0.35 mmol) was added thereto and the mixture was stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a yellow solid (15.4 mg, 17%).
[1168] .sup.1H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 10.95 (s, 1H), 8.70 (s, 1H), 7.04 (s, 1H), 6.72 (s, 1H), 6.39 (s, 1H), 6.32-6.17 (m, 1H), 4.46 (s, 1H), 3.30 (s, 2H), 2.62 (dd, J=7.2, 4.0 Hz, 4H), 2.17 (s, 3H), 1.97-1.89 (m, 2H), 1.84-1.59 (m, 6H).
[1169] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 40
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)pronionitrile
[1170] ##STR00408##
Step 1: preparation of 2,4-dichloro-5-((2-nitrophenyl)sulfonyl)-5H-pyrrolo[3,2-d]pyrimidine
[1171] ##STR00409##
[1172] Under ice water bath condition, sodium hydride (120 mg, 5 mmol) was slowly added dropwise in the solution of 2,4-dichloro-5H-pyrrole[3,2-D]pyrimidine(470 mg, 2.5 mmol) and o-nitrobenzene sulfonyl chloride (600 mg, 2.75 mmol) in tetrahydrofuran (20 mL). The mixture was slowly warmed to room temperature and stirred for 1 hour. When the reaction was completed, under ice water bath condition, the reaction was quenched by slowly adding water (150 mL) dropwise into the reaction system. The mixture was stirred at room temperature for 1 hour and then filtered to obtain the title compound as a pale yellow solid (800 mg, 86%).
[1173] MS m/z (ESI): 372.9 [M+H].sup.+.
Step 2: preparation of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-((2-nitrophenyl)sulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine
[1174] ##STR00410##
[1175] 3-Amino-5-methylpyrazol (250 mg, 2.58 mmol), DIPEA (555 mg, 4.3 mmol) were successively added into the solution of 2,4-dichloro-5-((2-nitrophenyl)sulfonyl)-5H-pyrrolo[3,2-d]pyrimidine (800 mg, 2.15 mmol) in ethanol (20 mL). The mixture was then stirred at 80° C. for 2 hours under reflux condition. When the reaction was completed, solid was precipitated from the reaction mixture, and the mixture was filtered. The filter cake was washed with ethanol (15 mL×3), and then dried to obtain the title compound as a yellow solid (370 mg, 40%).
[1176] MS m/z (ESI): 434.0 [M+H].sup.+.
Step 3: preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1177] ##STR00411##
[1178] Tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (233 mg, 1.03 mmol) and DIPEA (220 mg, 1.71 mmol) were successively added into the solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-((2-nitrophenyl)sulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(370 mg, 0.85 mmol) in n-butanol (5 mL), then the mixture was heated to 160° C. under microwave condition and stirred for 10 hours. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=98:2) to obtain the title compound as a pale yellow solid (40 mg, 11%).
[1179] MS m/z (ESI): 593.1 [M+H].sup.+.
Step 4: 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1180] ##STR00412##
[1181] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (30 mg, 0.07 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 2 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and dissolved in methanol (5 mL). DIPEA (35 mg, 0.28 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (5 mg, 0.1 mmol) was added thereto and the mixture was stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a pale yellow solid (8.2 mg, 31%).
[1182] .sup.1H NMR (400 MHz, DMSO) δ 11.93 (s, 1H), 10.57 (s, 1H), 9.43 (s, 1H), 7.29 (s, 1H), 6.77 (s, 1H), 6.02 (s, 1H), 5.77 (s, 1H), 4.12 (s, 1H), 3.28 (s, 2H), 2.62 (s, 4H), 2.22 (s, 3H), 1.90 (s, 2H), 1.81-1.43 (m, 6H).
[1183] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 41
3-((3-exo)-3-((5-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1184] ##STR00413##
[1185] The preparation of 3-((3-exo)-3-((5-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 3.
[1186] MS m/z (ESI): 406.2 [M+H].sup.+.
Embodiment 42
3-((3-exo)-3-((5-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1187] ##STR00414##
[1188] The preparation of 3-((3-exo)-3-((5-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1189] MS m/z (ESI): 406.2 [M+H].sup.+.
Embodiment 43
3-((3-exo)-3-((6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1190] ##STR00415##
[1191] The preparation of 3-((3-exo)-3-((6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 3.
[1192] MS m/z (ESI): 406.2 [M+H].sup.+.
Embodiment 44
3-((3-exo)-3-((6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1193] ##STR00416##
[1194] The preparation of 3-((3-exo)-3-((6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1195] MS m/z (ESI): 406.2 [M+H].sup.+.
Embodiment 45
2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-formonitrile
[1196] ##STR00417##
[1197] The preparation of 2-((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-formonitrile was carried out with the reference to Embodiment 3.
[1198] MS m/z (ESI): 417.2 [M+H].sup.+.
Embodiment 46
3-((3-exo)-3-((5-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1199] ##STR00418##
[1200] The preparation of 3-((3-exo)-3-((5-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 3.
[1201] MS m/z (ESI): 410.2 [M+H].sup.+.
Embodiment 47
3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-9H-purin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1202] ##STR00419##
[1203] The preparation of 3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-9H-purin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 3.
[1204] MS m/z (ESI): 393.2 [M+H].sup.+.
Embodiment 48
3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)-9H-purin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1205] ##STR00420##
[1206] The preparation of 3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)-9H-purin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1207] MS m/z (ESI): 393.2 [M+H].sup.+.
Embodiment 49
3-((3-exo)-3-((8-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-9H-purin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1208] ##STR00421##
[1209] The preparation of 3-((3-exo)-3-((8-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-9H-purin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1210] MS m/z (ESI): 407.2 [M+H].sup.+.
Embodiment 50
3-((3-exo)-3-((3-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1211] ##STR00422##
[1212] The preparation of 3-((3-exo)-3-((3-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1213] MS m/z (ESI): 407.2 [M+H].sup.+.
Embodiment 51
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1214] ##STR00423##
Step 1: Preparation of 4,6-dichloro-1-(4H-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine
[1215] ##STR00424##
[1216] P-toluenesulfonic acid monohydrate(19 mg, 0.1 mmol), 3,4-2H-2H-pyran (133 mg, 1.59 mmol) were successively added to the solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine(200 mg, 1.06 mmol) in tetrahydrofuran (5 mL). The mixture was then stirred at 60° C. for 2 hours under reflux condition. When the reaction was completed, the mixture was extracted with dichloromethane (15 mL×3) and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. The resulting product was purified by silica gel column chromatography (dichloromethane 100%) to obtain the title compound as a white solid (269 mg, 93%).
[1217] MS m/z (ESI): 273.0 [M+H].sup.+.
Step 2: preparation of 6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-1-(4H-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
[1218] ##STR00425##
[1219] 3-Amino-5-methylpyrazol (108 mg, 1.12 mmol) and DIPEA (240 mg, 1.86 mmol) were successively added to the solution of 4,6-dichloro-1-(4H-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine(250 mg, 0.93 mmol) in ethanol (10 mL). The mixture was then stirred at 60° C. for 1 hour. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=98:2) to obtain the title compound as a white solid (254 mg, 82%).
[1220] MS m/z (ESI): 334.1 [M+H].sup.+.
Step 3: preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-1-(4H-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1221] ##STR00426##
[1222] Tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (203 mg, 0.9 mmol) and DIPEA (155 mg, 1.2 mmol) were successively added to the solution of 6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-1-(4H-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.6 mmol) in n-butanol (5 mL). The mixture was stirred at 160° C. for 15 hours under microwave condition. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound as a pale yellow solid (144 mg, 46%).
[1223] MS m/z (ESI): 524.2 [M+H].sup.+.
Step 4: preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1224] ##STR00427##
[1225] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-1-(4H-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (144 mg, 0.28 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and dissolved in methanol (10 mL). DIPEA (142 mg, 1.12 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (22 mg, 0.41 mmol) was added thereto and the mixture was stirred for another 2 hours. When the reaction was completed, the reaction mixture was concentrated under reduced pressure, and purified by prep-HPLC to obtain the title compound as a white solid (54.6 mg, 51%).
[1226] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.49 (s, 1H), 12.03 (s, 1H), 10.02 (s, 1H), 8.05 (s, 1H), 6.81-6.47 (m, 2H), 4.11 (s, 1H), 3.29 (s, 2H), 2.62 (s, 4H), 2.19 (s, 3H), 1.91 (s, 2H), 1.71-1.62 (m, 6H).
[1227] MS m/z (ESI): 393.2 [M+H].sup.+.
Embodiment 52
3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1228] ##STR00428##
[1229] The preparation of 3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1230] MS m/z (ESI): 393.2 [M+H].sup.+.
Embodiment 53
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[3,2-c]pyridin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1231] ##STR00429##
[1232] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[3,2-c]pyridin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 3.
[1233] MS m/z (ESI): 391.2 [M+H].sup.+.
Embodiment 54
3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[3,2-c]pyridin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1234] ##STR00430##
[1235] The preparation of 3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[3,2-c]pyridin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1236] MS m/z (ESI): 391.2 [M+H].sup.+.
Embodiment 55
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-c]pyridin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1237] ##STR00431##
[1238] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-c]pyridin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 51.
[1239] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 56
3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-c]pyridin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1240] ##STR00432##
[1241] The preparation of 3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-c]pyridin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1242] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 57
3-((3-exo)-3-((7-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)-7H-purin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1243] ##STR00433##
[1244] The preparation of 3-((3-exo)-3-((7-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)-7H-purin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 40.
[1245] MS m/z (ESI): 407.2 [M+H].sup.+.
Embodiment 58
3-((3-exo)-3-((7-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-purin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1246] ##STR00434##
[1247] The preparation of 3-((3-exo)-3-((7-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-purin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1248] MS m/z (ESI): 407.2 [M+H].sup.+.
Embodiment 59
3-((3-exo)-3-((9-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)-9H-purin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1249] ##STR00435##
[1250] The preparation of 3-((3-exo)-3-((9-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)-9H-purin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 40.
[1251] MS m/z (ESI): 407.2 [M+H].sup.+.
Embodiment 60
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1252] ##STR00436##
Step 1: preparation of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine
[1253] ##STR00437##
[1254] 3-Amino-5-methylpyrazol (116 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) were successively added to the solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in N-methylpyrrolidone(10 mL). The mixture was stirred at 70° C. for 1 hour. When the reaction was completed, water (50 mL) was added to the reaction mixture, the precipitated solid was filtered off and slurried with ethyl acetate to obtain the title compound as a pale yellow solid (135 mg, 51%).
[1255] MS m/z (ESI): 266.0 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1256] ##STR00438##
[1257] Tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (138 mg, 0.61 mmol) and DIPEA (129 mg, 1 mmol) were successively added to 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine(135 mg, 0.51 mmol) in the solution of n-butanol (5 mL). The mixture was stirred at 160° C. for 15 hours under microwave condition. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=98:2) to obtain the title compound as a pale yellow solid (146 mg, 63%).
[1258] MS m/z (ESI): 456.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1259] ##STR00439##
[1260] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (146 mg, 0.32 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and dissolved in methanol (10 mL). DIPEA (166 mg, 1.28 mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (25 mg, 0.48 mmol) was added thereto and the mixture stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (14.4 mg, 11%).
[1261] .sup.1H NMR (400 MHz, DMSO) δ 12.02 (s, 1H), 9.70 (s, 1H), 7.89 (s, 1H), 6.99 (s, 1H), 6.44 (d, J=59.6 Hz, 2H), 4.14 (s, 1H), 3.29 (s, 2H), 2.62 (s, 4H), 2.22 (s, 3H), 1.89 (s, 2H), 1.64 (dd, J=47.8, 17.6 Hz, 6H).
[1262] MS m/z (ESI): 409.2 [M+H].sup.+.
Embodiment 61
3-((3-exo)-3-((7-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1263] ##STR00440##
[1264] The preparation of 3-((3-exo)-3-((7-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 60.
[1265] MS m/z (ESI): 423.2 [M+H].sup.+.
Embodiment 62
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1266] ##STR00441##
Step 1: preparation of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine
[1267] ##STR00442##
[1268] 3-Amino-5-methylpyrazol (116 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) were successively added to the solution of 2,4-dichlorothieno[2,3-d]pyrimidine (205 mg, 1 mmol) in N-methylpyrrolidone (10 mL). The mixture was stirred at 70° C. for 1 hour. When the reaction was completed, water (50 mL) was added to the reaction mixture, and a solid was precipitated, which was then filtered and slurried with ethyl acetate to obtain the title compound as a yellow solid (250 mg, 94%).
[1269] MS m/z (ESI): 266.0 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1270] ##STR00443##
[1271] Tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (256 mg, 1.13 mmol) and DIPEA (242 mg, 1.88 mmol) were successively added to the solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine(250 mg, 0.94 mmol) in n-butanol (10 mL). The mixture was then stirred at 160° C. for 15 hours under microwave condition. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=98:2) to obtain the title compound as a pale yellow solid (200 mg, 47%).
[1272] MS m/z (ESI): 456.1 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1273] ##STR00444##
[1274] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (200 mg, 0.44 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes and the mixture was concentrated; then methanol (10 mL) was added to the mixture for dissolution, DIPEA (227 mg, 1.76 mmol) was slowly added dropwise to the mixture, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (35 mg, 0.66 mmol) was added thereto and the mixture was stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (31.6 mg, 18%).
[1275] .sup.1H NMR (400 MHz, DMSO) δ 12.13 (s, 1H), 9.93 (s, 1H), 7.73 (s, 1H), 6.88 (d, J=117.2 Hz, 3H), 4.27 (s, 1H), 3.37 (s, 2H), 2.70 (s, 4H), 2.32 (s, 3H), 1.99 (s, 2H), 1.86-1.61 (m, 6H).
[1276] MS m/z (ESI): 409.2 [M+H].sup.+.
Embodiment 63
3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1277] ##STR00445##
[1278] The preparation of 3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1279] MS m/z (ESI): 409.2 [M+H].sup.+.
Embodiment 64
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[4,5-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1280] ##STR00446##
[1281] The preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[4,5-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 60.
[1282] MS m/z (ESI): 410.2 [M+H].sup.+.
Embodiment 65
3-((3-exo)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[4,5-d]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1283] ##STR00447##
[1284] The preparation of 3-((3-exo)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[4,5-d]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1285] MS m/z (ESI): 410.2 [M+H].sup.+.
Embodiment 66
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1286] ##STR00448##
Step 1: preparation of 5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazolo[5,4-d]pyrimidin-7-amine
[1287] ##STR00449##
[1288] 3-Amino-5-methylpyrazol (116 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) were successively added to the solution of 5,7-dichlorothiazolo[5,4-d]pyrimidine(206 mg, 1 mmol) in dimethyl sulfoxide (10 mL), and the mixture was then stirred at 70° C. for 1 hour. When the reaction was completed, water (50 mL) was added to the reaction mixture, and a solid was precipitated, which was then filtered and slurried with ethyl acetate to obtain the title compound as a yellow solid (200 mg, 75%).
[1289] MS m/z (ESI): 267.0 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1290] ##STR00450##
[1291] Tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (204 mg, 0.9 mmol) and DIPEA (193 mg, 1.5 mmol) were successively added to the solution of 5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazolo[5,4-d]pyrimidin-7-amine(200 mg, 0.75 mmol) in n-butanol (10 mL). The mixture was stirred at 160° C. for 15 hours under microwave condition. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound as a pale yellow solid (74 mg, 22%).
[1292] MS m/z (ESI): 457.1 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1293] ##STR00451##
[1294] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (74 mg, 0.16 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 2 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and dissolved in methanol (10 mL). DIPEA (83 mg, 0.64 mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (9 mg, 0.24 mmol) was added thereto and the mixture stirred for another 2 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (16.3 mg, 25%).
[1295] .sup.1H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 9.33 (s, 1H), 8.76 (d, J=20.4 Hz, 1H), 6.96 (s, 1H), 6.55 (d, J=12.0 Hz, 1H), 4.14 (s, 1H), 3.31 (s, 2H), 2.61 (s, 4H), 2.21 (s, 3H), 1.91 (s, 2H), 1.78-1.54 (m, 6H).
Embodiment 67
3-((3-exo)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1296] ##STR00452##
[1297] The preparation of 3-((3-exo)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1298] MS m/z (ESI): 410.2 [M+H].sup.+.
Embodiment 68
3-((3-exo)-3-((8-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-a]pyrazin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1299] ##STR00453##
[1300] The preparation of 3-((3-exo)-3-((8-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-a]pyrazin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 40.
[1301] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 69
3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-a]pyrazin-8-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1302] ##STR00454##
[1303] The preparation of 3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-a]pyrazin-8-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1304] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 70
3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrazin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1305] ##STR00455##
[1306] The preparation of 3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrazin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1307] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 71
3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1308] ##STR00456##
[1309] The preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 2.
[1310] MS m/z (ESI): 425.2 [M+H].sup.+.
Embodiment 72
3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1311] ##STR00457##
Step 1: preparation of 3-((3-exo)-3-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1312] ##STR00458##
[1313] Tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (271 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) were successively added to the solution of 5,7-dichloropyrrolo[2,1-f][1,2,4]triazin(188 mg, 1 mmol) in ethanol (10 mL). The mixture was then stirred at 80° C. for 2 hours under reflux. When the reaction was completed, the mixture was extracted with dichloromethane (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane 100%) to obtain the title compound as a pale yellow solid (350 mg, 93%).
[1314] MS m/z (ESI): 378.1 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4] triazin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1315] ##STR00459##
[1316] 3-((3-exo)-3-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (350 mg, 0.93 mmol), tert-butyl-3amino-5-methyl-1H-pyrazol-1-carboxylic acid(219 mg, 1.11 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (73 mg, 0.093 mmol) and potassium phosphate (591 mg, 2.79 mmol) were suspended in ultra-dry 1,4-dioxane (20 mL), and the mixture was filled with nitrogen for 3 times. The reaction mixture was then sealed, and stirred at 110° C. overnight. When the reaction was completed, the mixture was extracted with dichloromethane (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound as a yellow solid (100 mg, 24%).
[1317] MS m/z (ESI): 439.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1318] ##STR00460##
[1319] Tert-butyl-(3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4] triazin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.23 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then dissolved in methanol (10 mL). DIPEA (119 mg, 0.92 mmol) was slowly added dropwise into the mixture, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (18 mg, 0.35 mmol) was added thereto and the mixture was stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (31.8 mg, 35%).
[1320] .sup.1H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 8.48 (s, 1H), 7.74 (s, 1H), 7.35 (s, 1H), 6.73 (s, 1H), 6.36 (s, 2H), 4.49 (s, 1H), 3.30 (s, 2H), 2.72-2.59 (m, 4H), 2.18 (s, 3H), 1.91 (s, 2H), 1.83-1.64 (m, 6H).
[1321] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 73
3-((3-exo)-3-((8-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-0)propionitrile
[1322] ##STR00461##
[1323] The preparation of 3-((3-exo)-3-((8-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 6.
[1324] MS m/z (ESI): 393.2 [M+H].sup.+.
Embodiment 74
3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1325] ##STR00462##
[1326] The preparation of 3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 72.
[1327] MS m/z (ESI): 393.2 [M+H].sup.+.
Embodiment 75
3-((3-exo)-3-((2-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1328] ##STR00463##
[1329] The preparation of 3-((3-exo)-3-((2-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 72.
[1330] MS m/z (ESI): 407.2 [M+H].sup.+.
Embodiment 76
3-((3-exo)-3-((8-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1331] ##STR00464##
[1332] The preparation of 3-((3-exo)-3-((8-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 66.
[1333] MS m/z (ESI): 393.2 [M+H].sup.+.
Embodiment 77
3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1334] ##STR00465##
[1335] The preparation of 3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 72.
[1336] MS m/z (ESI): 393.2 [M+H].sup.+.
Embodiment 78
3-((3-exo)-3-((5-((5-(hydroxymethyl)thiazol-2-yl)amino)imidazo[1,2-c]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1337] ##STR00466##
[1338] The preparation of 3-((3-exo)-3-((5-((5-(hydroxymethyl)thiazol-2-yl)imidazo[1,2-c]pyrimidin-7-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 2.
[1339] MS m/z (ESI): 425.2 [M+H].sup.+.
Embodiment 79
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1340] ##STR00467##
Step 1: preparation of 3-((3-exo)-3-((7-chloroimidazo[1,2-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1341] ##STR00468##
[1342] Tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (271 mg, 1.2 mmol), DIPEA (258 mg, 2 mmol) were successively added to the solution of 5,7-dichloroimidazo[1,2-c]pyrimidine(188 mg, 1 mmol) in ethanol (10 mL), and the mixture was stirred at room temperature overnight. When the reaction was completed, the mixture was extracted with dichloromethane (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=99:1) to obtain the title compound as a pale yellow solid (374 mg, 99%).
[1343] MS m/z (ESI): 378.1 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1344] ##STR00469##
[1345] 3-((3-exo)-3-((7-chloroimidazo[1,2-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (330 mg, 0.87 mmol), tert-butyl-3amino-5-methyl-1H-pyrazol-1-carboxylate (259 mg, 1.31 mmol), methanesulfonato(2-dicyclohexylphosphine-3,6-dimethoxyl-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (82 mg, 0.09 mmol) and sodium tert-butoxide (252 mg, 2.62 mmol) were suspended in ultra-dry 1,4-dioxane (20 mL). The mixture was filled with nitrogen for 3 times, then heated to 130° C. with microwave and reacted for 4 hours. When the reaction was completed, the mixture was extracted with dichloromethane (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound as a yellow solid (30 mg, 8%).
[1346] MS m/z (ESI): 439.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1347] ##STR00470##
[1348] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (30 mg, 0.07 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 2 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then dissolved in methanol (5 mL). DIPEA (36 mg, 0.28 mmol) was slowly added dropwise into the mixture, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (5 mg, 0.1 mmol) was added thereto and the mixture stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a yellow solid (8.9 mg, 32%).
[1349] .sup.1H NMR (400 MHz, DMSO) δ=11.73 (s, 1H), 8.65 (s, 1H), 7.71 (s, 1H), 7.23 (d, J=8.4, 1H), 7.19 (d, J=1.2, 1H), 6.55 (s, 1H), 5.99 (s, 1H), 4.48-4.21 (m, 1H), 3.30 (s, 2H), 2.62 (m, 4H), 2.20 (s, 3H), 1.97-1.90 (m, 2H), 1.87-1.79 (m, 2H), 1.76-1.56 (m, 4H).
[1350] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 80
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)pyrazolo[1,5-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1351] ##STR00471##
[1352] The preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)pyrazolo[1,5-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 66.
[1353] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 81
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1354] ##STR00472##
[1355] The preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 79.
[1356] MS m/z (ESI): 393.2 [M+H].sup.+.
Embodiment 82
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1357] ##STR00473##
[1358] The preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 79.
[1359] MS m/z (ESI): 393.2 [M+H].sup.+.
Embodiment 83
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,5-b]pyridazin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1360] ##STR00474##
[1361] The preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,5-b]pyridazin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 6.
[1362] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 84
3-((3-exo)-3-((8-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,5-a]pyrimidin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1363] ##STR00475##
[1364] The preparation of 3-((3-exo)-3-((8-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,5-a]pyrimidin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 66.
[1365] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 85
3-((3-exo)-3-((1-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,5-a]pyrazin-3-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1366] ##STR00476##
[1367] The preparation of 3-((3-exo)-3-((1-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,5-a]pyrazin-3-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 66.
[1368] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 86
3-((3-exo)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1369] ##STR00477##
[1370] The preparation of 3-((3-exo)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 4.
[1371] MS m/z (ESI): 403.2 [M+H].sup.+.
Embodiment 87
3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1372] ##STR00478##
[1373] The preparation of 3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1374] .sup.1H NMR (400 MHz, DMSO) δ=11.76 (s, 1H), 8.90 (s, 1H), 8.08 (d, J=8.0, 1H), 7.72 (s, 1H), 7.53 (t, J=7.4, 1H), 7.36 (s, 1H), 7.10 (s, 1H), 6.55 (s, 1H), 4.72-4.58 (m, 1H), 3.30 (s, 2H), 2.64 (s, 4H), 2.20 (s, 3H), 1.92 (s, 2H), 1.86-1.62 (m, 6H).
[1375] MS m/z (ESI): 403.2 [M+H].sup.+.
Embodiment 88
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[3,4-b]pyrazin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1376] ##STR00479##
Step 1: preparation of 3-((3-exo)-3-((7-chloropyrido[3,4-b]pyrazin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1377] ##STR00480##
[1378] Tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (271 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) were successively added to the solution of 5,7-dichloropyrido[3,4-b]pyrazin (200 mg, 1 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 2 hours. When the reaction was completed, the mixture was extracted with dichloromethane (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=99:1) to obtain the title compound as a pale yellow solid (350 mg, 90%).
[1379] MS m/z (ESI): 390.1 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[3,4-b]pyrazin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1380] ##STR00481##
[1381] 3-((3-exo)-3-((7-chloropyrido[3,4-b]pyrazin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (350 mg, 0.9 mmol), tert-butyl-3amino-5-methyl-1H-pyrazol-1-carboxylate (266 mg, 1.35 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (71 mg, 0.09 mmol) and cesium carbonate (880 mg, 2.7 mmol) were suspended in ultra-dry 1,4-dioxane (20 mL), and the mixture was filled with nitrogen for 3 times. The reaction mixture was then sealed, heated to 130° C. and reacted overnight. When the reaction was completed, the mixture was extracted with dichloromethane (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=98:2) to obtain the title compound as a yellow solid (32.4 mg, 8%).
[1382] MS m/z (ESI): 451.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[3,4-b]pyrazin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1383] ##STR00482##
[1384] 3-((3-exo)-3-((7-chloropyrido[3,4-b]pyrazin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (32.4 mg, 0.07 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 2 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then dissolved in methanol (5 mL). DIPEA (36 mg, 0.28 mmol) was slowly added dropwise into the mixture, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (5 mg, 0.1 mmol) was added thereto and the mixture was stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a yellow solid (8.2 mg, 29%).
[1385] .sup.1H NMR (400 MHz, DMSO) δ=11.80 (s, 1H), 9.16 (s, 1H), 8.71 (d, J=2.0, 1H), 8.31 (d, J=1.6, 1H), 7.48 (d, J=8.4, 1H), 6.69 (s, 1H), 6.29 (s, 1H), 4.66-4.51 (m, 1H), 3.30 (s, 2H), 2.76 (dt, J=12.4, 6.8, 4H), 2.30 (s, 3H), 2.08-1.93 (m, 2H), 1.85-1.83 (m, 6H).
[1386] MS m/z (ESI): 404.2 [M+H].sup.+.
Embodiment 89
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1387] ##STR00483##
Step 1: preparation of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-4-amine
[1388] ##STR00484##
[1389] 2,4-Dichloropyrido[2,3-d]pyrimidine (200 mg, 1.0 mmol), 5-methyl-1H-pyrazol-3-amine (107 mg, 1.1 mmol) and DIPEA (0.5 mL, 3.0 mmol) were added to anhydrous ethanol (5 mL), and the mixture was stirred at room temperature for 13.5 hours. Then the mixture was concentrated under reduced pressure, and the residue solid was washed with water-ethanol (v\v=9:1, 20 mL), followed by filtration. The filter residue was then dried under reduced pressure to obtain the title compound (185 mg, 71%).
[1390] MS m/z (ESI): 261.1 [M+H].sup.+.
Step 2: preparation of Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1391] ##STR00485##
[1392] 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-4-amine (50 mg, 0.192 mmol) and tert-butyl (3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (87 mg, 0.383 mmol) were added to n-butanol (3 mL). The mixture was heated to 150° C. with a microwave reactor and reacted for 4 hour. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by reverse phase chromatography to obtain the title compound (39.5 mg, 46%).
[1393] MS m/z (ESI): 451.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1394] ##STR00486##
[1395] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (39.5 mg, 0.088 mmol) was dissolved in 4M HCl in 1,4-dioxane solution (10 mL). The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in anhydrous methanol (10 mL), followed by successive addition of DIPEA (0.72 mL, 4.38 mmol) and acrylonitrile (0.29 mL, 4.38 mmol). The reaction mixture was stirred at room temperature for 75 minutes, and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse phase HPLC to obtain the title compound (10.6 mg, 30%).
[1396] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.07 (s, 1H), 10.11 (s, 1H), 8.71 (dd, J=9.4, 1.8 Hz, 1H), 8.63 (dd, J=3.7, 1.1 Hz, 1H), 7.02 (ddd, J=11.4, 10.6, 6.7 Hz, 2H), 6.76 (d, J=84.4 Hz, 1H), 4.26 (s, 1H), 3.31-3.25 (m, 2H), 2.64 (t, J=11.0 Hz, 4H), 2.25 (d, J=13.7 Hz, 3H), 1.92 (d, J=8.5 Hz, 2H), 1.64 (dt, J=25.4, 10.4 Hz, 6H).
[1397] MS m/z (ESI): 404.3 [M+H].sup.+.
Embodiment 90
3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1398] ##STR00487##
[1399] 3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 6.
[1400] .sup.1H NMR (400 MHz, DMSO) δ=11.83 (s, 1H), 9.19 (s, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 7.93 (s, 1H), 7.09 (s, 1H), 6.54 (s, 1H), 4.58 (s, 1H), 3.30 (s, 2H), 2.68-2.59 (m, 4H), 2.22 (s, 3H), 1.93 (s, 2H), 1.86-1.67 (m, 6H).
[1401] MS m/z (ESI): 404.2 [M+H].sup.+.
Embodiment 91
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[4,3-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1402] ##STR00488##
[1403] 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[4,3-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 88.
[1404] MS m/z (ESI): 404.2 [M+H].sup.+.
Embodiment 92
3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)pteridin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1405] ##STR00489##
[1406] 3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)pteridin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 88.
[1407] MS m/z (ESI): 405.2 [M+H].sup.+.
Embodiment 93
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-2-carbonyl-1,2-2H-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1408] ##STR00490##
[1409] 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-2-carbonyl-1,2-2H-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 88.
[1410] MS m/z (ESI): 419.2 [M+H].sup.+.
Embodiment 94
3-((3-exo)-3-((1-methyl-7-((5-methyl-1H-pyrazol-3-yl)amino)-2-carbonyl-1,2-2H-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1411] ##STR00491##
[1412] 3-((3-exo)-3-((1-methyl-7-((5-methyl-1H-pyrazol-3-yl)amino)-2-carbonyl-1,2-2H-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 88.
[1413] MS m/z (ESI): 433.2 [M+H].sup.+.
Embodiment 95
3-((3-exo)-3-((6-methyl-3-((5-methyl-1H-pyrazol-3-yl)amino)-5-carbonyl-5,6-2H-2,6-diazanaphthalen-1-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1414] ##STR00492##
[1415] 3-((3-exo)-3-((6-methyl-3-((5-methyl-1H-pyrazol-3-yl)amino)-5-carbonyl-5,6-2H-2,6-diazanaphthalen-1-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 88.
[1416] MS m/z (ESI): 433.2 [M+H].sup.+.
Embodiment 96
5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-2-formonitrile
[1417] ##STR00493##
[1418] 5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-2-formonitrile was carried out with the reference to Embodiment 88.
[1419] MS m/z (ESI): 428.2 [M+H].sup.+.
Embodiment 97
3-((3-exo)-3-((3-fluoro-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1420] ##STR00494##
[1421] 3-((3-exo)-3-((3-fluoro-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 88.
[1422] MS m/z (ESI): 421.2 [M+H].sup.+.
Embodiment 98
3-((3-exo)-3-((4-hydroxy-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1423] ##STR00495##
[1424] 3-((3-exo)-3-((4-hydroxy-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 88.
[1425] MS m/z (ESI): 419.2 [M+H].sup.+.
Embodiment 99
3-((3-exo)-3-((8-methyl-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1426] ##STR00496##
[1427] 3-((3-exo)-3-((8-methyl-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 88.
[1428] MS m/z (ESI): 417.2 [M+H].sup.+.
Embodiment 100
3-((3-exo)-3-((8-methoxyl-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1429] ##STR00497##
[1430] 3-((3-exo)-3-((8-methoxyl-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 88.
[1431] MS m/z (ESI): 433.2 [M+H].sup.+.
Embodiment 101
5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-8-formonitrile
[1432] ##STR00498##
[1433] 5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-8-formonitrile was carried out with the reference to Embodiment 88.
[1434] MS m/z (ESI): 428.2 [M+H].sup.+.
Embodiment 102
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6,7-2H-5H-pyrano[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1435] ##STR00499##
[1436] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6,7-2H-5H-pyrano[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 4.
[1437] MS m/z (ESI): 409.2 [M+H].sup.+.
Embodiment 103
3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)-6,7-2H-5H-pyrano[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1438] ##STR00500##
[1439] 3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)-6,7-2H-5H-pyrano[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1440] MS m/z (ESI): 409.2 [M+H].sup.+.
Embodiment 104
3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)-6,7-2H-[1,4]dioxino[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1441] ##STR00501##
[1442] 3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)-6,7-2H-[1,4]dioxino[2,3-d]pyrimidin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 39.
[1443] MS m/z (ESI): 411.2 [M+H].sup.+.
Embodiment 105
3-(5-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-2-azatricyclic[3.3.1.13,7]dec-2-yl)propionitrile
[1444] ##STR00502##
[1445] 3-((5-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-2-azatricyclic[3.3.1.13,7]dec-2-yl)propionitrile was carried out with the reference to Embodiment 5.
[1446] MS m/z (ESI): 429.2 [M+H].sup.+.
Embodiment 106
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-6-azabicyclo[3.1.1]hept-6-yl)propionitrile
[1447] ##STR00503##
[1448] 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-6-azabicyclo[3.1.1]hept-6-yl)propionitrile was carried out with the reference to Embodiment 5.
[1449] MS m/z (ESI): 389.2 [M+H].sup.+.
Embodiment 107
3-((1S,4S,5S)-5-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-2-azabicyclo[2.2.2]oct-2-yl)propionitrile
[1450] ##STR00504##
[1451] 3-((1S,4S,5S)-5-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-2-azabicyclo[2.2.2]oct-2-yl)propionitrile was carried out with the reference to Embodiment 5.
[1452] MS m/z (ESI): 403.2 [M+H].sup.+.
Embodiment 108
3-((1S,4S,5S)-5-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-2-azabicyclo[2.2.1]hept-2-yl)propionitrile
[1453] ##STR00505##
[1454] 3-((1S,4S,5S)-5-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-2-azabicyclo[2.2.1]hept-2-yl)propionitrile was carried out with the reference to Embodiment 5.
[1455] MS m/z (ESI): 389.2 [M+H].sup.+.
Embodiment 109
3-(3-(7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile
[1456] ##STR00506##
Step 1: Preparation of tert-butyl-3-(7-chloro-1,6-diazanaphthalen-5-yl)-3,8-diazabicyclo[3.2.1]oct-8-carboxylate
[1457] ##STR00507##
[1458] Tert-butyl-3,8-diazabicyclo[3.2.1]oct-8-carboxylate (119 mg, 0.53 mmol), 5,7-dichloro-1,6-diazanaphthalen (100 mg, 0.5 mmol) and diisopropylethylamine (95 mg, 1.5 mmol) were dissolved in DMSO (4 mL). The mixture was stirred at room temperature for dissolution, then heated to 110° C. and stirred for 22 hours. The reaction mixture was diluted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to remove the organic solvent. The resulting product was purified by silica gel column chromatography to obtain the title compound (173 mg, 92%).
[1459] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.97 (dd, J=4.1, 1.1 Hz, 1H), 8.47 (d, J=8.4 Hz, 1H), 7.53 (dd, J=8.5, 4.2 Hz, 1H), 7.37 (s, 1H), 4.22 (s, 2H), 3.86 (d, J=12.2 Hz, 2H), 3.34 (s, 1H), 3.31-3.29 (m, 1H), 1.96-1.80 (m, 4H), 1.44 (s, 9H).
[1460] MS m/z (ESI): 375.2 [M+H].sup.+.
Step 2: Preparation of 3-(3-(7-chloro-1,6-diazanaphthalen-5-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile
[1461] ##STR00508##
[1462] Tert-butyl-3-(7-chloro-1,6-diazanaphthalen-5-yl)-3,8-diazabicyclo[3.2.1]oct-8-carboxylate (169 mg, 0.45 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetate acid (1 mL) was added thereto with stirring. The resulting mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure to obtain brown oil. The obtained brown oil was dissolved in anhydrous methanol (2 mL), followed by successive addition of diisopropylethylamine (0.745 mL, 4.5 mmol) and acrylonitrile (0.036 mL, 0.54 mmol) at room temperature with stirring. The mixture was stirred at room temperature for 12 hours, and then concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography to obtain the title compound (135 mg, 91%).
[1463] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.94 (dd, J=4.1, 1.1 Hz, 1H), 8.43 (d, J=8.3 Hz, 1H), 7.50 (dd, J=8.5, 4.2 Hz, 1H), 7.29 (s, 1H), 3.81 (d, J=10.2 Hz, 2H), 3.36 (d, J=11.6 Hz, 4H), 2.67 (t, J=6.4 Hz, 2H), 2.58 (t, J=6.4 Hz, 2H), 1.85 (dd, J=12.4, 6.7 Hz, 2H), 1.80-1.72 (m, 2H).
[1464] MS m/z (ESI): 328.2 [M+H].sup.+.
Step 3: preparation of 3-(3-(7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile
[1465] ##STR00509##
[1466] 3-(3-(7-Chloro-1,6-diazanaphthalen-5-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile (50 mg, 0.153 mmol), tert-butyl 3-amino-5-methyl-1H-pyrazol-1-carboxylate (36 mg, 0.183 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (7 mg, 0.009 mmol) and cesium carbonate(65 mg, 0.20 mmol) were added to ultra-dry 1,4-dioxane (5 mL), and the reaction mixture was filled with dry nitrogen. The reaction mixture was then sealed, heated to 110° C., stirred for 36 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure. The mixture was dissolved in dichloromethane (2 mL), followed by addition of trifluoroacetate acid (1 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain the title compound (2.7 mg, 5%).
[1467] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.61 (d, J=2.8 Hz, 1H), 8.32 (dd, J=8.3, 2.6 Hz, 1H), 7.22-6.99 (m, 2H), 6.07 (s, 1H), 3.73 (dd, J=11.7, 1.5 Hz, 2H), 3.51-3.36 (m, 4H), 2.69 (qd, J=8.2, 1.7 Hz, 4H), 2.29 (s, 3H), 2.04 (s, 4H).
[1468] MS m/z (ESI): 389.3 [M+H].sup.+.
Embodiment 110
3-((3-(7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)-3-azabicyclo[3.2.1]oct-8-yl)amino)propionitrile
[1469] ##STR00510##
[1470] The preparation of 3-((3-(7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)-3-azabicyclo[3.2.1]oct-8-yl)amino)propionitrile was carried out with the reference to Embodiment 109.
[1471] MS m/z (ESI): 403.2 [M+H].sup.+.
Embodiment 111
3-((3-exo)-3-(methyl(7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1472] ##STR00511##
Step 1: Preparation of tert-butyl (3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1473] ##STR00512##
[1474] 5,7-Dichloro-1,6-diazanaphthalen (200 mg, 1.0 mmol), tert-butyl (3-exo)-3-(methylamino)-8-azabicyclo[3.2.1]oct-8-carboxylate (264 mg, 1.1 mmol) and DIPEA (0.5 mL, 3.0 mmol) were dissolved in dimethyl sulfoxide (3 mL). The reaction mixture was then heated to 120° C. and stirred for 30 hours. Then the mixture was cooled to room temperature, and diluted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was used directly in the next step.
[1475] MS m/z (ESI): 403.1 [M+H].sup.+.
Step 2: Preparation of 3-((3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1476] ##STR00513##
[1477] Tert-butyl (3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate was dissolved in 4M HCl in 1,4-dioxane (10 mL). The resulting reaction mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure. The oily residue was dissolved in anhydrous methanol (15 mL), followed by successive addition of DIPEA (8.24 mL, 50 mmol) and acrylonitrile (1.32 mL, 20 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography to obtain the title compound (242 mg, 68%).
[1478] MS m/z (ESI): 356.1 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-(methyl(7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1479] ##STR00514##
[1480] 3-((3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (50 mg, 0.14 mmol), tert-butyl3-amino-5-methyl-1H-pyrazol-1-carboxylate (42 mg, 0.21 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (24 mg, 0.03 mmol) and cesium carbonate (138 mg, 0.42 mmol) were added to ultra-dry 1,4-dioxane (5 mL), and the reaction mixture was filled with dry nitrogen. The reaction mixture was then sealed, heated to 100° C., stirred for 26 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and then purified by prep-HPLC to obtain the title compound (23.7 mg, 41%).
[1481] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.76 (s, 1H), 8.82 (s, 1H), 8.65 (dd, J=4.1, 1.3 Hz, 1H), 8.13 (d, J=8.1 Hz, 1H), 7.19 (s, 1H), 7.06 (dd, J=8.3, 4.2 Hz, 1H), 5.96 (s, 1H), 4.27-4.14 (m, 1H), 3.33-3.31 (m, 2H), 2.93 (s, 3H), 2.61 (dd, J=11.0, 5.0 Hz, 4H), 2.20 (s, 3H), 1.94 (t, J=11.1 Hz, 2H), 1.87-1.79 (m, 2H), 1.68-1.60 (m, 2H), 1.52 (d, J=7.7 Hz, 2H).
[1482] MS m/z (ESI): 417.3 [M+H].sup.+.
Embodiment 112
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)oxo)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1483] ##STR00515##
[1484] The preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)oxo)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 5.
[1485] MS m/z (ESI): 404.2 [M+H].sup.+.
Embodiment 113
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)methyl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1486] ##STR00516##
[1487] The preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)methyl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1488] MS m/z (ESI): 402.2 [M+H].sup.+.
Embodiment 114
3-(3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)methyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile
[1489] ##STR00517##
[1490] The preparation of 3-(3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)methyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1491] MS m/z (ESI): 403.2 [M+H].sup.+.
Embodiment 115
3-(3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile
[1492] ##STR00518##
[1493] The preparation of 3-(3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1494] MS m/z (ESI): 453.2 [M+H].sup.+.
Embodiment 116
[1495] 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-carbonyl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
##STR00519##
[1496] The preparation of 3-((3-exo)-3-(7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-carbonyl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1497] MS m/z (ESI): 416.2 [M+H].sup.+.
Embodiment 117
3-((3-exo)-3-((S)-hydroxyl(7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)methyl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1498] ##STR00520##
[1499] The preparation of 3-((3-exo)-3-((S)-hydroxyl(7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)methyl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1500] MS m/z (ESI): 418.2 [M+H].sup.+.
Embodiment 118
N7-(5-methyl-1H-pyrazol-3-yl)-N5-((3-exo)-8-(oxetan-3-ylmethyl)-8-azabicyclo[3.2.1]oct-3-yl)-1,6-diazanaphthalen-5,7-diamine
[1501] ##STR00521##
[1502] The preparation of N7-((5-methyl-1H-pyrazol-3-yl)-N5-((3-exo)-8-(oxetan-3-ylmethyl)-8-azabicyclo[3.2.1]oct-3-yl)-1,6-diazanaphthalen-5,7-diamine was carried out with the reference to Embodiment 111.
[1503] MS m/z (ESI): 420.2 [M+H].sup.+.
Embodiment 119
(cis)-3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)cyclobutane-1-formonitrile
[1504] ##STR00522##
[1505] The preparation of (cis)-3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)cyclobutane-1-formonitrile was carried out with the reference to Embodiment 111.
[1506] MS m/z (ESI): 429.2 [M+H].sup.+.
Embodiment 120
(trans)-3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)cyclobutane-1-formonitrile
[1507] ##STR00523##
[1508] The preparation of (trans)-3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)cyclobutane-1-formonitrile was carried out with the reference to Embodiment 111.
[1509] MS m/z (ESI): 429.2 [M+H].sup.+.
Embodiment 121
(cis)-3-(((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)methyl)cyclobutane-1-formonitrile
[1510] ##STR00524##
[1511] The preparation of (cis)-3-(((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)methyl)cyclobutane-1-formonitrile was carried out with the reference to Embodiment 111.
[1512] MS m/z (ESI): 443.3 [M+H].sup.+.
Embodiment 122
(trans)-3-(((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)methyl)cyclobutane-1-formonitrile
[1513] ##STR00525##
[1514] The preparation of (trans)-3-(((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)methyl)cyclobutane-1-formonitrile was carried out with the reference to Embodiment 111.
[1515] MS m/z (ESI): 443.3 [M+H].sup.+.
Embodiment 123
N5-((3-exo)-8-(azetindin-3-ylmethyl)-8-azabicyclo[3.2.1]oct-3-yl)-N7-((5-methyl-1H-pyrazol-3-yl)-1,6-diazanaphthalen-5,7-diamine
[1516] ##STR00526##
[1517] The preparation of N5-((3-exo)-8-(azetindin-3-ylmethyl)-8-azabicyclo[3.2.1]oct-3-yl)-N7-((5-methyl-1H-pyrazol-3-yl)-1,6-diazanaphthalen-5,7-diamine was carried out with the reference to Embodiment 111.
[1518] MS m/z (ESI): 419.3 [M+H].sup.+.
Embodiment 124
N7-((5-methyl-1H-pyrazol-3-yl)-N5-((3-exo)-8-(piperidin-4-ylmethyl)-8-azabicyclo[3.2.1]oct-3-yl)-1,6-diazanaphthalen-5,7-diamine
[1519] ##STR00527##
[1520] The preparation of N7-((5-methyl-1H-pyrazol-3-yl)-N5-((3-exo)-8-(piperidin-4-ylmethyl)-8-azabicyclo[3.2.1]oct-3-yl)-1,6-diazanaphthalen-5,7-diamine was carried out with the reference to Embodiment 111.
[1521] MS m/z (ESI): 447.3 [M+H].sup.+.
Embodiment 125
3-(3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)azetindin-1-yl)propionitrile
[1522] ##STR00528##
[1523] The preparation of 3-(3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)azetindin-1-yl)propionitrile was carried out with the reference to Embodiment 111.
[1524] MS m/z (ESI): 458.3 [M+H].sup.+.
Embodiment 126
1-(((3-exo)-3-(methyl(7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1525] ##STR00529##
[1526] The preparation of 1-(((3-exo)-3-(methyl(74(5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 111.
[1527] MS m/z (ESI): 522.2 [M+H].sup.+.
Embodiment 127
(3-exo)-N-(2-cyanoethyl)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-sulfonamide
[1528] ##STR00530##
[1529] The preparation of (3-exo)-N-(2-cyanoethyl)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-sulfonamide was carried out with the reference to Embodiment 111.
[1530] MS m/z (ESI): 496.2 [M+H].sup.+.
Embodiment 128
1-(((3-exo)-3-((7-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1531] ##STR00531##
[1532] The preparation of 1-(((3-exo)-3-((7-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 2.
[1533] MS m/z (ESI): 538.2 [M+H].sup.+.
Embodiment 129
1-(((3-exo)-3-((7-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1534] ##STR00532##
[1535] The preparation of 1-(((3-exo)-3-((7-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 2.
[1536] MS m/z (ESI): 524.2 [M+H].sup.+.
Embodiment 130
1-(((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1537] ##STR00533##
[1538] The preparation of 1-(((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 2.
[1539] MS m/z (ESI): 541.2 [M+H].sup.+.
Embodiment 131
1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1540] ##STR00534##
[1541] The preparation of 1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 3.
[1542] MS m/z (ESI): 527.2 [M+H].sup.+.
Embodiment 132
1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1543] ##STR00535##
Step 1: preparation of (3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol
[1544] ##STR00536##
[1545] 2,4-Dichlorothieno[2,3-d]pyrimidine (100 mg, 0.49 mmol), (3-amino-1H-pyrazol-5-yl)methanol (55 mg, 0.49 mmol) and DIPEA (190 mg, 1.47 mmol) were added to N′N-dimethylformamide(2 mL), and the reaction mixture was stirred at 70° C. overnight. Then the mixture was concentrated under reduced pressure, and the crude product obtained was purified by flash silica gel chromatography to obtain the title compound as a yellow solid (100 mg, 73%).
[1546] MS m/z (ESI):282.0 [M+H].sup.+.
Step 2: preparation of tert-butyl (3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate
[1547] ##STR00537##
[1548] (3-((2-Chlorothieno[2,3-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol (100 mg, 0.36 mmol), tert-butyl (3-exo)-3-(methylamino)-9-azabicyclo[3.3.1]non-9-carboxylate (135 mg, 0.53 mmol) and DIPEA (140 mg, 1.08 mmol) were added to n-butanol (2.5 mL). The mixture was mixed evenly, then heated to 150° C. by microwave and reacted for 10 hours. The mixture was then cooled to room temperature, and concentrated under reduced pressure. The crude product obtained was purified by flash silica gel chromatography to obtain the target product as a white solid (70 mg, 39%).
[1549] MS m/z (ESI): 500.1 [M+H].sup.+.
Step 3: preparation of 1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1550] ##STR00538##
[1551] Hydrochloride dioxane (4N, 2.5 mL) was slowly added dropwise to the solution of tert-butyl (3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (70 mg, 0.14 mmol) in methanol (10 mL). The reaction was carried out at room temperature for 2 hours, and then concentrated under reduced pressure. The crude product was dissolved in DMF (5 mL), followed by successive addition of DIPEA (0.3 mL) and 3-cyanoazacyclobutane-1-sulfonylchlorine (22 mg, 0.12 mmol) at 0° C. under ice water bath condition. The reaction was carried out at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and purified by prep-HPLC to obtain the target compound as a white solid (9.7 mg, 13%).
[1552] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.81 (s, 1H), 7.68 (d, J=4.4 Hz, 1H), 7.04 (d, J=6.0 Hz, 1H), 6.52-6.54 (m, 1H), 5.53-5.55 (m, 1H), 5.33-5.35 (m, 1H), 4.44 (d, J=5.2 Hz, 2H), 4.05-4.01 (m, 4H), 3.94-3.90 (m, 2H), 382-3.79 (m, 1H), 2.89 (d, J=8.4 Hz, 3H), 2.08-1.68 (m, 11H).
[1553] MS m/z (ESI): 544.1 [M+H].sup.+.
Embodiment 133
1-(((3-exo)-3-((7-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1554] ##STR00539##
[1555] The preparation of 1-(((3-exo)-3-((7-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 2.
[1556] MS m/z (ESI): 545.2 [M+H].sup.+.
Embodiment 134
1-(((3-exo)-3-((5-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-7-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1557] ##STR00540##
[1558] The preparation of 1-(((3-exo)-3-((5-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-7-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 132.
[1559] MS m/z (ESI): 538.2 [M+H].sup.+.
Embodiment 135
1-(((3-exo)-3-((7-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)pyrido[3,4-b]pyrazin-5-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1560] ##STR00541##
[1561] The preparation of 1-(((3-exo)-3-((7-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)pyrido[3,4-b]pyrazin-5-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 2.
[1562] MS m/z (ESI): 539.2 [M+H].sup.+.
Embodiment 136
1-(((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1563] ##STR00542##
[1564] The preparation of 1-(((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 3.
[1565] MS m/z (ESI): 544.2 [M+H].sup.+.
Embodiment 137
1-(((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)thieno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1566] ##STR00543##
[1567] The preparation of 1-(((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)thieno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 132.
[1568] MS m/z (ESI): 561.1 [M+H].sup.+.
Embodiment 138
1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)amino)quinazolin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1569] ##STR00544##
[1570] The preparation of 1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)amino)quinazolin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 132.
[1571] MS m/z (ESI): 556.2 [M+H].sup.+.
Embodiment 139
1-(((3-exo)-3-((6-((5-(hydroxymethyl)thiazol-2-yl)amino)-1H-pyrrolo[3,2-c]pyridin-4-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1572] ##STR00545##
[1573] The preparation of 1-(((3-exo)-3-((6-((5-(hydroxymethyl)thiazol-2-yl)amino)-1H-pyrrolo[3,2-c]pyridin-4-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 2.
[1574] MS m/z (ESI): 529.2 [M+H].sup.+.
Embodiment 140
1-(((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)imidazo[1,2-c]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1575] ##STR00546##
[1576] The preparation of 1-(((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)imidazo[1,2-c]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 2.
[1577] MS m/z (ESI): 530.2 [M+H].sup.+.
Embodiment 141
3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1578] ##STR00547##
[1579] The preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 132.
[1580] MS m/z (ESI): 425.2 [M+H].sup.+.
Embodiment 142
3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1581] ##STR00548##
[1582] The preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 132.
[1583] MS m/z (ESI): 442.1 [M+H].sup.+.
Embodiment 143
3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1584] ##STR00549##
[1585] The preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 132.
[1586] MS m/z (ESI): 436.2 [M+H].sup.+.
Embodiment 144
3-((3-exo)-3-((6-((5-(hydroxymethyl)thiazol-2-yl)amino)-1H-pyrrolo[3,2-c]pyridin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1587] ##STR00550##
[1588] The preparation of 3-((3-exo)-3-((6-((5-(hydroxymethyl)thiazol-2-yl)amino)-1H-pyrrolo[3,2-c]pyridin-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 2.
[1589] MS m/z (ESI): 424.2 [M+H].sup.+.
Embodiment 145
3-((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)imidazo[1,2-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1590] ##STR00551##
[1591] The preparation of 3-((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)imidazo[1,2-c]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 2.
[1592] MS m/z (ESI): 425.2 [M+H].sup.+.
Embodiment 146
N-(5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)-5-methyl-1H-pyrazol-3-formamide
[1593] ##STR00552##
[1594] The preparation of N-(5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)-5-methyl-1H-pyrazol-3-formamide was carried out with the reference to Embodiment 1.
[1595] MS m/z (ESI): 431.2 [M+H].sup.+.
Embodiment 147
3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1596] ##STR00553##
[1597] The preparation of 3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-4-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 3.
[1598] MS m/z (ESI): 376.2 [M+H].sup.+.
Embodiment 148
3-((3-exo)-3-(3-((5-methyl-1H-pyrazol-3-yl)amino)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1599] ##STR00554##
[1600] The preparation of 3-((3-exo)-3-(3-((5-methyl-1H-pyrazol-3-yl)amino)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1601] MS m/z (ESI): 377.2 [M+H].sup.+.
Embodiment 149
3-((3-exo)-3-(6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1602] ##STR00555##
[1603] The preparation of 3-((3-exo)-3-(6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1604] MS m/z (ESI): 378.2 [M+H].sup.+.
Embodiment 150
3-((3-exo)-3-(6-((5-methyl-1H-pyrazol-3-yl)amino)-2-carbonyl-2,3-2H-1H-imidazo[4,5-b]pyrazin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1605] ##STR00556##
[1606] The preparation of 3-((3-exo)-3-(6-((5-methyl-1H-pyrazol-3-yl)amino)-2-carbonyl-2,3-2H-1H-imidazo[4,5-b]pyrazin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1607] MS m/z (ESI): 394.2 [M+H].sup.+.
Embodiment 151
3-((3-exo)-3-(6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyrazin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1608] ##STR00557##
[1609] The preparation of 3-((3-exo)-3-(6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyrazin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1610] MS m/z (ESI): 378.2 [M+H].sup.+.
Embodiment 152
3-((3-exo)-3-(2-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyrazin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1611] ##STR00558##
[1612] The preparation of 3-((3-exo)-3-(2-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyrazin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1613] MS m/z (ESI): 392.2 [M+H].sup.+.
Embodiment 153
3-((3-exo)-3-((7-methoxyl-5-((5-methyl-1H-pyrazol-3-yl)amino)-3H-imidazo[4,5-b]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1614] ##STR00559##
[1615] The preparation of 3-((3-exo)-3-((7-methoxyl-5-((5-methyl-1H-pyrazol-3-yl)amino)-3H-imidazo[4,5-b]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1616] MS m/z (ESI): 407.2 [M+H].sup.+.
Embodiment 154
3-((3-exo)-3-(6-methoxyl-8-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-9H-purin-9-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1617] ##STR00560##
[1618] The preparation of 3-((3-exo)-3-(6-methoxyl-8-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-9H-purin-9-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1619] MS m/z (ESI): 422.2 [M+H].sup.+.
Embodiment 155
3-((3-exo)-3-((4-methoxyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1620] ##STR00561##
[1621] The preparation of 3-((3-exo)-3-(4-methoxyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1622] MS m/z (ESI): 407.2 [M+H].sup.+.
Embodiment 156
3-((3-exo)-3-(2-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholino-9H-purin-9-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1623] ##STR00562##
[1624] The preparation of 3-((3-exo)-3-(2-(((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholino-9H-purin-9-yl)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 111.
[1625] MS m/z (ESI): 463.3 [M+H].sup.+.
Embodiment 157
3-((1R,5S)-3-(2-(((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-b][1,2,4]triazin-7-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile
[1626] ##STR00563##
[1627] The preparation of 3-((1R,5S)-3-(2-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-b][1,2,4]triazin-7-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 109.
[1628] MS m/z (ESI): 379.2 [M+H].sup.+.
Embodiment 158
3-((1R,5S)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile
[1629] ##STR00564##
[1630] The preparation of 3-((1R,5S)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 109.
[1631] MS m/z (ESI): 378.2 [M+H].sup.+.
Embodiment 159
[1632] 3-((1R,5S)-3-(3-((5-methyl-1H-pyrazol-3-yl)amino)quinoxalin-5-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile
##STR00565##
[1633] The preparation of 3-((1R,5S)-3-(3-((5-methyl-1H-pyrazol-3-yl)amino)quinoxalin-5-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 109.
[1634] MS m/z (ESI): 389.2 [M+H].sup.+.
Embodiment 160
2-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)thiazol-5-formonitrile
[1635] ##STR00566##
Step 1: preparation of (3-exo)-3-((7-((5-cyanothiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1636] ##STR00567##
[1637] (3-exo)-3-((7-Chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (194 mg, 0.5 mmol), 2-aminothiazol-5-formonitrile (125 mg, 1.0 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (196 mg, 0.25 mmol) and cesium carbonate (489 mg, 1.5 mmol) were added to 10 mL ultra-dry 1,4-dioxane. The reaction mixture was filled with dry nitrogen, heated to 150° C. with microwave and stirred for 9 hours. Then the mixture was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (151.6 mg, 63%).
[1638] MS m/z (ESI): 478.1 [M+H].sup.+.
Step 2: preparation of 2-((5-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)thiazol-5-formonitrile
[1639] ##STR00568##
[1640] Tert-butyl (3-exo)-3-((7-((5-cyanothiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (180 mg, 0.377 mmol) was dissolved in 4M HCl in 1,4-dioxane (20 mL), and the mixture was stirred at room temperature for 30 minutes. Then the mixture was concentrated under reduced pressure, and the residue was dissolved in anhydrous methanol (10 mL), followed by successive addition of DIPEA (1.86 mL, 11.3 mmol) and acrylonitrile (0.25 mL, 3.77 mmol). The resulting reaction mixture was stirred at room temperature for 105 minutes, and concentrated under reduced pressure to remove the solvent. The residue was successively purified by silica gel chromatography and prep-HPLC to obtain the title compound (8.6 mg, 2.0%).
[1641] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.91 (s, 1H), 8.76 (d, J=3.2 Hz, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.23 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.23 (dd, J=8.3, 4.3 Hz, 1H), 6.59 (s, 1H), 4.76 (td, J=17.4, 8.7 Hz, 1H), 3.38 (s, 2H), 2.65 (s, 4H), 2.07-1.72 (m, 8H).
[1642] MS m/z (ESI): 431.1 [M+H].sup.+.
Embodiment 161
3-((3-exo)-3-((7-((5-(2-hydroxylethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1643] ##STR00569##
[1644] The preparation of 3-((3-exo)-3-((7-((5-(2-hydroxylethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 2.
[1645] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.78 (s, 1H), 8.67 (d, J=4.8 Hz, 1H), 8.55 (d, J=7.1 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.12-7.04 (m, 2H), 6.47 (s, 1H), 4.87-4.77 (m, 2H), 3.61 (dd, J=12.7, 7.0 Hz, 2H), 3.34 (s, 2H), 2.85-2.79 (m, 2H), 2.65 (s, 4H), 1.88 (ddd, J=29.8, 26.6, 7.6 Hz, 8H).
[1646] MS m/z (ESI): 450.2 [M+H].sup.+.
Embodiment 162
3-((3-exo)-3-((7-((5-(1-hydroxylethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1647] ##STR00570##
Step 1: preparation of 1-(2-aminothiazol-5-yl)ethane-1-ol
[1648] ##STR00571##
[1649] 2-Aminothiazol-5-formaldehyde (256 mg, 2.0 mmol) was dissolved in dry tetrahydrofuran (10 mL). The reaction mixture was then cooled to 0° C., followed by addition of methyl magnesium bromide (3M ether solution, 3.5 mL, 10 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 70 minutes. The reaction mixture was then quenched with water, and extracted with ethyl acetate. The organic phase was successively washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (150 mg, 52%).
[1650] MS m/z (ESI): 145.2 [M+H].sup.+.
Step 2: preparation of 3-((3-exo)-3-((7-((5-(1-hydroxylethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1651] ##STR00572##
[1652] 3-((3-exo)-3-((7-Chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile (50 mg, 0.146 mmol), 1-(2-aminothiazol-5-yl)ethane-1-ol (42 mg, 0.292 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (57 mg, 0.073 mmol) and cesium carbonate (143 mg, 0.438 mmol) were added to ultra-dry 1,4-dioxane (5 mL). The reaction mixture was filled with dry nitrogen then heated to 140° C. with microwave and stirred for 4 hours. Then the mixture was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain the title compound (1.9 mg, 3%).
[1653] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.79 (s, 1H), 8.67 (d, J=3.0 Hz, 1H), 8.56 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.16-7.07 (m, 2H), 6.49 (s, 1H), 5.29 (d, J=4.2 Hz, 1H), 4.92-4.81 (m, 2H), 3.34 (s, 2H), 2.65 (s, 4H), 1.93 (s, 4H), 1.81 (d, J=9.9 Hz, 4H), 1.44 (d, J=6.4 Hz, 3H).
[1654] MS m/z (ESI): 450.2, 452.0 [M+H].sup.+.
Embodiment 163
3-((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[1655] ##STR00573##
Step 1: preparation of tert-butyl (3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate
[1656] ##STR00574##
[1657] 5,7-Dichloro-1,6-diazanaphthalen (300 mg, 1.51 mmol), tert-butyl-(3-exo)-3-amino-9-azabicyclo[3.3.1]non-9-carboxylate oxalate (750 mg, 2.26 mmol) and DIPEA (580 mg, 4.53 mmol) were added to DMSO (5 mL). The reaction mixture was mixed evenly, reacted at 110° C. overnight. The mixture was then cooled to room temperature, and concentrated under reduced pressure. The crude product obtained was purified by flash silica gel chromatography to obtain the title compound as a yellow solid (500 mg, 82%).
[1658] MS m/z (ESI): 403.1 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((7-((5-formylthiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate
[1659] ##STR00575##
[1660] (3-exo)-3-((7-Chloro-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (200 mg, 0.5 mmol), 2-aminothiazol-5-formaldehyde (96 mg, 0.75 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (60 mg, 0.1 mmol) and cesium carbonate(490 mg, 1.5 mmol) were added to 1,4-dioxane (5 mL). Under nitrogen atmosphere, the mixture was heated to 160° C. under microwave and reacted for 3 hours. Then the mixture was cooled to room temperature, and concentrated under reduced pressure. The crude product obtained was purified by flash silica gel chromatography to obtain the title compound as a yellow solid (150 mg, 61%).
[1661] MS m/z (ESI): 495.1 [M+H].sup.+.
Step 3: preparation of (3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate
[1662] ##STR00576##
[1663] (3-exo)-3-((7-((5-formylthiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (150 mg, 0.3 mmol) was added to methanol (10 mL) at 0° C., and sodium borohydride (45 mg, 1.2 mmol) was slowly added to the reaction mixture. After 0.5 hour, the reaction mixture was quenched with water (0.2 mL), and concentrated under reduced pressure. The crude product obtained was purified by flash silica gel chromatography to obtain the title compound as a yellow solid (100 mg, 67%).
[1664] MS m/z (ESI): 497.2 [M+H].sup.+.
Step 4: preparation of 3-((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[1665] ##STR00577##
[1666] (3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.2 mmol) was added to methanol (10 mL), and hydrochloride dioxanesolution (4N, 2 mL) was slowly added to the reaction mixture. The reaction was carried out at room temperature for 1 hour, and then the mixture was concentrated under reduced pressure. A mixed solution of acrylonitrile (0.2 mL), DIPEA (0.2 mL) and methanol (10 mL) was added to the crude product obtained (100 mg), and the reaction was carried out at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by prep-HPLC to obtain the title compound as a white solid (19.2 mg, 15%).
[1667] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.88 (s, 1H), 8.69 (t, J=2.8 Hz, 1H), 8.58 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.18-7.12 (m, 2H), 6.50 (s, 1H), 5.18-5.09 (m, 2H), 4.50 (d, J=5.2 Hz, 2H), 3.03-2.92 (m, 4H), 2.63 (t, J=6.4 Hz, 2H), 2.24-2.16 (m, 1H), 1.98-1.87 (m, 6H), 1.73-1.67 (m, 3H).
[1668] MS m/z (ESI): 450.1 [M+H].sup.+.
Embodiment 164
1-((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-(pyrrolidin-1-yl)ethane-1-one
[1669] ##STR00578##
[1670] The preparation of 1-((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-(pyrrolidin-1-yl)ethane-1-one was carried out with the reference to Embodiment 163.
[1671] MS m/z (ESI): 508.2 [M+H].sup.+.
Embodiment 165
1-((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)-2-(piperidin-1-yl)ethane-1-one
[1672] ##STR00579##
[1673] The preparation of 1-((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)-2-(piperidin-1-yl)ethane-1-one was carried out with the reference to Embodiment 163.
[1674] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.89 (s, 1H), 8.68 (dd, J=4.0, 1.2 Hz, 1H), 8.52 (d, J=8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.19-7.11 (m, 2H), 6.52 (s, 1H), 5.18-5.09 (m, 2H), 4.56-4.54 (m, 4H), 3.16-3.13 (m, 1H), 3.03-3.00 (m, 1H), 2.51-2.39 (m, 4H), 2.09-1.76 (m, 8H), 1.52-1.50 (m, 4H), 1.38-1.35 (m, 2H).
[1675] MS m/z (ESI): 508.1 [M+H].sup.+.
Embodiment 166
2,2-difluoro-1-((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one
[1676] ##STR00580##
Step 1: preparation of 1-((3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)-2,2-difluoroethane-1-one
[1677] ##STR00581##
[1678] The compound (3-exo)-3-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (300 mg, 0.771 mmol) was added to methanol (2 mL), and the solution of HCl in methanol (2 mL, 4 M) was added to the mixture at room temperature. Then the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain the orange solid.
[1679] The orange solid (100 mg, 0.251 mmol), 2,2-difluoroacetic acid (29 mg, 0.301 mmol) and DIPEA (143 mg, 0.377 mmol) were separately added to DCM (2 mL), and HATU (143 mg, 113 mmol) was added to the mixture in batches at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was slurried in the mixed solution of methanol and water (each 2 mL) to obtain the title compound as a white solid (33 mg, 36%).
[1680] MS m/z (ESI): 367.1 [M+H].sup.+.
Step 2: preparation of 2,2-difluoro-1-((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one
[1681] ##STR00582##
[1682] 1-((3-exo)-3-((7-Chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)-2,2-difluoroethane-1-one (72 mg, 0.197 mmol), (2-aminothiazol-5-yl)methanol (38 mg, 0.295 mmol), cesium carbonate (128 mg, 0.394 mmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (X-Phos Pd G2) (31 mg, 0.0394 mmol) and XPhos (19 mg, 0.0394 mmol) were separately added to dioxane (3.5 mL). The mixture was filled with nitrogen for 3 times, then heated to 90° C. and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was successively purified by silica gel chromatography and prep-HPLC to obtain the title compound as a yellow solid (7.4 mg, 8%).
[1683] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.91 (s, 1H), 8.69 (dd, J=4.3, 1.6 Hz, 1H), 8.50 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.19 (s, 1H), 7.13 (dd, J=8.4, 4.3 Hz, 1H), 6.69 (t, J=53.0 Hz, 1H), 6.54 (s, 1H), 5.31-5.04 (m, 2H), 4.63-4.49 (m, 4H), 2.20-1.72 (m, 8H).
[1684] MS m/z (ESI): 461.1 [M+H].sup.+.
Embodiment 167
(2-((5-(((3-exo)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)thiazol-5-yl)methanol
[1685] ##STR00583##
Step 1: preparation of 7-chloro-N-((3-exo)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]oct-3-yl)-1,6-diazanaphthalen-5-amine
[1686] ##STR00584##
[1687] (3-exo)-3-((7-Chloro-1,6-diazanaphthalen-5-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (200 mg, 0.514 mmol) was dissolved in methanol (1.6 mL), and the solution of HCl in dioxane (1.2 mL, 4 M) was added thereto at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with N,N-dimethylformamide (2 mL), followed by addition of cesium carbonate (670 mg, 2.06 mmol) and 1-bromine-2-fluoroethane (131 mg, 1.03 mmol). The mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate, and washed with saturated sodium chloride aqueous solution. The organic phase was collected and dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure to remove the organic solvent, and the resulting product obtained was purified by silica gel chromatography to obtain the title compound as a brown solid (108 mg, 63%).
[1688] MS m/z (ESI): 335.1 [M+H].sup.+.
Step 2: preparation of (2-((5-(((3-exo)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]oct-3-yl)amino)-1,6-diazanaphthalen-7-yl)amino)thiazol-5-yl)methanol
[1689] ##STR00585##
[1690] 7-Chloro-N-((3-exo)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]oct-3-yl)-1,6-diazanaphthalen-5-amine (60 mg, 0.179 mmol), (2-aminothiazol-5-yl)methanol (47 mg, 0.358 mmol), cesium carbonate (117 mg, 0.358 mmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (X-Phos Pd G2) (28 mg, 0.0358 mmol) and XPhos(17 mg, 0.0358 mmol) were separately added to dioxane (2 mL). The mixture was filled with nitrogen for 3 times, then stirred at 85° C. for 16 hours. The reaction mixture was cooled down, diluted with methanol, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound as a yellow solid (6.0 mg, 8%).
[1691] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.86 (s, 1H), 8.68 (dd, J=4.3, 1.6 Hz, 1H), 8.54 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.18 (s, 1H), 7.11 (dd, J=8.4, 4.3 Hz, 1H), 6.49 (s, 1H), 5.17 (t, J=5.3 Hz, 1H), 4.95-4.79 (m, 1H), 4.64-4.53 (m, 3H), 4.46 (t, J=5.2 Hz, 1H), 2.77 (t, J=5.2 Hz, 1H), 2.71 (t, J=5.3 Hz, 1H), 2.00-1.74 (m, 8H).
[1692] MS m/z (ESI): 429.1 [M+H].sup.+.
Embodiment 168
3-((3-exo)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)oxo)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1693] ##STR00586##
[1694] The preparation of 3-((3-ex)-3-((7-((5-(hydroxymethyl)thiazol-2-yl)amino)-1,6-diazanaphthalen-5-yl)oxo)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 2.
[1695] MS m/z (ESI): 437.2 [M+H].sup.+.
Embodiment 169
3-((3-exo)-3-((7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1696] ##STR00587##
Step 1: preparation of 2-chloro-7-methoxyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine
[1697] ##STR00588##
[1698] 2,4-Dichloro-7-methoxylquinazoline (500 mg, 2.18 mmol), 5-methyl-1H-pyrazol-3-amine(223 mg, 2.29 mmol) and DIPEA (592 mg, 4.58 mmol) were separately added to anhydrous ethanol (10 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (5 mL), and dried under vacuum to obtain the title compound as a white solid (355 mg, 56%).
[1699] MS m/z (ESI): 290.1 [M+H].sup.+.
Step 2: preparation of (3-exo)-3-((7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1700] ##STR00589##
[1701] 2-Chloro-7-methoxyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (355 mg, 1.23 mmol), Tert-butyl (3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate acetate (421 mg, 1.47 mmol) and DIPEA (475 mg, 3.68 mmol) were mixed in n-butanol (7 mL). The reaction mixture was then heated to 150° C. with microwave and stirred for 4 hours. The reaction mixture was then cooled down to room temperature, and then concentrated under reduced pressure. The resulting product was purified by silica gel chromatography to obtain the title compound as a white solid (259 mg, 44%).
[1702] MS m/z (ESI): 480.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1703] ##STR00590##
[1704] Tert-butyl (3-exo)-3 #7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (259 mg, 0.540 mmol) was dissolved in methanol (3 mL), and the mixture was stirred at room temperature, followed by addition of 4M HCl in 1,4-dioxane (4 mL). The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (3 mL), followed by successive addition of DIPEA (349 mg, 2.70 mmol) and acrylonitrile (43 mg, 0.810 mmol). The resulting reaction mixture was stirred at room temperature for 0.5 hour, and filtered. The filtrate was concentrated under reduced pressure, and the resulting product was purified by silica gel chromatography to obtain the title compound as a white solid (76.8 mg, 33%).
[1705] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.12 (s, 1H), 7.14-6.75 (m, 2H), 6.50 (s, 1H), 4.50-4.21 (m, 1H), 3.92 (s, 3H), 3.41 (s, 2H), 2.91-2.55 (m, 4H), 2.34 (s, 3H), 2.14-1.50 (m, 7H), 1.40-1.23 (m, 1H).
[1706] MS m/z (ESI): 433.2[M+H].sup.+.
Embodiment 170
3-((3-exo)-3-((7-bromine-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1707] ##STR00591##
Step 1: preparation of 7-bromine-2-chloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine
[1708] ##STR00592##
[1709] 7-Bromine-2,4-dichloroquinazoline (3.36 g, 12.1 mmol), 5-methyl-1H-pyrazol-3-amine (1.29 g, 13.3 mmol) and TEA (2.57 g, 25.4 mmol) were separately added to anhydrous ethanol (67 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filter cake was washed with anhydrous ethanol (20 mL), dried under vacuum to obtain the title compound as a white solid (4.17 g, 100%).
Step 2: preparation of tert-butyl (3-exo)-3-((7-bromine-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1710] ##STR00593##
[1711] 7-Bromine-2-chloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (500 mg, 1.48 mmol), tert-butyl (3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate acetate (465 mg, 1.62 mmol) and DIPEA (591 mg, 4.58 mmol) were mixed in NMP (5 mL), and the mixture was then heated to 130° C. with microwave and stirred for 4 hours. The reaction mixture was cooled to room temperature, followed by addition of 25 mL ice water, and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with acetonitrile (2 mL), dried under reduced pressure to obtain the title compound as a gray solid (877 mg, 100%).
Step 3: preparation of 3-((3-exo)-3-((7-bromine-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1712] ##STR00594##
[1713] Tert-butyl (3-exo)-3-((7-bromine-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (220 mg, 0.416 mmol) was dissolved in methanol (2 mL), followed by addition of 4M HCl in 1,4-dioxane (2 mL) with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (2 mL), and DIPEA (269 mg, 2.08 mmol) and acrylonitrile (66 mg, 1.25 mmol) were successively added thereto. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting product was purified by silica gel chromatography to obtain the title compound as a white solid (17.4 mg, 9%).
[1714] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.94 (d, J=8.8 Hz, 1H), 7.74-7.37 (m, 1H), 7.24 (dd, J=8.9, 2.0 Hz, 1H), 6.59 (s, 0.8H), 5.92 (s, 0.2H), 4.51-4.12 (m, 1H), 3.42-3.35 (m, 2H), 2.75 (t, J=6.9 Hz, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.31 (s, 3H), 2.09-1.61 (m, 8H).
[1715] MS m/z (ESI): 481.1 [M+H].sup.+.
Embodiment 171
3-((3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1716] ##STR00595##
Step 1: preparation of 2,7-dichloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine
[1717] ##STR00596##
[1718] 2,4,7-Trifluoroquinazoline (2.0 g, 8.58 mmol), 5-methyl-1H-pyrazol-3-amine (915 mg, 9.42 mmol) and TEA (1.82 g, 18.0 mmol) were separately added to anhydrous ethanol (40 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filter cake was washed with anhydrous ethanol (5 mL), and dried under vacuum to obtain the title compound as a white solid (2.5 g, 99%).
[1719] MS m/z (ESI): 294.0 [M+H].sup.+.
Step 2: preparation of Tert-butyl (3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1720] ##STR00597##
[1721] 2,7-Dichloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (500 mg, 1.70 mmol), Tert-butyl (3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate acetate (535 mg, 1.87 mmol) and DIPEA (681 mg, 5.27 mmol) were mixed in NMP (7 mL). The reaction mixture was then heated to 180° C. with microwave and stirred for 2 hours. The reaction mixture was then cooled to room temperature, followed by addition of ice water with stirring. A solid was precipitated out and filtered. The filter cake was washed with water, dried under vacuum, and then purified by silica gel chromatography to obtain the title compound as a white solid (405 mg, 49%).
[1722] MS m/z (ESI): 484.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1723] ##STR00598##
[1724] Tert-butyl (3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (405 mg, 0.837 mmol) was dissolved in methanol (4 mL), and the mixture was stirred at room temperature, followed by addition of 4M HCl in 1,4-dioxane (2.5 mL). The reaction mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (4 mL), and DIPEA (486 mg, 3.77 mmol) and acrylonitrile (53 mg, 1.00 mmol) were successively added thereto. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was successively purified by silica gel chromatography and prep-HPLC to obtain the title compound as a white solid (40 mg, 11%).
[1725] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.02 (d, J=8.8 Hz, 1H), 7.54-7.22 (m, 1H), 7.14-7.07 (m, 1H), 6.71-6.49 (m, 0.6H), 6.05-5.76 (m, 0.4H), 4.44-4.17 (m, 1H), 3.40-3.35 (m, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.46-2.12 (m, 3H), 2.07-2.00 (m, 2H), 1.96-1.75 (m, 4H), 1.71-1.61 (m, 2H).
[1726] MS m/z (ESI): 437.2[M+H].sup.+.
Embodiment 172
3-((3-exo)-3-((7-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1727] Exact Mass: 420.2
##STR00599##
[1728] The preparation of 3-((3-exo)-3-((7-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 171.
[1729] MS m/z (ESI): 421.2 [M+H].sup.+.
Embodiment 173
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1730] ##STR00600##
Step 1: preparation of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4-amine
[1731] ##STR00601##
[1732] 2,4-Dichloropyrido[3,4-d]pyrimidine (120 mg, 0.6 mmol), 5-methyl-1H-pyrazol-3-amine (64 mg, 0.66 mmol) and DIPEA (150 mg, 1.2 mmol) were added to N,N-dimethylformamide(4 mL). The reaction mixture was mixed evenly, heated at 70° C. in oil bath and stirred overnight. Then the mixture was concentrated under reduced pressure, and the crude product obtained was added to methanol (5 mL). A solid was precipitated, filtered, and dried to obtain the title compound as a yellow solid (140 mg, 89%).
[1733] MS m/z (ESI): 261.1 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1734] ##STR00602##
[1735] 2,4-Dichloropyrido[3,4-d]pyrimidine (100 mg, 0.22 mmol), Tert-butyl (3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate acetate (95 mg, 0.33 mmol) and DIPEA (85 mg, 0.66 mmol) were added to n-butanol (2 mL). The reaction mixture was mixed evenly, then heated to 150° C. with microwave and reacted for 16 hours. The mixture was then cooled down to room temperature, and concentrated under reduced pressure. The crude product obtained was purified by flash silica gel chromatography to obtain the title compound as a pale yellow solid (40 mg, 40%).
[1736] MS m/z (ESI):451.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1737] ##STR00603##
[1738] Methanol (10 mL) was added to tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (40 mg, 0.09 mmol). The reaction mixture was mixed evenly, and hydrochloride dioxanesolution (4 N, 2 mL) was slowly added dropwise thereto. The reaction was carried out at room temperature for 2 hours, and then the mixture was concentrated under reduced pressure. The crude product obtained was added to the mixed solution of methanol (5 mL), DIPEA (0.5 mL) and acrylonitrile (1 mL), and then the reaction was carried out at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and purified by prep-HPLC to obtain the title compound as a yellow solid (5 mg, 14%).
[1739] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 9.50-9.38 (m, 1H), 8.96-8.91 (m, 2H), 7.47-7.45 (m, 1H), 5.05-5.02 (m, 2H), 4.10 (s, 2H), 3.94 (s, 1H), 3.53-3.48 (s, 2H), 3.14-3.08 (m, 3H), 2.84-2.40 (m, 8H).
[1740] MS m/z (ESI):404.2 [M+H].sup.+.
Embodiment 174
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1741] ##STR00604##
[1742] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 169.
[1743] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.46-8.36 (m, 1H), 7.86-7.60 (m, 1H), 7.55 (dd, J=8.5, 4.2 Hz, 1H), 6.81 (s, 0.8H), 5.99 (s, 0.2H), 4.54-4.17 (m, 1H), 3.47-3.35 (m, 2H), 2.76 (t, J=7.0 Hz, 2H), 2.62 (t, J=7.0 Hz, 2H), 2.41-2.21 (m, 3H), 2.13-2.01 (m, 2H), 1.97-1.81 (m, 4H), 1.75-1.64 (m, 2H).
[1744] MS m/z (ESI): 404.2 [M+H].sup.+.
Embodiment 175
3-((3-exo)-3-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1745] ##STR00605##
[1746] The preparation of 3-((3-exo)-3-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 169.
[1747] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.24 (s, 1H), 9.62 (s, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.33-6.92 (m, 3H), 6.92-6.55 (m, 1H), 4.32-4.15 (m, 1H), 3.33-3.25 (m, 2H), 2.68-2.56 (m, 4H), 2.26 (s, 3H), 2.00-1.85 (m, 2H), 1.83-1.54 (m, 6H).
[1748] MS m/z (ESI): 437.2 [M+H].sup.+.
Embodiment 176
3-((3-exo)-3-((8-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1749] ##STR00606##
[1750] The preparation of 3-((3-exo)-3-((8-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 169.
[1751] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.86 (d, 1H), 7.44 (d, J=7.1 Hz, 1H), 7.03 (t, J=7.7 Hz, 1H), 6.70-6.54 (m, 0.6H), 5.96-5.84 (m, 0.4H), 4.49-4.32 (m, 1H), 3.46-3.36 (m, 2H), 2.75 (t, J=6.9 Hz, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.48 (s, 3H), 2.38-2.17 (m, 3H), 2.10-1.89 (m, 4H), 1.88-1.77 (m, 2H), 1.64 (t, J=12.0 Hz, 2H).
[1752] MS m/z (ESI): 417.2 [M+H].sup.+.
Embodiment 177
3-((3-exo)-3-((8-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1753] ##STR00607##
[1754] The preparation of 3-((3-exo)-3-((8-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 169.
[1755] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.01 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.09 (s, 1H), 6.83-5.77 (m, 1H), 4.52-4.26 (m, 1H), 3.57-3.36 (m, 2H), 2.94-2.71 (m, 2H), 2.71-2.53 (m, 2H), 2.32 (s, 3H), 2.19-1.49 (m, 8H).
[1756] MS m/z (ESI): 437.2 [M+H].sup.+.
Embodiment 178
3-((3-exo)-3-((6-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1757] ##STR00608##
[1758] The preparation of 3-((3-exo)-3-((6-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 169.
[1759] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.15 (d, J=2.3 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.49-7.21 (m, 1H), 6.72-6.46 (m, 0.6H), 6.08-5.75 (m, 0.4H), 4.46-4.20 (m, 1H), 3.41-3.36 (m, 2H), 2.76 (t, J=7.0 Hz, 2H), 2.62 (t, J=7.0 Hz, 2H), 2.42-2.22 (m, 3H), 2.08-2.01 (m, 2H), 1.97-1.77 (m, 4H), 1.72-1.61 (m, 2H).
[1760] MS m/z (ESI): 437.2 [M+H].sup.+.
Embodiment 179
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1761] ##STR00609##
Step 1: preparation of Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1762] ##STR00610##
[1763] Tert-butyl (3-exo)-3-((7-bromine-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (400 mg, 0.758 mmol), 3-eboronic acid(187 mg, 1.52 mmol), Pd(dppf)Cl.sub.2 (110 mg, 0.152 mmol), and cesium carbonate (740 g, 2.27 mmol) were separately added to the mixed solvent of dioxane (8 mL) and water (0.8 mL). Under nitrogen atmosphere, the mixture was stirred at 100° C. for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography to obtain the title compound as pale yellow colloid (160 mg, 40%).
Step 2: preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1764] ##STR00611##
[1765] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (160 mg, 0.302 mmol) was dissolved in methanol (4 mL). The mixture was stirred at room temperature, and 4M HCl in 1,4-dioxane (4 mL) was added thereto. The reaction mixture was then stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (2 mL), and DIPEA (195 mg, 1.51 mmol) and acrylonitrile (48 mg, 0.906 mmol) were successively added thereto. The resulting reaction mixture was stirred at room temperature for 2 hours. When the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was preliminarily purified by silica gel chromatography to obtain a gray solid, which was slurried with N,N-dimethylformamide/acetonitrile (2 mL/4 mL), followed by filtration. The filtered solid was slurried with N,N-dimethylformamide/acetonitrile (1.1 mL/2.2 mL), filtered, and dried under vacuum to obtain the title compound as a white solid (49 mg, 34%).
[1766] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.90 (d, J=2.3 Hz, 1H), 8.59 (dd, J=4.9, 1.6 Hz, 1H), 8.31-8.08 (m, 2H), 7.84-7.40 (m, 3H), 6.63 (s, 0.8H), 5.94 (s, 0.2H), 4.49-4.26 (m, 1H), 3.45-3.37 (m, 2H), 2.77 (t, J=6.9 Hz, 2H), 2.63 (t, J=6.9 Hz, 2H), 2.34 (s, 3H), 2.13-1.63 (m, 8H).
[1767] MS m/z (ESI): 480.2[M+H].sup.+.
Embodiment 180
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1768] ##STR00612##
[1769] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 179.
[1770] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.73-8.58 (m, 2H), 8.21 (d, J=8.5 Hz, 1H), 7.95-7.64 (m, 3H), 7.59-7.49 (m, 1H), 6.64 (s, 1H), 4.49-4.22 (m, 1H), 3.45-3.35 (m, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.63 (t, J=7.0 Hz, 2H), 2.33 (s, 3H), 2.16-1.58 (m, 8H).
[1771] MS m/z (ESI): 480.2[M+H].sup.+.
Embodiment 181
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-2-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1772] ##STR00613##
[1773] The preparation of 3-((3-exo)-3-((7-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 179.
[1774] MS m/z (ESI): 480.3 [M+H].sup.+.
Embodiment 182
3-((3-exo)-3-((7-((5-methoxylpyridin-3-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1775] ##STR00614##
[1776] The preparation of 3-((3-exo)-3-((7-((5-methoxylpyridin-3-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 179.
[1777] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.54-8.41 (m, 1H), 8.27 (d, J=2.7 Hz, 1H), 8.17 (d, J=8.5 Hz, 1H), 7.88-7.56 (m, 2H), 7.47 (dd, J=8.5, 1.8 Hz, 1H), 6.62 (s, 1H), 4.49-4.25 (m, 1H), 3.97 (s, 3H), 3.44-3.37 (m, 2H), 2.76 (t, J=7.0 Hz, 2H), 2.63 (t, J=7.0 Hz, 2H), 2.32 (s, 3H), 2.10-1.64 (m, 8H).
[1778] MS m/z (ESI): 510.2[M+H].sup.+.
Embodiment 183
3-((3-exo)-3-((7-(6-methoxylpyridin-3-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1779] ##STR00615##
[1780] The preparation of 3-((3-exo)-3-((7-((6-methoxylpyridin-3-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 179.
[1781] MS m/z (ESI): 510.3 [M+H].sup.+.
Embodiment 184
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-phenylquinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1782] ##STR00616##
[1783] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-phenylquinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 179.
[1784] .sup.1H NMR (400 MHz, DMSO-d.sub.6, a small amount of CD.sub.3OD) δ 8.47-8.23 (m, 1H), 7.88-7.69 (m, 2H), 7.67-7.25 (m, 5H), 6.92-6.62 (m, 0.8H), 5.88 (s, 0.2H), 4.41-4.20 (m, 1H), 3.58 (s, 2H), 2.76-2.57 (m, 4H), 2.38-2.11 (m, 3H), 2.06-1.47 (m, 8H).
[1785] MS m/z (ESI): 479.3 [M+H].sup.+.
Embodiment 185
3-((3-exo)-3-((7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1786] ##STR00617##
Step 1: Preparation of Tert-butyl (3-exo)-3-((7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1787] ##STR00618##
[1788] Tert-butyl (3-exo)-3-((7-bromine-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.189 mmol), (1-cyclopropyl-1H-pyrazol-4-yl) boric acid (35 mg, 0.227 mmol), cesium carbonate (185 mg, 0.567 mmol), and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1 biphenyl)]palladium(n) (X-Phos Pd G2) (15 mg, 0.0189 mmol) were separately added to the mixed solvent of dioxane (2 mL) and water (0.4 mL). The mixture was filled with nitrogen for 3 times, and then stirred at 100° C. for 2 hours. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound as brown oil (60 mg, 57%).
Step 2: preparation of 3-((3-exo)-3-((7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1789] ##STR00619##
[1790] Tert-butyl (3-exo)-3-((7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (60 mg, 0.108 mmol) was dissolved in methanol (2 mL). The mixture was stirred at room temperature, and 4M HCl in 1,4-dioxane (2 mL) was added thereto. The reaction mixture was then stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (1 mL), and DIPEA (70 mg, 0.542 mmol) and acrylonitrile (17 mg, 0.324 mmol) were successively added to the mixture. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (30 mL), washed with water (10 mL), and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound as a gray solid (20 mg, 36%).
[1791] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.20 (s, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.93 (s, 1H), 7.72-7.34 (m, 2H), 6.60 (s, 1H), 4.45-4.23 (m, 1H), 3.78-3.67 (m, 1H), 3.43-3.36 (m, 2H), 2.76 (t, J=6.8 Hz, 2H), 2.63 (t, J=6.8 Hz, 2H), 2.32 (s, 3H), 2.09-1.64 (m, 8H), 1.24-1.00 (m, 4H).
[1792] MS m/z (ESI): 509.2 [M+H].sup.+.
Embodiment 186
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1793] ##STR00620##
[1794] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 185.
[1795] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.09 (s, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.93 (s, 1H), 7.64-7.43 (m, 1H), 7.38 (dd, J=8.6, 1.7 Hz, 1H), 6.62 (s, 0.8H), 5.92 (s, 0.2H), 4.42-4.28 (m, 1H), 3.95 (s, 3H), 3.42-3.36 (m, 2H), 2.76 (t, J=7.0 Hz, 2H), 2.63 (t, J=7.0 Hz, 2H), 2.32 (s, 3H), 2.08-2.01 (m, 2H), 2.00-1.80 (m, 4H), 1.77-1.62 (m, 2H).
[1796] MS m/z (ESI): 483.2 [M+H].sup.+.
Embodiment 187
3-((3-exo)-3-((7-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1797] ##STR00621##
[1798] The preparation of 3-((3-exo)-3-((7-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 185.
[1799] MS m/z (ESI): 515.3 [M+H].sup.+.
Embodiment 188
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(thiazol-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1800] ##STR00622##
[1801] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(thiazol-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 185.
[1802] MS m/z (ESI): 486.2 [M+H].sup.+.
Embodiment 189
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[1803] ##STR00623##
[1804] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile was carried out with the reference to Embodiment 179.
[1805] MS m/z (ESI): 494.3 [M+H].sup.+.
Embodiment 190
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[1806] ##STR00624##
[1807] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile was carried out with the reference to Embodiment 179.
[1808] MS m/z (ESI):497.3 [M+H].sup.+.
Embodiment 191
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1809] ##STR00625##
Step 1: preparation of Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1810] ##STR00626##
[1811] Tert-butyl (3-exo)-3-((7-bromine-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (300 mg, 0.568 mmol), morpholine (494 mg, 5.68 mmol), Pd.sub.2(dba).sub.3 (104 mg, 0.114 mmol), DavePhos (90 mg, 0.227 mmol) and t-BuONa (109 mg, 1.14 mmol) were separately added to dioxane (6 mL). Under nitrogen atmosphere, the mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with water (20 mL) and saturated sodium chloride aqueous solution (10 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product obtained was purified by silica gel chromatography to obtain the title compound as pale yellow oil (66 mg, 22%).
Step 2: preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1812] ##STR00627##
[1813] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (66 mg, 0.123 mmol) was dissolved in methanol (2 mL). The mixture was stirred at room temperature, and 4M HCl in 1,4-dioxane (2 mL) was added thereto. The reaction mixture was then stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (1 mL), and DIPEA (80 mg, 0.617 mmol) and acrylonitrile (20 mg, 0.369 mmol) were successively added thereto. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was successively purified by silica gel chromatography and preparative TLC, to obtain the title compound as a gray solid (12 mg, 20%).
[1814] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.06 (d, J=9.3 Hz, 1H), 7.08 (d, J=9.4 Hz, 1H), 6.68 (s, 1H), 6.49 (s, 1H), 4.46-4.28 (m, 1H), 3.97-3.73 (m, 4H), 3.52-3.36 (m, 6H), 2.73 (t, J=6.7 Hz, 2H), 2.62 (t, J=6.7 Hz, 2H), 2.34 (s, 3H), 2.11-1.61 (m, 8H).
[1815] MS m/z (ESI): 488.2[M+H].sup.+.
Embodiment 192
3-((3-exo)-3-((7-(3-methoxylazetindin-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1816] ##STR00628##
[1817] The preparation of 3-((3-exo)-3-((7-(3-methoxylazetindin-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 191.
[1818] MS m/z (ESI): 488.3 [M+H].sup.+.
Embodiment 193
3-((3-exo)-3-((7-((4-methoxylpiperidin-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1819] ##STR00629##
[1820] The preparation of 3-((3-exo)-3-((7-((4-methoxylpiperidin-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 191.
[1821] MS m/z (ESI): 516.3 [M+H].sup.+.
Embodiment 194
3-((3-exo)-3-((7-((4-(dimethylamine)piperidin-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1822] ##STR00630##
[1823] The preparation of 3-((3-exo)-3-((7-(4-(dimethylamine)piperidin-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 191.
[1824] MS m/z (ESI): 529.3 [M+H].sup.+.
Embodiment 195
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyrrolidin-1-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1825] ##STR00631##
[1826] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyrrolidin-1-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 191.
[1827] MS m/z (ESI): 472.3 [M+H].sup.+.
Embodiment 196
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(methylamino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1828] ##STR00632##
[1829] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(methylamino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 191.
[1830] MS m/z (ESI): 432.3 [M+H].sup.+.
Embodiment 197
3-((3-exo)-3-((7-(methyl(oxetan-3-ylmethyl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1831] ##STR00633##
[1832] The preparation of 3-((3-exo)-3-((7-(methyl(oxetan-3-ylmethyl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 191.
[1833] MS m/z (ESI): 502.3 [M+H].sup.+.
Embodiment 198
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-74(1-methylazetindin-3-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1834] ##STR00634##
[1835] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((1-methylazetindin-3-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 191.
[1836] MS m/z (ESI): 501.3 [M+H].sup.+.
Embodiment 199
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((4H-2H-pyran-4-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1837] ##STR00635##
[1838] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((4H-2H-pyran-4-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 191.
[1839] MS m/z (ESI): 516.3 [M+H].sup.+.
Embodiment 200
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((l-methylpiperidin-4-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1840] ##STR00636##
[1841] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((1-methylpiperidin-4-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 191.
[1842] MS m/z (ESI): 529.3 [M+H].sup.+.
Embodiment 201
3-((3-exo)-3-((7-(methyl(pyridin-3-ylmethyl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1843] ##STR00637##
[1844] The preparation of 3-((3-exo)-3-((7-(methyl(pyridin-3-ylmethyl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 191.
[1845] MS m/z (ESI): 523.3 [M+H].sup.+.
Embodiment 202
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[1846] ##STR00638##
[1847] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile was carried out with the reference to Embodiment 191.
[1848] MS m/z (ESI): 502.3 [M+H].sup.+.
Embodiment 203
3-((3-exo)-3-((7-(1H-imidazol-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1849] ##STR00639##
[1850] The preparation of 3-((3-exo)-3-((7-((1H-imidazol-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 191.
[1851] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.29 (s, 1H), 8.21 (d, J=8.9 Hz, 1H), 7.70 (s, 1H), 7.64-7.26 (m, 2H), 7.19 (s, 1H), 6.62 (s, 0.8H), 5.93 (s, 0.2H), 4.47-4.22 (m, 1H), 3.41-3.36 (m, 2H), 2.76 (t, J=6.9 Hz, 2H), 2.63 (t, J=6.9 Hz, 2H), 2.33 (s, 3H), 2.08-2.01 (m, 2H), 2.00-1.79 (m, 4H), 1.74-1.63 (m, 2H).
[1852] MS m/z (ESI): 469.2 [M+H].sup.+.
Embodiment 204
3-((3-exo)-3-((7-(2-methoxyl ethoxyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1853] ##STR00640##
[1854] The preparation of 3-((3-exo)-3-((7-(2-methoxylethoxyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 169.
[1855] MS m/z (ESI): 477.3 [M+H].sup.+.
Embodiment 205
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(oxetan-3-ylmethoxyl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[1856] ##STR00641##
[1857] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(oxetan-3-ylmethoxyl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile was carried out with the reference to Embodiment 169.
[1858] MS m/z (ESI): 503.3 [M+H].sup.+.
Embodiment 206
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylazetindin-3-yl)methoxyl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1859] ##STR00642##
[1860] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylazetindin-3-yl)methoxyl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 169.
[1861] MS m/z (ESI): 502.3 [M+H].sup.+.
Embodiment 207
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-ylmethoxyl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1862] ##STR00643##
[1863] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-ylmethoxyl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 169.
[1864] MS m/z (ESI): 510.3 [M+H].sup.+.
Embodiment 208
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylazetindin-3-yl)oxo)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1865] ##STR00644##
[1866] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylazetindin-3-yl)oxo)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 169.
[1867] MS m/z (ESI): 488.3 [M+H].sup.+.
Embodiment 209
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylpiperidin-4-yl)oxo)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1868] ##STR00645##
[1869] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylpiperidin-4-yl)oxo)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 169.
[1870] MS m/z (ESI): 516.3 [M+H].sup.+.
Embodiment 210
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(morpholinomethyl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[1871] ##STR00646##
[1872] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(morpholinomethyl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile was carried out with the reference to Embodiment 169.
[1873] MS m/z (ESI): 516.3 [M+H].sup.+.
Embodiment 211
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methylazetindin-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[1874] ##STR00647##
[1875] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methylazetindin-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile was carried out with the reference to Embodiment 169.
[1876] MS m/z (ESI):486.3 [M+H].sup.+.
Embodiment 212
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(oxetan-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[1877] ##STR00648##
[1878] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(oxetan-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile was carried out with the reference to Embodiment 169.
[1879] MS m/z (ESI):473.3 [M+H].sup.+.
Embodiment 213
1-(((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[1880] ##STR00649##
[1881] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.222 mmol) was dissolved in 4M HCl in 1,4-dioxane solution (10 mL). The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in anhydrous N,N-dimethylformamide (10 mL), then cooled to 0° C., and DIPEA (0.73 mL, 4.44 mmol) and 3-cyanoazetindin-1-sulfonyl chloride (44 mg, 0.244 mmol) were successively added thereto. The reaction mixture was stirred at 0° C. for 5 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse phase HPLC to obtain the title compound (59.3 mg, 54%).
[1882] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.12 (s, 1H), 7.50 (s, 1H), 7.29 (d, J=44.1 Hz, 1H), 7.06 (s, 1H), 6.58 (s, 1H), 4.36 (s, 1H), 4.12 (s, 2H), 4.03 (t, J=8.4 Hz, 2H), 3.90 (t, J=7.0 Hz, 2H), 3.69-3.57 (m, 1H), 2.20 (s, 3H), 2.10-1.51 (m, 8H).
[1883] MS m/z (ESI): 494.2 [M+H].sup.+.
Embodiment 214
1-(((3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonynazetindin-3-formonitrile
[1884] ##STR00650##
[1885] Tert-butyl (3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (174 mg, 0.36 mmol) was dissolved in 4M HCl in 1,4-dioxane solution (20 mL). The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in anhydrous N,N-dimethylformamide (10 mL), then cooled to 0° C., and DIPEA (1.19 mL, 7.2 mmol) and 3-cyanoazetindin-1-sulfonyl chloride (78 mg, 0.432 mmol) were successively added thereto. The reaction mixture was stirred at 0° C. for 16.5 hour, and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse phase HPLC to obtain the title compound (17.7 mg, 9%).
[1886] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 8.02 (s, 1H), 7.42 (s, 1H), 7.20 (s, 1H), 6.57 (s, 1H), 4.51-4.40 (m, 1H), 4.27 (s, 2H), 4.17 (t, J=8.5 Hz, 2H), 4.13-4.05 (m, 2H), 3.64-3.53 (m, 1H), 2.34 (s, 3H), 2.16 (s, 4H), 1.98 (d, J=42.2 Hz, 2H), 1.76 (t, J=11.9 Hz, 2H).
[1887] MS m/z (ESI): 528.2 [M+H].sup.+.
Embodiment 215
1-(((3-exo)-3-((7-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[1888] ##STR00651##
[1889] The preparation of 1-(((3-exo)-3-((7-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 213.
[1890] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.11 (dd, J=9.1, 6.1 Hz, 1H), 7.21-6.82 (m, 2H), 6.56 (s, 0.8H), 5.88 (s, 0.2H), 4.58-4.34 (m, 1H), 4.29-4.19 (m, 2H), 4.17-4.08 (m, 2H), 4.06-3.96 (m, 2H), 3.72-3.58 (m, 1H), 2.31 (s, 3H), 2.18-1.85 (m, 6H), 1.82-1.66 (m, 2H).
[1891] MS m/z (ESI): 512.1[M+H].sup.+.
Embodiment 216
1-(((3-exo)-3-((7-cyclopropyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[1892] ##STR00652##
[1893] The preparation of 1-(((3-exo)-3-((7-cyclopropyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 213.
[1894] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.04 (s, 1H), 7.26-6.93 (m, 2H), 6.50 (s, 1H), 4.58-4.37 (m, 1H), 4.31-4.18 (m, 2H), 4.18-4.07 (m, 2H), 4.06-3.95 (m, 2H), 3.71-3.58 (m, 1H), 2.32 (s, 3H), 2.17-1.71 (m, 8H), 1.34-1.25 (m, 1H), 1.19-1.03 (m, 2H), 0.94-0.75 (m, 2H).
[1895] MS m/z (ESI): 534.1[M+H].sup.+.
Embodiment 217
3-((3-exo)-3-(((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azacyclobutane-3-nitrile
[1896] ##STR00653##
Step 1: preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate
[1897] ##STR00654##
[1898] Tert-butyl-(3-exo)-3-amino-9-azabicyclo[3.3.1]non-9-carboxylate (222 mg, 0.92 mmol) and DIPEA (199 mg, 1.54 mmol) were successively added to the solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (200 mg, 0.77 mmol) in n-butanol (10 mL). The mixture was then stirred at 170° C. under microwave condition for 4 hours. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound as a white solid (275 mg, 77%).
[1899] MS m/z (ESI): 464.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-(((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azacyclobutane-3-nitrile
[1900] ##STR00655##
[1901] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then dissolved in N,N-dimethylformamide (10 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was stirred at room temperature for 10 minutes. 3-Nitrile azacyclobutane-1-sulfonylchlorine (45 mg, 0.25 mmol) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (30.5 mg, 29%).
[1902] .sup.1H NMR (400 MHz, DMSO) δ=12.09 (s, 1H), 10.04 (s, 1H), 8.24 (s, 1H), 7.45 (s, 1H), 7.33-6.42 (m, 4H), 4.79 (s, 1H), 4.01-3.79 (m, 6H), 3.74-3.67 (m, 1H), 2.15 (s, 3H), 2.09-1.57 (m, 10H).
[1903] MS m/z (ESI): 508.2 [M+H].sup.+.
Embodiment 218
1-(((3-exo)-3-((7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[1904] ##STR00656##
Step 1: preparation of 2-chloro-7-methoxyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine
[1905] ##STR00657##
[1906] 2,4-Dichloro-7-methoxylquinazoline (497 mg, 2.17 mmol), 5-methyl-1H-pyrazol-3-amine (221 mg, 2.28 mmol) and DIPEA (0.75 mL, 4.56 mmol) were added to anhydrous ethanol (10 mL). The mixture was stirred at room temperature for 24 hours, heated to 50° C., reacted for 5 hour and then concentrated under reduced pressure to remove the solvent. The residue was washed with the mixed solvent of ethanol-water (v/v=1:9, 20 mL), and filtered. The residue was dried under reduced pressure to obtain the title compound (509 mg, 81%).
[1907] MS m/z (ESI): 290.0 [M+H].sup.+.
Step 2: preparation of Tert-butyl (3-exo)-3-((7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1908] ##STR00658##
[1909] 2-Chloro-7-methoxyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (150 mg, 0.518 mmol), Tert-butyl (3-exo)-3-(methylamino)-8-azabicyclo[3.2.1]oct-8-carboxylate (249 mg, 1.036 mmol) and DIPEA (0.43 mL, 2.59 mmol) were added to n-butanol (3 mL). The mixture was heated to 170° C. with a microwave reactor, reacted for 6 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse phase chromatography to obtain the title compound (193 mg, 75%).
[1910] MS m/z (ESI): 494.2 [M+H].sup.+.
Step 3: preparation of 1-(((3-exo)-3-((7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[1911] ##STR00659##
[1912] Tert-butyl (3-exo)-3-((7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (193 mg, 0.39 mmol) was dissolved in 4 M HCl in 1,4-dioxane (20 mL). The mixture was stirred at room temperature for 60 minutes, and concentrated under reduced pressure to remove the solvent. The residue solid was dissolved in anhydrous N,N-dimethylformamide (10 mL), then cooled to 0° C., and DIPEA (1.93 mL, 11.7 mmol) and 3-cyanoazetindin-1-sulfonyl chloride (71 mg, 0.39 mmol) were successively added thereto. The reaction mixture stirred at 0° C. for 4 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC to obtain the title compound (97 mg, 46%).
[1913] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.11 (s, 1H), 9.77 (s, 1H), 8.23 (d, J=8.9 Hz, 1H), 6.72 (s, 1H), 6.67 (d, J=8.8 Hz, 1H), 6.48 (s, 1H), 5.40-5.25 (m, 1H), 4.18 (s, 2H), 4.06 (t, J=8.6 Hz, 2H), 4.01-3.92 (m, 2H), 3.87-3.74 (m, 4H), 2.96 (s, 3H), 2.23 (s, 3H), 2.06-1.89 (m, 4H), 1.83 (d, J=5.8 Hz, 2H), 1.61 (d, J=11.2 Hz, 2H).
[1914] MS m/z (ESI): 538.2 [M+H].sup.+.
Embodiment 219
1-(((3-exo)-3-((7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1915] ##STR00660##
Step 1: preparation of tert-butyl (3-exo)-3-((7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)aminol-9-azabicyclo[3.3.1]non-9-carboxylate
[1916] ##STR00661##
[1917] 2-Chloro-7-methoxyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (50 mg, 0.173 mmol) and Tert-butyl (3-exo)-3-amino-9-azabicyclo[3.3.1]non-9-carboxylate oxalate (171 mg, 0.518 mmol) were added to n-butanol (10 mL). The mixture was heated to 170° C. with a microwave reactor, reacted for 8 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography to obtain the title compound (68 mg, 80%).
[1918] MS m/z (ESI): 494.2 [M+H].sup.+.
Step 2: preparation of 1-(((3-exo)-3-((7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[1919] ##STR00662##
[1920] Tert-butyl (3-exo)-3-((7-methoxyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (68 mg, 0.138 mmol) was dissolved in 4 M HCl in 1,4-dioxane (15 mL). The mixture was stirred at room temperature for 60 minutes, and concentrated under reduced pressure to remove the solvent. The residue solid was dissolved in anhydrous N,N-dimethylformamide (10 mL), then cooled to 0° C., and DIPEA (0.68 mL, 4.14 mmol) and 3-cyanoazetindin-1-sulfonyl chloride (25 mg, 0.138 mmol) were successively added thereto. The reaction mixture was stirred at 0° C. for 8 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC to obtain the title compound (6.9 mg, 9%).
[1921] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.10 (s, 1H), 9.83 (s, 1H), 8.24 (d, J=7.3 Hz, 1H), 6.65 (dd, J=29.7, 20.4 Hz, 4H), 4.83 (s, 1H), 4.02 (t, J=8.5 Hz, 2H), 3.92 (dd, J=14.9, 8.4 Hz, 4H), 3.87-3.73 (m, 4H), 2.21 (s, 3H), 2.04 (d, J=4.3 Hz, 3H), 1.92-1.68 (m, 7H).
[1922] MS m/z (ESI): 538.2 [M+H].sup.+.
Embodiment 220
1-(((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[1923] ##STR00663##
[1924] The preparation of 1-(((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrido[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 213.
[1925] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.61-12.05 (m, 1H), 10.86 (s, 0.2H), 9.45-9.08 (m, 0.8H), 8.40 (s, 1H), 7.82-7.49 (m, 2H), 7.20-6.96 (m, 1H), 6.93-6.59 (m, 0.8H), 6.08 (s, 0.2H), 4.47-4.27 (m, 1H), 4.22-4.11 (m, 2H), 4.10-4.01 (m, 2H), 3.99-3.88 (m, 2H), 3.87-3.74 (m, 1H), 2.26 (s, 3H), 2.14-1.79 (m, 6H), 1.76-1.57 (m, 2H).
[1926] MS m/z (ESI): 495.1[M+H].sup.+.
Embodiment 221
1-(((3-exo)-3-((4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[1927] ##STR00664##
Step 1: preparation of Tert-butyl (3-exo)-3-((4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1928] ##STR00665##
[1929] 2,4-Dichloroquinazoline (398 mg, 2.0 mmol), 5-methylthioazole-2-amine (251 mg, 2.2 mmol) and DIPEA (1 mL, 6.0 mmol) were dispersed in anhydrous ethanol (10 mL). The resulting reaction mixture was heated to 70° C. and stirred for 24 hours. Then mixture was then cooled to room temperature, and filtered. The yellow solid obtained was washed with a small amount of anhydrous ethanol and dried. The crude product was dispersed in n-butanol (10 mL), and Tert-butyl (3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (452 mg, 2.0 mmol) and DIPEA (0.33 mL, 2.0 mmol) were added thereto. The mixture was stirred at room temperature and mixed evenly. The mixture was then transferred to a microwave reactor, heated to 170° C., and reacted for 3 hour. The mixture was concentrated under reduced pressure to remove the solvent, and the crude product was purified by silica gel chromatography to obtain the title compound as a pale yellow solid (45 mg, 5%).
[1930] MS m/z (ESI): 467.1 [M+H].sup.+.
Step 2: preparation of 1-(((3-exo)-3-((4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[1931] ##STR00666##
[1932] Tert-butyl (3-exo)-3-((4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (45 mg, 0.097 mmol) was dissolved in 4 M HCl in 1,4-dioxane (15 mL). The mixture was stirred at room temperature for 60 minutes, and concentrated under reduced pressure to remove the solvent. The residue solid was dissolved in anhydrous N,N-dimethylformamide (5 mL), then cooled to 0° C., and DIPEA (0.32 mL, 1.94 mmol) and 3-cyanoazetindin-1-sulfonyl chloride (19 mg, 0.106 mmol) were successively added thereto. The reaction mixture was stirred at 0° C. for 5 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC to obtain the title compound as a pale yellow solid compound (12.4 mg, 25%).
[1933] .sup.1H NMR (400 MHz, CD.sub.3OD: CDCl.sub.3, v/v=1:2) δ 8.30 (d, J=4.5 Hz, 1H), 7.71-7.65 (m, 1H), 7.39-7.27 (m, 2H), 7.17 (s, 1H), 4.86-4.79 (m, 1H), 4.32 (s, 2H), 4.19 (t, J=8.5 Hz, 2H), 4.11-4.04 (m, 2H), 3.62 (ddd, J=15.1, 8.5, 6.1 Hz, 1H), 2.45 (s, 3H), 2.32-2.16 (m, 4H), 2.09 (d, J=7.6 Hz, 2H), 1.93-1.84 (m, 2H).
[1934] MS m/z (ESI): 511.1 [M+H].sup.+.
Embodiment 222
1-(((3-exo)-3-((7-chloro-4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[1935] ##STR00667##
[1936] The preparation of 1-(((3-exo)-3-((7-chloro-4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 221.
[1937] MS m/z (ESI): 545.1 [M+H].sup.+.
Embodiment 223
1-(((3-exo)-3-((7-methoxyl-4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[1938] ##STR00668##
[1939] The preparation of 1-(((3-exo)-3-((7-methoxyl-4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 221.
[1940] MS m/z (ESI): 541.2 [M+H].sup.+.
Embodiment 224
[1941] ##STR00669##
[1942] Tert-butyl (3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate was dispersed in dichloromethane (2 mL), and 4 M HCl in 1,4-dioxane solution (20 mL) was added thereto. The mixture was stirred at room temperature for 1.5 hours, and concentrated under reduced pressure to remove the solvent. The residue was dried with an oil pump under reduced pressure for 10 minutes. The crude product obtained was dissolved in anhydrous N,N-dimethylformamide (8 mL), then cooled in ice water bath to 0° C., and DIPEA (1.2 mL, 7.1 mmol), dimethyl glycine (0.31 mL, 4.72 mmol) and HATU (118 mg, 0.31 mmol) were successively added thereto with stirring. The resulting reaction mixture was stirred at 0° C. for 60 minutes, and concentrated under reduced pressure to remove the solvent. The crude product was purified by prep-HPLC to obtain the title compound as a white solid (20.7 mg, 21%).
[1943] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.12 (s, 1H), 8.33 (s, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 7.13-6.86 (m, 2H), 6.60 (s, 1H), 4.52 (s, 1H), 4.42 (d, J=3.4 Hz, 2H), 3.16 (s, 2H), 2.38-2.12 (m, 9H), 2.05-1.94 (m, 2H), 1.93-1.73 (m, 4H), 1.63-1.46 (m, 2H).
[1944] MS m/z (ESI): 469.1 [M+H].sup.+.
Embodiment 225
2-(dimethylamine)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one
[1945] ##STR00670##
[1946] The preparation of 2-(dimethyl amine)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one was carried out with the reference to Embodiment 224.
[1947] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.21 (s, 1H), 10.13 (s, 1H), 8.33 (s, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.27 (d, J=30.8 Hz, 1H), 7.08 (s, 1H), 6.78 (s, 1H), 6.61 (s, 1H), 4.56 (d, J=6.1 Hz, 1H), 4.48 (s, 1H), 4.32 (d, J=5.3 Hz, 1H), 3.65 (dd, J=32.9, 14.8 Hz, 2H), 2.53 (s, 6H), 2.25 (s, 3H), 1.94 (ddd, J=36.8, 20.0, 10.6 Hz, 6H), 1.56 (dd, J=19.2, 9.5 Hz, 2H).
[1948] MS m/z (ESI): 435.2 [M+H].sup.+.
Embodiment 226
((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)(pyridin-2-yl)methanone
[1949] ##STR00671##
[1950] The preparation of ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)(pyridin-2-yl)methanone was carried out with the reference to Embodiment 224.
[1951] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.29 (s, 1H), 10.80 (s, 1H), 10.33 (s, 1H), 8.61 (d, J=4.3 Hz, 1H), 8.52-8.24 (m, 1H), 7.96 (td, J=7.8, 1.7 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.71-7.57 (m, 1H), 7.52 (ddd, J=7.5, 4.9, 1.0 Hz, 1H), 7.39 (d, J=18.4 Hz, 1H), 7.21 (d, J=39.2 Hz, 1H), 6.60 (s, 1H), 4.74 (s, 1H), 4.69-4.44 (m, 2H), 2.27 (s, 3H), 2.12-1.69 (m, 8H).
[1952] MS m/z (ESI): 455.2 [M+H].sup.+.
Embodiment 227
((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)(pyridin-3-yl)methanone
[1953] ##STR00672##
[1954] The preparation of ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)(pyridin-3-yl)methanone was carried out with the reference to Embodiment 224.
[1955] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.25 (s, 1H), 10.36 (s, 1H), 10.05 (s, 1H), 8.78-8.62 (m, 2H), 8.34 (d, J=29.6 Hz, 1H), 7.90 (d, J=7.0 Hz, 1H), 7.62-7.48 (m, 2H), 7.31 (dd, J=19.3, 8.1 Hz, 1H), 7.12 (s, 1H), 6.60 (s, 1H), 4.68 (d, J=4.8 Hz, 1H), 4.53 (d, J=9.2 Hz, 1H), 4.02 (d, J=3.1 Hz, 1H), 2.25 (s, 3H), 2.16-1.48 (m, 8H).
[1956] MS m/z (ESI): 455.2 [M+H].sup.+.
Embodiment 228
((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)(pyridin-4-yl)methanone
[1957] ##STR00673##
[1958] The preparation of ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)(pyridin-4-yl)methanone was carried out with the reference to Embodiment 224.
[1959] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.23 (s, 1H), 10.21 (s, 1H), 8.70 (d, J=5.5 Hz, 2H), 8.32 (dd, J=28.3, 8.1 Hz, 1H), 7.59-7.51 (m, 1H), 7.45 (d, J=1.8 Hz, 2H), 7.36-7.22 (m, 1H), 7.09 (t, J=7.4 Hz, 1H), 6.86 (s, 1H), 6.59 (s, 1H), 4.67 (d, J=4.9 Hz, 1H), 4.61-4.44 (m, 1H), 3.94 (d, J=1.9 Hz, 1H), 2.24 (s, 3H), 2.09-1.53 (m, 8H).
[1960] MS m/z (ESI): 455.2 [M+H].sup.+.
Embodiment 229
1-((3-exo)-3-((4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl-2-morpholinoethane-1-one
[1961] ##STR00674##
[1962] The preparation of 1-((3-exo)-3-((4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)-2-morpholinoethane-1-one was carried out with the reference to Embodiment 224.
[1963] MS m/z (ESI): 494.2 [M+H].sup.+.
Embodiment 230
2-(methylamino)-1-((3-exo)-3-((4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)ethane-1-one
[1964] ##STR00675##
[1965] The preparation of 2-(methylamino)-1-((3-exo)-3-((4-((5-methylthioazole-2-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)ethane-1-one was carried out with the reference to Embodiment 224.
[1966] MS m/z (ESI): 452.2 [M+H].sup.+.
Embodiment 231
2,2-difluoro-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one
[1967] ##STR00676##
[1968] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.222 mmol) was dissolved in 4M HCl in 1,4-dioxane solution (10 mL). The mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure to remove the solvent. The residue was dissolved in anhydrous N,N-dimethylformamide (10 mL), then cooled to 0° C., and DIPEA (0.73 mL, 4.44 mmol) was added thereto. The mixture was mixed evenly and the mixture (pre-dissolved in 1 mL dry N,N-dimethylformamide for 10 minutes reaction) of difluoroacetic acid (0.023 mL, 0.233 mmol) and HATU (169 mg, 4.44 mmol) were added thereto. The reaction mixture was stirred at 0° C. for 1 hour, and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse phase HPLC to obtain the title compound (48.9 mg, 52%).
[1969] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 7.99 (d, J=7.7 Hz, 1H), 7.56-7.44 (m, 1H), 7.40-7.19 (m, 1H), 7.13-7.03 (m, 1H), 6.55 (d, J=4.7 Hz, 1H), 6.33 (t, J=53.6 Hz, 1H), 4.57 (s, 2H), 4.46-4.40 (m, 1H), 2.18 (d, J=33.6 Hz, 3H), 2.09-1.75 (m, 6H), 1.56 (t, J=12.1 Hz, 2H).
[1970] MS m/z (ESI): 428.1 [M+H].sup.+.
Embodiment 232
N4-((5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-8-(pyridin-3-ylsulfonyl)-8-azabicyclo[3.2.1]oct-3-yl)quinazolin-2,4-diamine
[1971] ##STR00677##
[1972] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.222 mmol) was dissolved in 4M HCl in 1,4-dioxane solution (10 mL). The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in anhydrous N,N-dimethylformamide (10 mL), then cooled to 0° C., and DIPEA (0.73 mL, 4.44 mmol) and 3-pyridinsulfonyl chloride hydrochloride (50 mg, 0.233 mmol) were successively added thereto. The reaction mixture was stirred at 0° C. for 0.5 hour, and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse phase HPLC to obtain the title compound (20.5 mg, 19%).
[1973] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.98 (d, J=2.0 Hz, 1H), 8.76 (dd, J=4.8, 1.4 Hz, 1H), 8.27-8.19 (m, 1H), 8.14-8.01 (m, 1H), 7.60-7.44 (m, 2H), 7.29 (ddd, J=15.0, 9.9, 4.2 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 6.58-6.39 (m, 1H), 4.30 (dd, J=6.0, 2.6 Hz, 3H), 2.17 (s, 3H), 2.08-1.95 (m, 2H), 1.74 (dd, J=16.7, 6.2 Hz, 2H), 1.64 (dd, J=17.3, 6.7 Hz, 2H), 1.43-1.32 (m, 2H).
[1974] MS m/z (ESI): 491.1 [M+H].sup.+.
Embodiment 233
N2-((3-exo)-8-((2-methoxylethyl)sulfonyl)-8-azabicyclo[3.2.1]oct-3-yl)-N4-(5-methyl-1H-pyrazol-3-yl)quinazolin-2,4-diamine
[1975] ##STR00678##
[1976] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.222 mmol) was dissolved in 4M HCl in 1,4-dioxane solution (10 mL). The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in anhydrous N,N-dimethylformamide (10 mL), then cooled to 0° C., and DIPEA (0.73 mL, 4.44 mmol) and 2-methoxylethane-1-sulfonyl chloride (37 mg, 0.233 mmol) were successively added thereto. The reaction mixture was stirred at 0° C. for 2 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse phase HPLC to obtain the title compound (25.1 mg, 43%).
[1977] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.31 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.24 (dd, J=23.8, 8.5 Hz, 1H), 6.61 (s, 1H), 4.49-4.43 (m, 1H), 4.26 (s, 2H), 3.76 (t, J=6.2 Hz, 2H), 3.43-3.29 (m, 5H), 2.32 (s, 3H), 2.11-1.86 (m, 6H), 1.74 (t, J=13.5 Hz, 2H).
[1978] MS m/z (ESI): 472.2 [M+H].sup.+.
Embodiment 234
N2-((3-exo)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]oct-3-yl)-N4-((5-methyl-1H-pyrazol-3-yl)quinazolin-2,4-diamine
[1979] ##STR00679##
[1980] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.222 mmol) was dissolved in 4M HCl in 1,4-dioxane solution (10 mL). The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in anhydrous N,N-dimethylformamide (5 mL), and anhydrous potassium carbonate (184 mg, 1.33 mmol) and 1-bromine-2-fluoroethane (50 mg, 0.233 mmol) were successively added thereto. The reaction mixture was stirred at 40° C. for 19 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse phase HPLC to obtain the title compound (27.3 mg, 31%).
[1981] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (d, J=17.8 Hz, 1H), 7.56 (s, 1H), 7.35 (d, J=44.5 Hz, 1H), 7.11 (s, 1H), 6.71 (s, 1H), 4.64-4.45 (m, 2H), 4.33-4.19 (m, 1H), 3.35 (s, 2H), 2.91-2.68 (m, 2H), 2.32 (s, 3H), 2.11-1.56 (m, 8H).
[1982] MS m/z (ESI): 396.2 [M+H].sup.+.
Embodiment 235
3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[1983] ##STR00680##
Step 1: preparation of (3-((2,7-dichloroquinazolin-4-yl)amino)-1H-pyrazol-5-yl)methanol
[1984] ##STR00681##
[1985] 2,4,7-Trifluoroquinazoline (300 mg, 1.29 mmol), (3-amino-1H-pyrazol-5-yl)methanol (180 mg, 1.55 mmol) nand DIPEA (500 mg, 3.87 mmol) were added to 1,4-dioxane (5 mL). The mixture was mixed evenly and the reaction was carried out at room temperature overnight. Then the mixture was concentrated under reduced pressure, and the crude product obtained was added to methanol (5 mL), and filtered. The solid was dried to obtain the title compound as a white solid (350 mg, 87%)
[1986] MS m/z (ESI): 310.0 [M+H].sup.+.
Step 2: preparation of tert-butyl (3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[1987] ##STR00682##
[1988] (3-((2,7-Dichloroquinazolin-4-yl)amino)-1H-pyrazol-5-yl)methanol (150 mg, 0.49 mmol), Tert-butyl (3-exo)-3-(methylamino)-9-azabicyclo[3.3.1]non-9-carboxylate (150 mg, 0.58 mmol) and DIPEA (190 mg, 1.47 mmol) were added to n-butanol (2 mL). The mixture was mixed evenly, heated to 150° C. under microwave condition, and reacted for 10 hour. The mixture was then cooled down to room temperature, and concentrated under reduced pressure. The crude product obtained was purified by flash silica gel chromatography to obtain the target product as a white solid (140 mg, 55%).
[1989] MS m/z (ESI): 528.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[1990] ##STR00683##
[1991] Hydrochloride dioxane (4N, 2 mL) was slowly added dropwise into the solution of tert-butyl (3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (140 mg, 0.27 mmol) in methanol (10 mL). The reaction was carried out at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure. The crude product obtained was dissolved in methanol (15 mL), and DIPEA (0.5 mL) and acrylonitrile (25 mg, 0.46 mmol) were separately added thereto at room temperature. The reaction was carried out at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and purified by prep-HPLC to obtain the title compound as a white solid (22 mg, 20%).
[1992] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.41 (s, 1H), 10.02 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 7.28 (s, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.52-6.54 (m, 1H), 5.53-5.55 (m, 1H), 5.25 (s, 1H), 4.46 (t, J=5.2 Hz, 2H), 3.31-2.87 (m, 7H), 2.66-2.59 (m, 2H), 2.08-1.87 (m, 5H), 1.60-1.41 (m, 5H).
[1993] MS m/z (ESI): 481.2 [M+H].sup.+.
Embodiment 236
3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[1994] ##STR00684##
[1995] The preparation of 3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 235.
[1996] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.45 (s, 1H), 10.08 (d, J=8.8 Hz, 1H), 8.36 (d, J=8.8 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.62-6.54 (m, 1H), 5.27-5.11 (m, 2H), 4.50 (d, J=5.6 Hz, 2H), 3.31-2.27 (m, 2H), 2.94 (d, J=16.0 Hz, 3H), 2.67-2.58 (m, 4H), 1.92-1.81 (m, 4H), 1.71-1.62 (m, 2H), 1.39-1.23 (m, 2H).
[1997] MS m/z (ESI): 467.2 [M+H].sup.+.
Embodiment 237
1-(((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[1998] ##STR00685##
[1999] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (200 mg, 0.439 mmol) was dissolved in 4M HCl in 1,4-dioxane solution (20 mL). The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in anhydrous N,N-dimethylformamide (10 mL), then cooled to 0° C., and DIPEA (1.45 mL, 8.78 mmol) and 3-cyanoazetindin-1-sulfonyl chloride (95 mg, 0.527 mmol) were successively added thereto. The reaction mixture was stirred at 0° C. for 16.5 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse phase HPLC to obtain the title compound (70 mg, 32%).
[2000] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 7.37 (d, J=6.0 Hz, 1H), 6.94 (d, J=6.0 Hz, 1H), 6.25 (s, 1H), 4.44-4.34 (m, 1H), 4.26 (s, 2H), 4.16 (t, J=8.5 Hz, 2H), 4.12-4.05 (m, 2H), 3.57 (ddd, J=15.3, 8.7, 6.5 Hz, 1H), 2.31 (s, 3H), 2.23-2.10 (m, 4H), 2.01 (d, J=7.4 Hz, 2H), 1.73 (dd, J=18.2, 7.1 Hz, 2H).
[2001] MS m/z (ESI): 500.1 [M+H].sup.+.
Embodiment 238
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino))-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azacyclobutane-3-nitrile
[2002] ##STR00686##
##STR00687##
[2003] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then dissolved in N,N-dimethylformamide (10 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was stirred at room temperature for 10 minutes. 3-Nitrile azacyclobutane-1-sulfonylchlorine (45 mg, 0.25 mmol) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (14.4 mg, 13%).
[2004] .sup.1H NMR (400 MHz, DMSO) δ=12.02 (s, 1H), 9.81 (s, 1H), 7.61 (s, 1H), 6.90 (s, 1H), 6.59 (d, J=57.6 Hz, 2H), 4.74 (s, 1H), 3.96 (t, J=8.4 Hz, 2H), 3.85 (dd, J=16.8 Hz, 6.4, 4H), 3.75-3.67 (m, 1H), 2.14 (s, 3H), 2.00 (d, J=8.4 Hz, 2H), 1.87-1.60 (m, 8H).
[2005] MS m/z (ESI): 514.1 [M+H].sup.+.
Embodiment 239
1-(((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azacyclobutane-3-nitrile
[2006] ##STR00688##
Step 1: preparation of tert-butyl-(3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate
[2007] ##STR00689##
[2008] Tert-butyl-(3-exo)-3-(methylamino)-9-azabicyclo[3.3.1]non-9-carboxylate (287 mg, 1.13 mmol) and DIPEA (242 mg, 1.88 mmol) were successively added to the solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine(250 mg, 0.94 mmol) in n-butanol (10 mL). The mixture was stirred at 160° C. under microwave condition for 15 hours. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=98:2) to obtain the title compound as pale white solid (228 mg, 50%).
[2009] MS m/z (ESI): 484.2 [M+H].sup.+.
Step 2: preparation of 1-(((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azacyclobutane-3-nitrile
[2010] ##STR00690##
[2011] Tert-butyl-(3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then dissolved in N,N-dimethylformamide (10 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was stirred at room temperature for 10 minutes. 3-Nitrile azacyclobutane-1-sulfonylchlorine (45 mg, 0.25 mmol) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (46.0 mg, 42%).
[2012] .sup.1H NMR (400 MHz, DMSO) δ=12.09 (s, 1H), 9.79 (s, 1H), 7.68 (d, J=6.0 Hz, 1H), 7.02 (d, J=6.0 Hz, 1H), 6.43 (s, 1H), 5.77 (s, 1H), 3.98 (dt, J=14.4, 8.4 Hz, 6H), 3.84-3.74 (m, 1H), 2.90 (s, 3H), 2.22 (s, 3H), 2.13-1.61 (m, 10H).
[2013] MS m/z (ESI): 528.2 [M+H].sup.+.
Embodiment 240
1-(((3-exo)-3-(methyl(6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[2014] ##STR00691##
Step 1: preparation of tert-butyl (3-exo)-3-(methyl(6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-0)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[2015] ##STR00692##
[2016] 2-Chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (150 mg, 0.536 mmol) and Tert-butyl (3-exo)-3-(methylamino)-8-azabicyclo[3.2.1]oct-8-carboxylate (257 mg, 1.072 mmol) were added to n-butanol (10 mL). The mixture was heated to 170° C. with a microwave reactor, reacted for 8 hours, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane. The mixture was successively washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to obtain the title compound (73 mg, 28%).
[2017] MS m/z (ESI): 484.2 [M+H].sup.+.
Step 2: preparation of 1-(((3-exo)-3-(methyl(6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[2018] ##STR00693##
[2019] Tert-butyl (3-exo)-3-(methyl(6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (73 mg, 0.151 mmol) was dissolved in 4 M HCl in 1,4-dioxane (20 mL). The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent. The residue solid was dissolved in anhydrous N,N-dimethylformamide (10 mL), then cooled to 0° C., and DIPEA (0.75 mL, 4.53 mmol) and 3-cyanoazetindin-1-sulfonyl chloride (30 mg, 0.166 mmol) were successively added thereto. The reaction mixture was stirred at 0° C. for 4.5 hour, and concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC to obtain the title compound (31.5 mg, 40%).
[2020] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.06 (s, 1H), 9.66 (s, 1H), 7.35 (s, 1H), 6.48 (s, 1H), 5.31-5.15 (m, 1H), 4.18 (d, J=1.0 Hz, 2H), 4.06 (t, J=8.6 Hz, 2H), 4.00-3.91 (m, 2H), 3.80 (ddd, J=12.8, 8.9, 6.5 Hz, 1H), 2.90 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H), 2.07-1.99 (m, 2H), 1.95 (dd, J=18.2, 7.0 Hz, 2H), 1.88-1.79 (m, 2H), 1.62 (dd, J=11.8, 4.1 Hz, 2H).
[2021] MS m/z (ESI): 528.2 [M+H].sup.+.
Embodiment 241
1-(((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[2022] ##STR00694##
Step 1: preparation of Tert-butyl (3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[2023] ##STR00695##
[2024] 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.376 mmol) and tert-butyl (3-exo)-3-(methylamino)-8-azabicyclo[3.2.1]oct-8-carboxylate (181 mg, 0.752 mmol) were added to n-butanol (3 mL). The mixture was heated by a microwave reactor to 170° C., reacted for 18 hours, and concentrated under reduced pressure to remove the solvent. The residue was used directly in the next step.
[2025] MS m/z (ESI): 470.2 [M+H].sup.+.
Step 2: preparation of 1-(((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[2026] ##STR00696##
[2027] Tert-butyl (3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate was dissolved in 4 M HCl in 1,4-dioxane (20 mL). The mixture was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse phase chromatography to obtain 117 mg white solid.
[2028] The white solid was dissolved in anhydrous N,N-dimethylformamide (10 mL), then cooled to 0° C., and DIPEA (0.14 mL, 0.632 mmol) and 3-cyanoazetindin-1-sulfonyl chloride (57 mg, 0.316 mmol) were successively added thereto. The reaction mixture was stirred at 0° C. for 17 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC to obtain the title compound (16.4 mg, 10%).
[2029] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 7.37 (d, J=5.9 Hz, 1H), 6.98 (d, J=5.7 Hz, 1H), 6.40 (s, 1H), 5.40-5.28 (m, 1H), 4.31-4.24 (m, 2H), 4.17 (t, J=8.5 Hz, 2H), 4.11-4.04 (m, 2H), 3.57 (ddd, J=15.4, 8.9, 6.7 Hz, 1H), 3.04 (s, 3H), 2.31 (s, 3H), 2.17 (dd, J=8.6, 3.3 Hz, 2H), 2.11-2.01 (m, 2H), 2.00-1.92 (m, 2H), 1.75 (ddd, J=10.8, 4.3, 2.7 Hz, 2H).
[2030] MS m/z (ESI): 514.1 [M+H].sup.+.
Embodiment 242
2-(dimethylamine)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)ethane-1-one
[2031] ##STR00697##
[2032] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (120 mg, 0.32 mmol), was added to the mixture. The mixture was then dissolved in N,N-dimethylformamide (5 mL), and DIPEA (108 mg, 0.84 mmol) was slowly added dropwise thereto. The mixture was then stirred under ice water bath for 10 minutes, dimethyl glycine (24 mg, 0.23 mmol) was added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (17.1 mg, 18%).
[2033] .sup.1H NMR (400 MHz, DMSO) δ=12.00 (s, 1H), 9.80 (s, 1H), 7.61 (s, 1H), 6.98-6.45 (m, 3H), 4.76 (s, 1H), 4.59 (s, 1H), 4.27 (s, 1H), 3.30 (s, 6H), 3.05 (s, 2H), 2.16 (s, 3H), 2.14 (s, 2H), 2.07-1.92 (m, 2H), 1.86-1.40 (m, 6H).
[2034] MS m/z (ESI): 455.2 [M+H].sup.+.
Embodiment 243
2-(dimethylamine)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one
[2035] ##STR00698##
[2036] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (40 mg, 0.09 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 2 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (51 mg, 0.13 mmol) was added to the mixture. The mixture was then dissolved in N,N-dimethylformamide (5 mL), and DIPEA (46 mg, 0.36 mmol) was slowly added dropwise thereto. The mixture was then stirred under ice water bath for 10 minutes. Dimethyl glycine (10 mg, 0.1 mmol) was added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (4.4 mg, 11%).
[2037] .sup.1H NMR (400 MHz, DMSO) δ=12.08 (s, 1H), 9.88 (s, 1H), 7.65 (s, 1H), 7.11-6.46 (m, 3H), 4.47 (d, J=30.0 Hz, 3H), 3.06 (s, 2H), 2.21 (s, 9H), 2.04-1.66 (m, 6H), 1.62-1.44 (m, 2H).
[2038] MS m/z (ESI): 441.2 [M+H].sup.+.
Embodiment 244
1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)-2-morpholinoethane-1-one
[2039] ##STR00699##
[2040] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (40 mg, 0.09 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 2 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (51 mg, 0.13 mmol) was added to the mixture. The mixture was dissolved in N,N-dimethylformamide (5 mL). DIPEA (46 mg, 0.36 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. 2-morpholino acetate (14.5 mg, 0.1 mmol) was added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (7.8 mg, 18%).
[2041] .sup.1H NMR (400 MHz, DMSO) δ=12.07 (s, 1H), 9.88 (s, 1H), 7.66 (s, 1H), 7.11-6.49 (m, 3H), 4.48 (d, J=26.4 Hz, 3H), 3.60 (s, 4H), 3.17 (s, 2H), 2.46 (s, 4H), 2.23 (s, 3H), 1.98 (s, 2H), 1.90-1.45 (m, 6H).
[2042] MS m/z (ESI): 483.2 [M+H].sup.+.
Embodiment 245
1-((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)-2-morpholinoethane-1-one
[2043] ##STR00700##
[2044] The preparation of 1-((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)-2-morpholinoethane-1-one was carried out with the reference to Embodiment 244.
[2045] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=9.85 (s, 1H), 8.22 (s, 1H), 7.68 (d, J=6.0 Hz, 1H), 7.02 (d, J=6.0 Hz, 1H), 6.53 (s, 1H), 5.37 (s, 1H), 4.54 (d, J=16.4 Hz, 2H), 3.58 (d, J=4.0 Hz, 4H), 3.04 (d, J=13.2 Hz, 2H), 2.85 (s, 3H), 2.45 (s, 4H), 2.23 (s, 3H), 2.03-1.97 (m, 2H), 1.87-1.59 (m, 6H).
[2046] MS m/z (ESI): 497.2 [M+H].sup.+.
Embodiment 246
1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-morpholinoethane-1-one
[2047] ##STR00701##
##STR00702##
[2048] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added to the mixture. The mixture was then dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. 2-Morpholino acetate (33 mg, 0.23 mmol) was added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (18.0 mg, 17%).
[2049] .sup.1H NMR (400 MHz, DMSO) δ=12.08 (s, 1H), 9.87 (s, 1H), 7.68 (s, 1H), 7.07-6.53 (m, 3H), 4.83 (s, 1H), 4.65 (s, 1H), 4.37 (s, 1H), 3.59 (d, J=4.0 Hz, 4H), 3.12 (dd, J=25.2, 12.4 Hz, 2H), 2.39 (s, 4H), 2.21 (s, 3H), 2.11-1.51 (m, 10H).
[2050] MS m/z (ESI): 497.2 [M+H].sup.+.
Embodiment 247
1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-(methylamino)-ethane-1-one
[2051] ##STR00703##
Step 1: preparation of tert-butylmethyl(2-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2carbonylethyl)amino formate
[2052] ##STR00704##
[2053] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (200 mg, 0.42 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 10 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (240 mg, 0.64 mmol) was added to the mixture, and the mixture was dissolved in N,N-dimethylformamide (5 mL). DIPEA (216 mg, 1.68 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. N-(tert-butoxycarbonyl)-N-methyl glycine (87 mg, 0.46 mmol) was added thereto and the mixture was stirred for another 1 hour. When the reaction was completed, the mixture was extracted with dichloromethane (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound as a white solid (205 mg, 90%).
[2054] MS m/z (ESI): 541.2 [M+H].sup.+.
Step 2: preparation of 1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-(methylamino)-ethane-1-one
[2055] ##STR00705##
[2056] Tert-butylmethyl(2-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2carbonylethyl)amino formate (205 mg, 0.38 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 10 mL). The mixture was stirred at room temperature for 30 minutes, and ammonia (10 mL) was added dropwise to the reaction mixture in an ice water bath. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (37.6 mg, 22%).
[2057] .sup.1H NMR (400 MHz, DMSO) δ=12.10 (s, 1H), 9.88 (s, 1H), 7.68 (s, 1H), 6.96 (s, 1H), 6.61 (s, 2H), 4.84 (s, 1H), 4.69 (s, 1H), 4.12 (s, 1H), 2.29 (s, 3H), 2.20 (s, 3H), 2.15-1.96 (m, 3H), 1.87-1.47 (m, 10H).
[2058] MS m/z (ESI): 441.2 [M+H].sup.+.
Embodiment 248
((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl) ((R)-pyrrolidin-2-yl)methanone
[2059] ##STR00706##
[2060] The preparation of ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl) ((R)-pyrrolidin-2-yl)methanone was carried out with the reference to Embodiment 247.
[2061] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.08 (s, 1H), 9.89 (s, 1H), 7.66 (s, 1H), 7.06-6.51 (m, 3H), 4.55-4.35 (m, 3H), 3.73 (s, 1H), 3.01 (s, 1H), 2.64 (d, J=6.8 Hz, 2H), 2.23 (s, 3H), 2.10-1.43 (m, 12H).
[2062] MS m/z (ESI): 453.1 [M+H].sup.+.
Embodiment 249
((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl) ((S)-pyrrolidin-2-yl)methanone
[2063] ##STR00707##
[2064] The preparation of ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl) ((S)-pyrrolidin-2-yl)methanone was carried out with the reference to Embodiment 247.
[2065] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.11 (s, 1H), 9.90 (s, 1H), 7.67 (s, 1H), 5.98-6.54 (m, 3H), 4.58-4.35 (m, 3H), 4.09-4.02 (m, 1H), 3.11 (s, 1H), 2.97-2.64 (m, 2H), 2.23 (s, 3H), 2.10-1.37 (m, 10H).
[2066] MS m/z (ESI): 453.1 [M+H].sup.+.
Embodiment 250
((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)((R)-morpholine-3-yl)methanone
[2067] ##STR00708##
[2068] The preparation of ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)((R)-morpholine-3-yl)methanone was carried out with the reference to Embodiment 247.
[2069] MS m/z (ESI): 483.2 [M+H].sup.+.
Embodiment 251
((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)((R)-pyrrolidin-2-yl)methanone
[2070] ##STR00709##
[2071] The preparation of ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)((R)-pyrrolidin-2-yl)methanone was carried out with the reference to Embodiment 247.
[2072] MS m/z (ESI): 467.2 [M+H].sup.+.
Embodiment 252
2-((2-methoxylethyl)amino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)ethane-1-one
[2073] ##STR00710##
[2074] The preparation of 2-((2-m ethoxyl ethyl)amino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)ethane-1-one was carried out with the reference to Embodiment 247.
[2075] MS m/z (ESI): 485.2 [M+H].sup.+.
Embodiment 253
1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-((pyridin-3-ylmethyl)amino)ethane-1-one
[2076] ##STR00711##
[2077] The preparation of 1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-((pyridin-3-ylmethyl)amino)ethane-1-one was carried out with the reference to Embodiment 247.
[2078] MS m/z (ESI): 518.2 [M+H].sup.+.
Embodiment 254
2-((4-methoxybenzyl)amino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one
[2079] ##STR00712##
[2080] The preparation of 2-((4-methoxybenzyl)amino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one was carried out with the reference to Embodiment 247.
[2081] MS m/z (ESI): 533.2 [M+H].sup.+.
Embodiment 255
2-(ethylamino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one
[2082] ##STR00713##
[2083] The preparation of 2-(ethyl amino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one was carried out with the reference to Embodiment 247.
[2084] MS m/z (ESI): 441.2 [M+H].sup.+.
Embodiment 256
2-(cyclopropylamino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one
[2085] ##STR00714##
[2086] The preparation of 2-(cyclopropylamino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one was carried out with the reference to Embodiment 247.
[2087] MS m/z (ESI): 453.2 [M+H].sup.+.
Embodiment 257
1-((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-(4-methylpiperazin-1-yl)ethane-1-one
[2088] ##STR00715##
[2089] Tert-butyl-(3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added to the mixture. The mixture was dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. 2-(4-Methylpiperazin-1-yl) acetic acid (36 mg, 0.23 mmol) was added thereto, and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (43.8 mg, 40%).
[2090] .sup.1H NMR (400 MHz, DMSO) δ=12.07 (s, 1H), 9.79 (s, 1H), 7.68 (d, J=6.0 Hz, 1H), 7.02 (d, J=6.0 Hz, 1H), 6.46 (s, 1H), 5.81 (s, 1H), 4.71 (s, 1H), 4.39 (s, 1H), 3.22 (d, J=12.8 Hz, 1H), 3.06 (d, J=12.8 Hz, 1H), 2.85 (s, 3H), 2.40 (s, 8H), 2.22 (s, 3H), 2.17 (s, 3H), 2.12-2.02 (m 2H), 1.90-1.61 (m, 8H).
[2091] MS m/z (ESI): 424.2 [M+H].sup.+.
Embodiment 258
1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-(4-methylpiperazin-1-yl)ethane-1-one
[2092] ##STR00716##
[2093] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added to the mixture. The mixture was dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. 2-(4-Methylpiperazin-1-yl) acetic acid (36 mg, 0.23 mmol) was added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (25.2 mg, 24%).
[2094] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.07 (s, 1H), 9.92 (s, 1H), 7.68 (s, 1H), 6.96-6.61 (m, 3H), 4.85 (s, 1H), 4.65 (s, 1H), 4.37 (s, 1H), 3.10 (s, 2H), 2.37 (s, 8H), 2.21 (s, 3H), 2.14 (s, 3H), 2.09-1.99 (m, 2H), 1.97-1.46 (m, 8H).
[2095] MS m/z (ESI): 510.2 [M+H].sup.+.
Embodiment 259
1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-(piperazin-1-yl)ethane-1-one
[2096] ##STR00717##
[2097] The preparation of 1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-(piperazin-1-yl)ethane-1-one was carried out with the reference to Embodiment 247.
[2098] MS m/z (ESI): 496.2 [M+H].sup.+.
Embodiment 260
((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)(pyridin-2-yl)methanone
[2099] ##STR00718##
##STR00719##
[2100] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added to the mixture. The mixture was dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. Pyridin-2-formic acid (28 mg, 0.23 mmol) was added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (27.3 mg, 21%).
[2101] .sup.1H NMR (400 MHz, DMSO) δ=12.07 (s, 1H), 9.86 (s, 1H), 8.59 (d, J=4.4 Hz, 1H), 7.94 (td, J=7.7, 1.6 Hz, 1H), 7.73-7.44 (m, 3H), 7.05-6.50 (m, 3H), 4.84 (d, J=28.0 Hz, 2H), 3.94 (s, 1H), 2.21 (s, 3H), 2.18-1.59 (m, 10H).
[2102] MS m/z (ESI): 475.1 [M+H].sup.+.
Embodiment 261
((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)(pyridin-3-yl)methanone
[2103] ##STR00720##
[2104] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added to the mixture. The mixture was dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. Pyridin-3-formic acid (28 mg, 0.23 mmol) was added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (28.6 mg, 22%).
[2105] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.07 (s, 1H), 9.87 (s, 1H), 8.71-8.58 (m, 2H), 7.84 (d, J=7.6 Hz, 1H), 7.69 (d, J=6.0 Hz, 1H), 7.51 (dd, J=7.6, 4.8 Hz, 1H), 6.96 (d, J=5.2 Hz, 1H), 6.68-6.50 (m, 2H), 4.83 (d, J=39.2 Hz, 2H), 3.78 (s, 1H), 2.21 (s, 3H), 2.13-1.61 (m, 10H).
[2106] MS m/z (ESI): 475.1 [M+H].sup.+.
Embodiment 262
((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)(pyridin-4-yl)methanone
[2107] ##STR00721##
[2108] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added to the mixture. The mixture was dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. Pyridin-4-formic acid (28 mg, 0.23 mmol) was added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (34.5 mg, 27%).
[2109] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.07 (s, 1H), 9.87 (s, 1H), 8.69 (d, J=6.0 Hz, 2H), 7.69 (d, J=5.6 Hz, 1H), 7.39 (d, J=5.6 Hz, 2H), 6.97 (d, J=6.0 Hz, 1H), 6.57 (d, J=7.6 Hz, 2H), 4.82 (d, J=41.6 Hz, 2H), 3.68 (s, 1H), 2.21 (s, 3H), 2.14-1.59 (m, 10H).
[2110] MS m/z (ESI): 475.1 [M+H].sup.+.
Embodiment 263
(1-methyl-1H-imidazol-2-yl) ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)methanone
[2111] ##STR00722##
[2112] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added to the mixture, which was dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. 1-Methyl-1H-imidazol-2-carboxylic acid (29 mg, 0.23 mmol) was added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (15.0 mg, 12%).
[2113] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.08 (s, 1H), 9.87 (s, 1H), 7.68 (s, 1H), 7.29 (s, 1H), 6.97 (s, 2H), 6.65 (s, 2H), 4.91-4.80 (m, 3H), 3.77 (s, 3H), 2.22 (s, 3H), 2.14-1.60 (m, 10H).
[2114] MS m/z (ESI): 478.2 [M+H].sup.+.
Embodiment 264
(1-methyl-1H-imidazol-4-yl) ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)methanone
[2115] ##STR00723##
[2116] The preparation of (1-methyl-1H-imidazol-4-yl) ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)methanone was carried out with the reference to Embodiment 250.
[2117] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.08 (s, 1H), 9.86 (s, 1H), 7.70-7.60 (m, 3H), 6.95 (s, 1H), 6.65 (s, 1H), 5.57 (s, 1H), 4.82 (d, J=65.2 Hz, 3H), 3.68 (s, 3H), 2.22 (s, 3H), 2.13-1.58 (s, 10H).
[2118] MS m/z (ESI): 478.1 [M+H].sup.+.
Embodiment 265
N.SUP.4.-(5-methyl-1H-pyrazol-3-yl)-N.SUP.2.-((3-exo)-8(pyridin-3yl sulfonyl)-8-azabicyclo[3.2.1]oct-3-yl)thieno[2,3-d]pyrimidin-2,4-diamine
[2119] ##STR00724##
[2120] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (40 mg, 0.09 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 2 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then N,N-dimethylformamide (5 mL) was added to the mixture for dissolution. DIPEA (46 mg, 0.36 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. Pyridin-3-sulfonylchlorine (18 mg, 0.1 mmol) was added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (5.6 mg, 13%).
[2121] .sup.1H NMR (400 MHz, DMSO) δ=12.01 (s, 1H), 9.86 (s, 1H), 9.05 (s, 1H), 8.87 (d, J=4.4 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H), 7.65 (dd, J=7.8 Hz, 5.0, 2H), 6.97 (s, 1H), 6.78 (s, 1H), 6.54 (s, 1H), 4.33 (s, 2H), 3.17 (d, J=5.2 Hz, 1H), 2.14 (s, 3H), 1.99 (s, 2H), 1.76-1.56 (m, 4H), 1.35-1.26 (m, 2H).
[2122] MS m/z (ESI): 497.1 [M+H].sup.+.
Embodiment 266
N4-(5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-8-(pyridin-2-ylsulfonyl)-8-azabicyclo[3.2.1]oct-3-yl)thieno[2,3-d]pyrimidin-2,4-diamine
[2123] ##STR00725##
[2124] The preparation of N4-((5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-8-(pyridin-2-yl sulfonyl)-8-azabicyclo[3.2.1]oct-3-yl)thieno[2,3-d]pyrimidin-2,4-diamine was carried out with the reference to Embodiment 252.
[2125] .sup.1H NMR (400 MHz, CD.sub.3OD: CDCl.sub.3, v/v=1:2) δ 8.70 (d, J=4.6 Hz, 1H), 8.00 (dt, J=8.0, 4.6 Hz, 2H), 7.60 (ddd, J=6.8, 4.8, 1.8 Hz, 1H), 7.35 (d, J=6.0 Hz, 1H), 6.92 (d, J=6.0 Hz, 1H), 6.19 (s, 1H), 4.43 (s, 2H), 4.40-4.32 (m, 1H), 2.27 (s, 3H), 2.15 (ddd, J=12.7, 5.3, 2.6 Hz, 2H), 1.88-1.81 (m, 2H), 1.80-1.70 (m, 2H), 1.62 (dd, J=8.6, 4.7 Hz, 2H).
[2126] MS m/z (ESI): 497.1 [M+H].sup.+.
Embodiment 267
N4-((5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-9-(pyridin-2-ylsulfonyl)-9-azabicyclo[3.3.1]non-3-yl)thieno[2,3-d]pyrimidin-2,4-diamine
[2127] ##STR00726##
[2128] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.213 mmol) was dispersed in 4 M HCl in 1,4-dioxane (15 mL). The mixture was stirred at room temperature for 60 minutes, and concentrated under reduced pressure to remove the solvent. The residue solid was dissolved in anhydrous N,N-dimethylformamide (10 mL), then cooled to 0° C., and DIPEA (1.05 mL, 6.39 mmol) and pyridin-2-sulfonyl chloride (40 mg, 0.224 mmol) successively added thereto. The reaction mixture was stirred at 0° C. for 2.5 hours, and concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC to obtain the title compound as a white solid (12.4 mg, 25%).
[2129] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.07 (s, 1H), 9.85 (s, 1H), 8.78 (d, J=4.0 Hz, 1H), 8.08 (td, J=7.7, 1.4 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.67 (dd, J=6.7, 4.7 Hz, 2H), 6.95 (s, 1H), 6.59 (d, J=30.3 Hz, 2H), 4.85-4.71 (m, 1H), 4.18 (s, 2H), 2.17 (s, 3H), 2.05 (dd, J=12.8, 4.9 Hz, 3H), 1.68 (d, J=2.6 Hz, 7H).
[2130] MS m/z (ESI): 511.1 [M+H].sup.+.
Embodiment 268
N4-((5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-9-(pyridin-3-yl sulfonyl)-9-azabicyclo[3.3.1]non-3-yl)thieno[2,3-d]pyrimidin-2,4-diamine
[2131] ##STR00727##
[2132] The preparation of N4-((5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-9-(pyridin-3-ylsulfonyl)-9-azabicyclo[3.3.1]non-3-yl)thieno[2,3-d]pyrimidin-2,4-diamine was carried out with the reference to Embodiment 267.
[2133] .sup.1H NMR (400 MHz, CD.sub.3OD:CDCl.sub.3, v/v=1:1) δ 9.11 (s, 1H), 8.84 (d, J=3.9 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H), 7.70-7.62 (m, 1H), 7.39 (d, J=5.9 Hz, 1H), 6.96 (d, J=5.8 Hz, 1H), 6.62 (s, 1H), 5.05-4.90 (m, 1H), 4.34 (d, J=2.8 Hz, 2H), 2.55-2.19 (m, 5H), 2.19-1.61 (m, 8H).
[2134] MS m/z (ESI): 511.1 [M+H].sup.+.
Embodiment 269
[2135] N2-((3-exo)-9-((1-methyl-1H-imidazol-2-yl)sulfonyl)-9-azabicyclo[3.3.1]non-3-yl)-N4-((5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-2,4-diamine
##STR00728##
[2136] The preparation of N2-((3-exo)-9-((1-methyl-1H-imidazol-2-yl)sulfonyl)-9-azabicyclo[3.3.1]non-3-yl)-N4-((5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-2,4-diamine was carried out with the reference to Embodiment 267.
[2137] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.05 (s, 1H), 9.86 (s, 1H), 7.67 (d, J=2.9 Hz, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 6.96 (d, J=4.9 Hz, 1H), 6.73-6.47 (m, 2H), 4.88-4.74 (m, 1H), 4.12 (s, 2H), 3.87 (s, 3H), 2.19 (s, 3H), 2.09 (ddd, J=5.5, 5.1, 1.0 Hz, 3H), 1.91-1.58 (m, 7H).
[2138] MS m/z (ESI): 514.1 [M+H].sup.+.
Embodiment 270
N,N-dimethyl-2-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)acetamide
[2139] ##STR00729##
[2140] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then N,N-dimethylformamide (5 mL) was added to the mixture for dissolution. DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. 2-Bromine-N,N-dimethylacetamide (38 mg, 0.23 mmol) were added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (16.6 mg, 17%).
[2141] .sup.1H NMR (400 MHz, DMSO) δ=12.00 (s, 1H), 9.80 (s, 1H), 7.63 (s, 1H), 6.74 (d, J=128.0 Hz, 3H), 4.62 (s, 1H), 3.42 (s, 2H), 3.04 (s, 3H), 2.86 (s, 2H), 2.77 (s, 3H), 2.16 (s, 3H), 1.96-1.47 (m, 10H).
[2142] MS m/z (ESI): 455.2 [M+H].sup.+.
Embodiment 271
N.SUP.4.-((5-methyl-1H-pyrazol-3-yl)-N.SUP.2.-((3-exo)-9-(pyridin-2-ylmethyl)-9-azabicyclo[3.3.1]non-3-yl)thieno[2,3-d]pyrimidin-2,4-diamine
[2143] ##STR00730##
[2144] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then the mixture was dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. 2-(Chloromethyl)pyridinyl hydrochloride (38 mg, 0.23 mmol) was added to the mixture, and the mixture was then stirred at 70° C. overnight. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (20.8 mg, 22%).
[2145] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.06 (s, 1H), 9.85 (s, 1H), 8.47 (d, J=4.0 Hz, 1H), 7.81-7.48 (m, 3H), 7.33-6.52 (m, 4H), 4.74 (s, 1H), 3.92 (s, 2H), 2.89 (s, 2H), 2.23 (d, J=13.6 Hz, 3H), 2.08-1.50 (m, 10H).
[2146] MS m/z (ESI): 461.1 [M+H].sup.+.
Embodiment 272
N.SUP.2.-((3-exo)-9-((1-methyl-1H-imidazol-2-yl)methyl)-9-azabicyclo[3.3.1]non-3-yl)-N.SUP.4.-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-2,4-diamine
[2147] ##STR00731##
[2148] The preparation of N.sup.2-((3-exo)-9-(1-methyl-1H-imidazol-2-yl)methyl)-9-azabicyclo[3.3.1]non-3-yl)-N.sup.4-((5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-2,4-diamine was carried out with the reference to Embodiment 271.
[2149] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.06 (s, 1H), 9.84 (s, 1H), 7.67 (s, 1H), 7.08 (s, 1H), 6.95 (s, 1H), 6.74-6.55 (m, 3H), 4.69 (s, 1H), 3.91 (s, 2H), 3.69 (s, 3H), 2.84 (s, 2H), 2.20 (s, 3H), 2.01-1.66 (m, 10H).
[2150] MS m/z (ESI): 464.2 [M+H].sup.+.
Embodiment 273
3-((3-exo))-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[2151] ##STR00732##
Step 1: preparation of (3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol
[2152] ##STR00733##
[2153] 2,4-Dichlorothieno[2,3-d]pyrimidine (100 mg, 0.49 mmol), (3-amino-1H-pyrazol-5-yl)methanol (55 mg, 0.49 mmol) and DIPEA (190 mg, 1.47 mmol) were added to N′N-dimethylformamide (2 mL). The reaction mixture was stirred at 70° C. overnight. Then the mixture was concentrated under reduced pressure, and the crude product obtained was purified by flash silica gel chromatography to obtain the title compound as a yellow solid (100 mg, 73%).
[2154] MS m/z (ESI):282.0 [M+H].sup.+.
Step 2: preparation of Tert-butyl (3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[2155] ##STR00734##
[2156] (3-((2-Chlorothieno[2,3-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol (100 mg, 0.36 mmol), N-Boc-exo-3-aminotropane acetate (113 mg, 0.40 mmol) and DIPEA (140 mg, 1.08 mmol) were added to n-butanol (2.5 mL). The reaction mixture was mixed evenly, then heated to 150° C. under microwave condition, reacted for 10 hours, then cooled down to room temperature, and concentrated under reduced pressure. The crude product obtained was purified by flash silica gel chromatography to obtain the title compound as a pale yellow solid (60 mg, 35%).
[2157] MS m/z (ESI):472.0 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[2158] ##STR00735##
[2159] Tert-butyl (3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (60 mg, 0.13 mmol) was dissolved in methanol (10 mL), and then hydrochloride dioxane (4N, 2.5 mL) was slowly added dropwise into the reaction mixture. The reaction was carried out at room temperature for 2 hours, and then the mixture was concentrated under reduced pressure. The crude product obtained were added to a mixed solution of methanol (15 mL), DIPEA (0.5 mL) and acrylonitrile (1 mL). The reaction was carried out at room temperature for 2 hour, and the mixture was concentrated under reduced pressure, and then purified by prep-HPLC to obtain the title compound as a white solid (11.6 mg, 21%).
[2160] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.39 (dd, J=6.0 Hz, 1H), 6.99 (dd, J=5.6 Hz, 1H), 6.02-6.04 (m, 1H), 4.60 (s, 2H), 4.21-4.24 (m, 1H), 3.45-3.42 (m, 2H), 2.83 (s, 2H), 2.69-2.65 (m, 2H),2.08-1.91 (m, 6H), 1.69 (t, J=12.4 Hz, 2H).
[2161] MS m/z (ESI):425.1[M+H].sup.+.
Embodiment 274
3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[2162] ##STR00736##
[2163] The preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile was carried out with the reference to Embodiment 273.
[2164] MS m/z (ESI): 439.2 [M+H].sup.+.
Embodiment 275
3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[2165] ##STR00737##
[2166] The preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile was carried out with the reference to Embodiment 273.
[2167] MS m/z (ESI): 453.2 [M+H].sup.+.
Embodiment 276
1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile
[2168] ##STR00738##
[2169] The preparation of 1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 273.
[2170] MS m/z (ESI): 530.2 [M+H].sup.+.
Embodiment 277
3-((3-exo)-3-((6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[2171] ##STR00739##
Step 1: preparation of tert-butyl-(3-exo)-3-((6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[2172] ##STR00740##
[2173] Tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (194 mg, 0.86 mmol) and DIPEA (186 mg, 1.44 mmol) were successively added the solution of 2-chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (200 mg, 0.72 mmol) in n-butanol (10 mL), and then the mixture was stirred at 160° C. for 15 hours. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=98:2) to obtain the title compound as a pale yellow solid (124 mg, 37%).
[2174] MS m/z (ESI): 470.2 [M+H].sup.+.
Step 2: preparation of 3-((3-exo)-3-((6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[2175] ##STR00741##
[2176] Tert-butyl-(3-exo)-3-((6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (124 mg, 0.26 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then methanol (10 mL) was added to the mixture for dissolution. DIPEA (137 mg, 1.06 mmol) was slowly added dropwise into the mixture, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (21 mg, 0.39 mmol) was added thereto and the mixture was stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (12.7 mg, 12%).
[2177] .sup.1H NMR (400 MHz, DMSO) δ=9.70 (s, 1H), 7.30 (s, 1H), 6.59 (s, 3H), 4.15 (s, 1H), 3.29 (s, 2H), 2.61 (s, 4H), 2.39 (s, 3H), 2.22 (s, 3H), 1.90 (s, 2H), 1.78-1.50 (m, 6H).
[2178] MS m/z (ESI): 423.2 [M+H].sup.+.
Embodiment 278
3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[2179] ##STR00742##
Step 1: preparation of 5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazolo[5,4-d]pyrimidin-7-amine
[2180] ##STR00743##
[2181] 3-Amino-5-methylpyrazol (116 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) were successively added to the solution of 5,7-dichlorothiazolo[5,4-d]pyrimidine (206 mg, 1 mmol) in dimethyl sulfoxide (10 mL), and then the mixture was stirred at 70° C. for 1 hour. When the reaction was completed, water (50 mL) was added to the reaction mixture, and a solid was precipitated, which was then filtered and slurried with ethyl acetate to obtain the title compound as a yellow solid (200 mg, 75%).
[2182] MS m/z (ESI): 267.0 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate
[2183] ##STR00744##
[2184] Tert-butyl-(3-exo)-3-amino-9-azabicyclo[3.3.1]non-9-carboxylate (216 mg, 0.9 mmol), DIPEA (193 mg, 1.5 mmol) were successively added to the solution of 5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.75 mmol) in n-butanol (10 mL), and the mixture was stirred at 160° C. under microwave condition for 15 hours. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound as a pale yellow solid (232 mg, 66%).
[2185] MS m/z (ESI): 471.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[2186] ##STR00745##
[2187] Tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (232 mg, 0.49 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes and the mixture was concentrated, and then methanol (10 mL) was added to the mixture for dissolution. DIPEA (127 mg, 0.98 mmol) was slowly added dropwise into the mixture, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (39 mg, 0.74 mmol) was added thereto and the mixture was stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a pale yellow solid (63 mg, 30%).
[2188] .sup.1H NMR (400 MHz, DMSO) δ=12.06 (s, 1H), 9.29 (s, 1H), 8.76 (d, J=18.8 Hz, 1H), 6.92 (d, J=7.2 Hz, 1H), 6.57 (s, 1H), 4.67 (s, 1H), 3.31 (s, 2H), 2.58 (t, J=6.2 Hz, 4H), 2.19 (s, 3H), 2.00-1.65 (m, 10H).
[2189] MS m/z (ESI): 424.2 [M+H].sup.+.
Embodiment 279
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)oxo)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[2190] ##STR00746##
Step 1: preparation of Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)oxo)-8-azabicyclo[3.2.1]oct-8-carboxylate
[2191] ##STR00747##
[2192] NaH (120 mg, 3.01 mmol, 60%) were added in batches to the solution of Tert-butyl (3-exo)-3-hydroxy-8-azabicyclo[3.2.1]oct-8-carboxylate (427 mg, 1.88 mmol) in N,N-dimethylformamide (2 mL) at room temperature. The mixture was stirred at room temperature for 5 minutes, and then the solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.376 mmol) in N,N-dimethylformamide (1 mL) was added dropwise. Under nitrogen atmosphere, the mixture was stirred at 120° C. for 2 hours, and cooled to room temperature. The mixture was then poured into ice water (10 mL), stirred for 10 minutes, and filtered. The filtrate was extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride aqueous solution. The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to remove the organic solvent. The resulting product obtained was purified by silica gel chromatography to obtain the title compound as a yellow oil (149 mg, 87%).
Step 2: preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)oxo)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[2193] ##STR00748##
[2194] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)oxo)-8-azabicyclo[3.2.1]oct-8-carboxylate (77 mg, 0.169 mmol) was dissolved in methanol (2 mL). The mixture was stirred at room temperature and 4M HCl in 1,4-dioxane (2 mL) was added thereto. The mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (1 mL), and DIPEA (109 mg, 0.844 mmol) and acrylonitrile (45 mg, 0.844 mmol) were successively added thereto. The resulting reaction mixture was stirred at room temperature for another 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was successively purified by silica gel chromatography and preparative TLC, to obtain the title compound gray solid (7 mg, 10%).
[2195] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.50 (d, J=6.1 Hz, 1H), 7.22 (d, J=5.9 Hz, 1H), 6.51 (s, 1H), 5.43-5.26 (m, 1H), 3.44-3.37 (m, 2H), 2.78 (t, J=6.9 Hz, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.33 (s, 3H), 2.12-2.00 (m, 4H), 1.86-1.74 (m, 4H).
[2196] MS m/z (ESI): 410.1[M+H].sup.+.
Embodiment 280
3-((3-exo)-3-((6-(methoxylmethyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[2197] ##STR00749##
[2198] The preparation of 3-((3-exo)-3-((6-(methoxylmethyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 277.
[2199] MS m/z (ESI): 453.2 [M+H].sup.+.
Embodiment 281
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinothieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[2200] ##STR00750##
[2201] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinothieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 277.
[2202] MS m/z (ESI):494.2 [M+H].sup.+.
Embodiment 282
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(morpholinomethyl)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[2203] ##STR00751##
[2204] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(morpholinomethyl)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile was carried out with the reference to Embodiment 277.
[2205] MS m/z (ESI): 508.3 [M+H].sup.+.
Embodiment 283
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-((4-methylpiperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[2206] ##STR00752##
[2207] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-((4-methylpiperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile was carried out with the reference to Embodiment 277.
[2208] MS m/z (ESI): 535.3 [M+H].sup.+.
Embodiment 284
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(pyridin-3-yl thio)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[2209] ##STR00753##
[2210] The preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(pyridin-3-yl thio)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile was carried out with the reference to Embodiment 277.
[2211] MS m/z (ESI): 532.2 [M+H].sup.+.
Embodiment 285
3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azacyclobutane-3-nitrile
[2212] ##STR00754##
[2213] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.22 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then the mixture was dissolved in N,N-dimethylformamide (10 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was stirred at room temperature for 10 minutes. 3-Nitrile azacyclobutane-1-sulfonylchlorine (45 mg, 0.25 mmol) were added thereto the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (23.2 mg, 21%).
[2214] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.07 (s, 1H), 9.74 (s, 1H), 7.90 (s, 1H), 7.00 (s, 1H), 6.54 (s, 2H), 4.27 (s, 1H), 4.13 (s, 2H), 4.04 (t, J=8.4 Hz, 2H), 3.98-3.89 (m, 2H), 3.80 (dd, J=15.2, 6.0 Hz, 1H), 2.23 (s, 3H), 1.99 (s, 4H), 1.84 (d, J=7.2 Hz, 2H), 1.63 (s, 2H).
[2215] MS m/z (ESI): 500.1 [M+H].sup.+.
Embodiment 286
1-(((3-exo)-3-((6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile
[2216] ##STR00755##
[2217] The preparation of 1-(((3-exo)-3-((6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 267.
[2218] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.02 (s, 1H), 9.64 (s, 1H), 6.77-6.45 (m, 3H), 4.25-4.23 (m, 1H), 4.12 (s, 2H), 4.06-4.02 (m, 2H), 3.95-3.88 (m, 2H), 3.83-3.77 (m, 1H), 2.24-2.21 (m, 4H), 1.99-1.98 (m, 5H), 1.84-1.81 (m, 2H), 1.64-1.59 (m, 3H).
[2219] MS m/z (ESI): 513.1 [M+H].sup.+.
Embodiment 287
2-(dimethylamine)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one
[2220] ##STR00756##
[2221] The preparation of 2-(dim ethyl amine)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one was carried out with the reference to Embodiment 285.
[2222] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.06 (s, 1H), 9.72 (s, 1H), 7.89 (s, 1H), 6.99 (s, 1H), 6.49 (d, J=58.8 Hz, 2H), 4.59-4.28 (m, 3H), 3.04 (s, 2H), 2.15 (s, 9H), 1.98-1.80 (m, 6H), 1.59-1.45 (m, 2H).
[2223] MS m/z (ESI): 441.1 [M+H].sup.+.
Embodiment 288
1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-morpholinoethane-1-one
[2224] ##STR00757##
Step 1: preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate
[2225] ##STR00758##
[2226] Tert-butyl-(3-exo)-3-amino-9-azabicyclo[3.3.1]non-9-carboxylate (271 mg, 1.13 mmol) was added to 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine (250 mg, 0.94 mmol) in n-butanol (10 mL), and DIPEA (242 mg, 1.88 mmol) were successively added thereto. The mixture was then stirred at 160° C. under microwave condition for 15 hours. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=98:2) to obtain the title compound as pale white solid (150 mg, 34%).
[2227] MS m/z (ESI): 470.1 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate
[2228] ##STR00759##
[2229] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then 2-(7-oxide benzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added to the mixture. The mixture was dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. 2-Morpholino acetic acid (33 mg, 0.23 mmol) was added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (17.8 mg, 17%).
[2230] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=11.99 (s, 1H), 9.69 (s, 1H), 7.84 (s, 1H), 7.07-6.23 (m, 3H), 4.77 (s, 1H), 4.58 (s, 1H), 4.30 (s, 1H), 3.52 (d, J=4.0 Hz, 4H), 3.10-3.01 (m, 2H), 2.32 (s, 3H), 2.14 (s, 2H), 2.09-1.39 (m, 10H).
[2231] MS m/z (ESI): 497.1 [M+H].sup.+.
Embodiment 289
1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-(methylamino)ethane-1-one
[2232] ##STR00760##
[2233] The preparation of 1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-(methylamino)ethane-1-one was carried out with the reference to Embodiment 247.
[2234] MS m/z (ESI): 441.2 [M+H].sup.+.
Embodiment 290
((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)(pyridin-2-yl)methanone
[2235] ##STR00761##
[2236] The preparation of ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)(pyridin-2-yl)methanone was carried out with the reference to Embodiment 288.
[2237] MS m/z (ESI): 475.2 [M+H].sup.+.
Embodiment 291
(1-methyl-1H-imidazol-2-yl)((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)methanone
[2238] ##STR00762##
[2239] The preparation of (1-methyl-1H-imidazol-2-yl)((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)methanone was carried out with the reference to Embodiment 288.
[2240] MS m/z (ESI): 478.2 [M+H].sup.+.
Embodiment 292
2-(dimethylamine)-1-((1R,3r,5S)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one
[2241] ##STR00763##
[2242] The preparation of 2-(dimethyl amine)-1-((1R,3r,5S)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)ethane-1-one was carried out with the reference to Embodiment 242.
[2243] MS m/z (ESI): 441.2 [M+H].sup.+.
Embodiment 293
N,N-dimethyl-2-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)acetamide
[2244] ##STR00764##
[2245] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (100 mg, 0.21 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then N,N-dimethylformamide (5 mL) was added to the mixture for dissolution. DIPEA (108 mg, 0.84 mmol) was slowly added dropwise into the mixture, and the mixture was then stirred under ice water bath for 10 minutes. 2-Bromine-N,N-dimethylacetamide (38 mg, 0.23 mmol) were added thereto and the mixture was stirred for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (16.4 mg, 17%).
[2246] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.05 (s, 1H), 9.74 (s, 1H), 7.90 (d, J=4.0 Hz, 1H), 7.14-6.30 (m, 3H), 4.15 (s, 1H), 3.32-3.23 (m, 4H), 3.08 (s, 3H), 2.83 (s, 3H), 2.22 (s, 3H), 1.97 (s, 2H), 1.82-1.55 (m, 6H).
[2247] MS m/z (ESI): 441.1 [M+H].sup.+.
Embodiment 294
3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methylthieno[3,2-d pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[2248] ##STR00765##
Step 1: preparation of (3-((2-chloro-6-methylthieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol
[2249] ##STR00766##
[2250] 2,4-Dichloro-6-methylthieno[3,2-d]pyrimidine (200 mg, 0.91 mmol), (3-amino-1H-pyrazol-5-yl)methanol (120 mg, 1.09 mmol) and DIPEA (350 mg, 2.73 mmol) was dissolved in N,N-dimethylformamide (10 mL). The mixture was mixed evenly and the reaction was carried out at 70° C. overnight. Then the mixture was cooled to room temperature, and successively extracted with water (30 mL) and ethyl acetate (20 mL*3). The organic phases were combined, and concentrated under reduced pressure. The crude product obtained was purified by flash silica gel chromatography to obtain the title compound as a white solid (200 mg, 75%).
[2251] MS m/z (ESI): 296.0 [M+H].sup.+.
Step 2: preparation of Tert-butyl (3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methylthieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate
[2252] ##STR00767##
[2253] (3-((2-Chloro-6-methylthieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol (150 mg, 0.51 mmol), Tert-butyl (3-exo)-3-amino-9-azabicyclo[3.3.1]non-9-carboxylate oxalate(200 mg, 0.61 mmol) and DIPEA (200 mg, 1.53 mmol) were added to n-butanol (3 mL). The mixture was mixed evenly, and the reaction was carried out at 165° C. for 8 hour. The mixture was then cooled to room temperature, and concentrated under reduced pressure. The crude product obtained (200 mg) was used directly in the next step without purification.
[2254] MS m/z (ESI): 500.1 [M+H].sup.+.
Step 3: preparation of (3-((2-(((3-exo)-9-azabicyclo[3.3.1]non-3-yl)amino)-6-methylthieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol
[2255] ##STR00768##
[2256] Hydrochloride dioxane (4N, 5 mL) was slowly added dropwise to the solution of Tert-butyl (3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methylthieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-carboxylate (200 mg, 0.40 mmol) in methanol (10 mL). The reaction was carried out at room temperature for 3 hours, and then the mixture was concentrated under reduced pressure. The crude product obtained was purified by prep-HPLC to obtain the title compound as a yellow solid (100 mg, 63%).
[2257] MS m/z (ESI): 400.1 [M+H].sup.+.
Step 4: 3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methylthieno[3,2-d pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)propionitrile
[2258] ##STR00769##
[2259] (3-((2-(((3-exo)-9-Azabicyclo[3.3.1]non-3-yl)amino)-6-methylthieno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol (100 mg, 0.25 mmol), acrylonitrile (0.2 mL) and DIPEA (0.1 mL) were added to methanol (10 mL). The mixture was mixed evenly, and the reaction was carried out at room temperature for 1 hour. The mixture was then concentrated under reduced pressure, and the crude product obtained was purified by prep-HPLC to obtain the title compound as a white solid (11.7 mg, 10%).
[2260] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.28 (s, 1H), 10.12 (s, 1H), 7.09-6.64 (m, 2H), 6.29-6.23 (s, 1H), 5.22-4.94 (m, 1H), 4.67-4.37 (m, 3H), 2.95 (s, 2H), 2.85-2.81 (m, 2H), 2.70-2.57 (m, 5H), 1.95-1.49 (m, 10H).
[2261] MS m/z (ESI): 453.2 [M+H].sup.+.
Embodiment 295
3-((3-exo)-3-((1-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[2262] ##STR00770##
Step 1: preparation of 6-chloro-1-methyl-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
[2263] ##STR00771##
[2264] 3-Amino-5-methylpyrazol (117 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) were successively added to the solution of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (203 mg, 1 mmol) in ethanol (10 mL). The mixture was then stirred at 60° C. for 1 hour. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=98:2) to obtain the title compound as a yellow solid (250 mg, 95%).
[2265] MS m/z (ESI): 264.0 [M+H].sup.+.
Step 2: preparation of tert-butyl-(3-exo)-3-((1-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate
[2266] ##STR00772##
[2267] Tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]oct-8-carboxylate (170 mg, 0.75 mmol) and DIPEA (129 mg, 1 mmol) were successively added to the solution of 6-chloro-1-methyl-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (132 mg, 0.5 mmol) in n-butanol (5 mL), then the mixture was stirred at 160° C. under microwave condition for 15 hours. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound as a white solid (165 mg, 73%).
[2268] MS m/z (ESI): 454.2 [M+H].sup.+.
Step 3: preparation of 3-((3-exo)-3-((1-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-yl)propionitrile
[2269] ##STR00773##
[2270] Tert-butyl-(3-exo)-3-((1-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-8-azabicyclo[3.2.1]oct-8-carboxylate (165 mg, 0.36 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then methanol (10 mL) was added to the mixture for dissolution. DIPEA (186 mg, 1.44 mmol) was slowly added dropwise into the mixture, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (29 mg, 0.55 mmol) was added thereto and the mixture was stirred for another 2 hours. When the reaction was completed, the reaction mixture was concentrated under reduced pressure, then purified by prep-HPLC to obtain the title compound as a white solid (60.4 mg, 41%).
[2271] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=11.96 (s, 1H), 10.04 (s, 1H), 7.99 (s, 1H), 6.64 (s, 2H), 4.18 (s, 1H), 3.63 (d, J=20.4 Hz, 3H), 3.22 (s, 2H), 2.55 (s, 4H), 2.17 (s, 3H), 1.84 (s, 2H), 1.73-1.48 (m, 6H).
[2272] MS m/z (ESI): 407.2 [M+H].sup.+.
Embodiment 296
[2273] 1-((3-exo)-3-((1-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-morpholinoethane-1-one
##STR00774##
[2274] The preparation of 1-((3-exo)-3-((1-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)-2-morpholinoethane-1-one was carried out with the reference to Embodiment 246.
[2275] MS m/z (ESI): 495.2 [M+H].sup.+.
Embodiment 297
((3-exo)-3-((1-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)(pyridin-2-yl)methanone
[2276] ##STR00775##
[2277] The preparation of ((3-exo)-3-((1-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-9-azabicyclo[3.3.1]non-9-yl)(pyridin-2-yl)methanone was carried out with the reference to Embodiment 260.
[2278] MS m/z (ESI): 473.2 [M+H].sup.+.
Embodiment 298
3-(cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile
[2279] ##STR00776##
Step 1: preparation of tert-butyl cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate
[2280] ##STR00777##
[2281] 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.376 mmol), tert-butyl cis-5-aminohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate (102 mg, 0.452 mmol) and DIPEA (146 mg, 1.13 mmol) were successively added to NMP (1 mL). Under nitrogen atmosphere, the mixture was heated to 160° C. by microwave and reacted for 8 hours. The reaction mixture was cooled to room temperature, then poured into ice water (10 mL), stirred for 10 minutes, and filtered. The filter cake was washed with water (15 mL) and dried under vacuum to obtain the title compound as a yellow solid (171 mg, the crude product).
Step 2: preparation of 3-(cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile
[2282] ##STR00778##
[2283] Tert-butylcis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate (86 mg, 0.188 mmol) was dissolved in methanol (2 mL). The mixture was stirred at room temperature and 4M HCl in 1,4-dioxane (2 mL) was added thereto. The reaction mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (2 mL), and DIPEA (121 mg, 0.938 mmol) and acrylonitrile (15 mg, 0.282 mmol) were successively added thereto. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (20 mL), and washed with water (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound as a white solid (17 mg, 22%).
[2284] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.36 (d, J=6.0 Hz, 1H), 7.02-6.86 (m, 1H), 6.54 (s, 0.6H), 5.80 (s, 0.4H), 4.34-4.09 (m, 1H), 2.86-2.72 (m, 4H), 2.73-2.57 (m, 4H), 2.40-2.19 (m, 7H), 1.57-1.37 (m, 2H).
[2285] MS m/z (ESI): 409.1[M+H].sup.+.
Embodiment 299
3-(cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile
[2286] ##STR00779##
Step 1: preparation of tert-butyl-cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate
[2287] ##STR00780##
[2288] Tert-butyl-cis-5-aminohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate (102 mg, 0.45 mmol) and DIPEA (98 mg, 0.76 mmol) were successively added to the solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine (100 mg, 0.38 mmol) in n-butanol (5 mL). The mixture was then stirred at 160° C. under microwave condition for 15 hours. When the reaction was completed, the reaction mixture was extracted with ethyl acetate (15 mL×3), and washed with saturated sodium chloride aqueous solution (15 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound as a pale yellow solid (80 mg, 46%).
[2289] MS m/z (ESI): 456.2 [M+H].sup.+.
Step 2: preparation of 3-(cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile
[2290] ##STR00781##
[2291] Tert-butyl-cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate (80 mg, 0.18 mmol) was dissolved in hydrochloride 1,4-dioxane solution (4.0 N, 2 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and then methanol (5 mL) was added to the mixture for dissolution. DIPEA (93 mg, 0.72 mmol) was slowly added dropwise into the mixture, and the mixture was stirred at room temperature for 10 minutes. Acrylonitrile (14 mg, 0.27 mmol) was added thereto and the mixture was stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to obtain the title compound as a white solid (26.3 mg, 37%).
[2292] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=12.30 (s, 1H), 9.92 (s, 1H), 7.90 (s, 1H), 7.51-6.25 (m, 3H), 4.11 (s, 1H), 2.66 (dd, J=13.6, 7.2 Hz, 6H), 2.22 (s, 8H), 1.31 (s, 3H).
[2293] MS m/z (ESI): 409.1 [M+H].sup.+.
Embodiment 300
3-(cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile
[2294] ##STR00782##
[2295] The preparation of 3-(cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile was carried out with the reference to Embodiment 281.
[2296] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.14 (s, 1H), 10.16 (s, 1H), 8.29 (s, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.32 (d, J=8.2 Hz, 2H), 7.09 (t, J=7.2 Hz, 1H), 6.63 (s, 1H), 4.26-4.09 (m, 1H), 2.63 (dd, J=25.8, 13.5 Hz, 8H), 2.42-1.98 (m, 7H), 1.34 (dd, J=15.0, 9.5 Hz, 2H).
[2297] MS m/z (ESI): 403.2 [M+H].sup.+.
Embodiment 301
3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)propionitrile
[2298] ##STR00783##
Step 1: preparation of tert-butyl4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-carboxylate
[2299] ##STR00784##
[2300] 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine(100 mg, 0.376 mmol), 1-BOC-4-aminopiperidin (108 mg, 0.539 mmol) and DIPEA (146 mg, 1.13 mmol) were successively added to NMP (1 mL). Under nitrogen atmosphere, the mixture was then heated to 130° C. by microwave, and reacted for 16 hours. The reaction mixture was cooled to room temperature, then poured into ice water (10 mL), stirred for 10 minutes, and filtered. The filter cake was washed with water (5 mL), dried under vacuum to obtain the title compound as a yellow solid (100 mg, the crude product).
Step 2: preparation of 3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)propionitrile
[2301] ##STR00785##
[2302] (1-Tert-butyl 4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-carboxylate (100 mg, 0.233 mmol) was dissolved in methanol (2 mL). The mixture was stirred at room temperature for 4M HCl in ethyl acetate (2 mL) was added thereto. The mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (2 mL), and DIPEA (150 mg, 1.17 mmol) and acrylonitrile (62 mg, 1.17 mmol) were successively added thereto. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (20 mL), and washed with water (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound as a white solid (18 mg, 20%).
[2303] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.37 (d, J=6.0 Hz, 1H), 6.97 (d, J=6.1 Hz, 1H), 6.55 (s, 0.5H), 5.81 (s, 0.5H), 3.92-3.74 (m, 1H), 3.04-2.88 (m, 2H), 2.81-2.57 (m, 4H), 2.44-2.15 (m, 5H), 2.14-1.97 (m, 2H), 1.73-1.52 (m, 2H).
[2304] MS m/z (ESI): 383.1[M+H].sup.+.
Embodiment 302
1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)azetindin-3-formonitrile
[2305] ##STR00786##
[2306] The preparation of 1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 237.
[2307] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.38 (d, J=6.0 Hz, 1H), 6.99 (d, J=6.0 Hz, 1H), 6.49 (s, 0.5H), 5.83 (s, 0.5H), 4.20-4.10 (m, 2H), 4.07-3.99 (m, 2H), 3.99-3.89 (m, 1H), 3.77-3.61 (m, 3H), 3.09-2.99 (m, 2H), 2.28 (s, 3H), 2.17-2.06 (m, 2H), 1.67-1.51 (m, 2H). MS m/z (ESI): 474.0[M+H].sup.+.
Embodiment 303
1-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-(methylamino)ethane-1-one
[2308] ##STR00787##
[2309] The preparation of 1-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-(methylamino)ethane-1-one was carried out with the reference to Embodiment 247.
[2310] MS m/z (ESI): 401.2 [M+H].sup.+.
Embodiment 304
1-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-morpholinoethane-1-one
[2311] ##STR00788##
[2312] The preparation of 1-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-morpholinoethane-1-one was carried out with the reference to Embodiment 246.
[2313] MS m/z (ESI): 457.2 [M+H].sup.+.
Embodiment 305
(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)(pyridin-2-yl)methanone
[2314] ##STR00789##
[2315] The preparation of (4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)(pyridin-2-yl)methanone was carried out with the reference to Embodiment 260.
[2316] MS m/z (ESI): 435.2 [M+H].sup.+.
Embodiment 306
3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)propionitrile
[2317] ##STR00790##
[2318] The preparation of 3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)propionitrile was carried out with the reference to Embodiment 60.
[2319] MS m/z (ESI): 383.2 [M+H].sup.+.
Embodiment 307
1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)azetindin-3-formonitrile
[2320] ##STR00791##
[2321] The preparation of 1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 60.
[2322] MS m/z (ESI): 474.1 [M+H].sup.+.
Embodiment 308
1-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-morpholinoethane-1-one
[2323] ##STR00792##
[2324] The preparation of 1-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-morpholinoethane-1-one was carried out with the reference to Embodiment 246.
[2325] MS m/z (ESI): 457.2 [M+H].sup.+.
Embodiment 309
(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)(pyridin-2-yl)methanone
[2326] ##STR00793##
[2327] The preparation of (4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)(pyridin-2-yl)methanone was carried out with the reference to Embodiment 260.
[2328] MS m/z (ESI): 435.2 [M+H].sup.+.
Embodiment 310
3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)piperidin-1-yl)propionitrile
[2329] ##STR00794##
[2330] The preparation of 3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)piperidin-1-yl)propionitrile was carried out with the reference to Embodiment 301.
[2331] .sup.1H NMR (400 MHz, CD.sub.3OD: CDCl.sub.3, v/v=1:1) δ 8.03 (d, J=8.1 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.44 (s, 1H), 7.20 (t, J=7.4 Hz, 1H), 6.63 (s, 1H), 5.92 (s, 1H), 4.01-3.87 (m, 1H), 2.98 (d, J=11.6 Hz, 2H), 2.77 (t, J=6.9 Hz, 2H), 2.64 (t, J=6.9 Hz, 2H), 2.45-2.22 (m, 5H), 2.19-2.07 (m, 2H), 1.65 (td, J=14.0, 3.4 Hz, 2H).
[2332] MS m/z (ESI): 377.1 [M+H].sup.+.
Embodiment 311
1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)piperidin-1-yl)sulfonyl)azetindin-3-formonitrile
[2333] ##STR00795##
[2334] The preparation of 1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)piperidin-1-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 213.
[2335] .sup.1H NMR (400 MHz, CD.sub.3OD: CDCl.sub.3, v/v=1:1) δ 8.04 (d, J=8.1 Hz, 1H), 7.65-7.59 (m, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 6.31 (s, 1H), 4.17 (t, J=8.3 Hz, 2H), 4.12-4.01 (m, 3H), 3.74 (d, J=12.7 Hz, 2H), 3.61 (ddd, J=15.1, 8.7, 6.4 Hz, 1H), 3.06 (t, J=11.3 Hz, 2H), 2.32 (s, 3H), 2.21-2.11 (m, 2H), 1.64 (td, J=13.6, 3.3 Hz, 2H).
[2336] MS m/z (ESI): 468.1 [M+H].sup.+.
Embodiment 312
3-(4-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)piperidin-1-yl)propionitrile
[2337] ##STR00796##
[2338] The preparation of 3-(4-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)piperidin-1-yl)propionitrile was carried out with the reference to Embodiment 111.
[2339] MS m/z (ESI): 377.2 [M+H].sup.+.
Embodiment 313
1-((4-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)piperidin-1-yl)sulfonyl)azetindin-3-formonitrile
[2340] ##STR00797##
[2341] The preparation of 1-((4-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)piperidin-1-yl)sulfonyl)azetindin-3-formonitrile was carried out with the reference to Embodiment 111.
[2342] MS m/z (ESI): 468.2 [M+H].sup.+.
Embodiment 314
3-(6-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-2-azaspiro[3.3]hept-2-yl)propionitrile
[2343] ##STR00798##
Step 1: preparation of tert-butyl6-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-2-azaspiro[3.3]hept-2-carboxylate
[2344] ##STR00799##
[2345] 5,7-Dichloro-1,6-diazanaphthalen (200 mg, 1.00 mmol), tert-butyl6-amino-2-azaspiro[3.3]hept-2-formate (256 mg, 1.21 mmol) and DIPEA (324 mg, 2.51 mmol) were successively added to NMP (2 mL), and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was cooled to room temperature, poured into ice water (20 mL), stirred for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride aqueous solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. The resulting product obtained was purified by silica gel chromatography to obtain the title compound as brown oil (340 mg, 91%).
Step 2: preparation of tert-butyl 6-((7-((1-(tert-butyl carbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-2-azaspiro[3.3]hept-2-carboxylate
[2346] ##STR00800##
[2347] Tert-butyl 6-((7-chloro-1,6-diazanaphthalen-5-yl)amino)-2-azaspiro[3.3]hept-2-carboxylate (100 mg, 0.267 mmol), 1-Boc-3-amino-5-methylpyrazol (79 mg, 0.400 mmol), cesium carbonate (174 mg, 0.534 mmol), XPhos Pd G2 (105 mg, 0.134 mmol) and XPhos(127 mg, 0.267 mmol) were successively added to dioxane (5 mL). The mixture was filled with nitrogen for 3 times, and then stirred at 100° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and filtered with diatomaceous earth. The filtrate was successively washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product obtained was purified by silica gel chromatography to obtain the title compound as a yellow oil (44 mg, the crude product).
Step 3: preparation of 3-(6-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-2-azaspiro[3.3]hept-2-yl)propionitrile
[2348] ##STR00801##
[2349] Tert-butyl 6-((7-((1-(tert-butyl carbonyl)-5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-2-azaspiro[3.3]hept-2-carboxylate (66 mg, the crude product) was dissolved in methanol (2 mL). The mixture was stirred at room temperature and 4M HCl in 1,4-dioxane (2 mL) was added thereto. The mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (1 mL), and DIPEA (48 mg, 0.370 mmol) and acrylonitrile (10 mg, 0.185 mmol) were successively added thereto. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was successively purified by silica gel chromatography and prep-HPLC to obtain the title compound as a yellow solid (6 mg, 12%).
[2350] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.55 (s, 1H), 8.38 (d, J=8.2 Hz, 1H), 7.16-6.98 (m, 1H), 6.64 (s, 0.4H), 6.11 (s, 0.6H), 4.61-4.37 (m, 1H), 3.56-3.46 (m, 2H), 3.37-3.32 (m, 2H), 2.83-2.63 (m, 4H), 2.55-2.44 (m, 2H), 2.39-2.16 (m, 5H).
[2351] MS m/z (ESI): 389.2 [M+H].sup.+.
Embodiment 315
N5-((3-exo)-8-((1H-pyrazol-4-yl)sulfonyl)-8-azabicyclo[3.2.1]oct-3-yl)-N7-(5-methyl-1H-pyrazol-3-yl)-1,6-diazanaphthalen-5,7-diamine
[2352] ##STR00802##
[2353] The preparation of N5-((3-exo)-8-((1H-pyrazol-4-yl)sulfonyl)-8-azabicyclo[3.2.1]oct-3-yl)-N7-((5-methyl-1H-pyrazol-3-yl)-1,6-diazanaphthalen-5,7-diamine was carried out with the reference to Embodiment 111.
[2354] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=9.03 (s, 1H), 8.78 (s, 1H), 8.59 (d, J=2.8 Hz, 1H), 8.49 (s, 2H), 8.37 (d, J=8.4 Hz, 1H), 8.32 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.98 (dd, J=8.4, 4.0 Hz, 1H), 6.69 (s, 1H), 6.05 (s, 1H), 4.62 (s, 1H), 4.35 (s, 2H), 2.16 (s, 3H), 2.10-2.02 (m, 2H), 1.78-1.73 (m, 4H), 1.41-1.32 (m, 2H).
[2355] MS m/z (ESI): 480.2 [M+H].sup.+.
Embodiment 316
3-(endo-6-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-3-azabicyclo[3.1.0]hex-3-yl)propionitrile
[2356] ##STR00803##
[2357] The preparation of 3-(endo-6-((7-((5-methyl-1H-pyrazol-3-yl)amino)-1,6-diazanaphthalen-5-yl)amino)-3-azabicyclo[3.1.0]hex-3-yl)propionitrile was carried out with the reference to Embodiment 111.
[2358] MS m/z (ESI): 375.2 [M+H].sup.+.
Embodiment 317
3-(endo-6-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-3-azabicyclo[3.1.0]hex-3-yl)propionitrile
[2359] ##STR00804##
[2360] The preparation of 3-(endo-6-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-3-azabicyclo[3.1.0]hex-3-yl)propionitrile was carried out with the reference to Embodiment 62.
[2361] MS m/z (ESI): 381.2 [M+H].sup.+.
Embodiment 318
3-(endo-6-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-3-azabicyclo[3.1.0]hex-3-yl)propionitrile
[2362] ##STR00805##
[2363] The preparation of 3-(endo-6-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-3-azabicyclo[3.1.0]hex-3-yl)propionitrile was carried out with the reference to Embodiment 60.
[2364] MS m/z (ESI): 381.2 [M+H].sup.+.
Embodiment 319
3-(endo-6-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-3-azabicyclo[3.1.0]hex-3-yl)propionitrile
[2365] ##STR00806##
[2366] The preparation of 3-(endo-6-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-3-azabicyclo[3.1.0]hex-3-yl)propionitrile was carried out with the reference to Embodiment 4.
[2367] MS m/z (ESI): 375.2 [M+H].sup.+.
Biological Test Evaluation
[2368] The present disclosure is further described and explained in combination with the following test embodiments, but these embodiments are not meant to limit the scope of the present disclosure.
Test Embodiment 1. Determination of the Inhibitory Effect of the Compound of the Present Disclosure on JAK Kinase Activity
[2369] Experimental objective: The objective of this test is to test the inhibitory effect of the compound on JAK kinase activity.
[2370] Experimental instrument: centrifuge (5702R) purchased from Eppendorf, pipette purchased from Eppendorf or Rainin, microplate reader purchased from American BioTek, the model of which was SynergyH1 full-function microplate reader.
[2371] Experimental method: the fluorescence resonance energy transfer (TR-FRET) method was used to test the inhibitory effect of the compound on JAK kinase activity, and the half inhibitory concentration IC.sub.50 of the compound on JAK kinase activity was obtained.
[2372] The specific experimental procedures are as follows:
[2373] Kinase reaction was carried out in a white 384-well plate (PerkinElmer). 1-5 μL of different concentrations of the compound diluted with DMSO and ddH.sub.2O was added into each well, and 1-5 μL of the corresponding solvent was added to the positive control wells, followed by addition of 0.1-20 nM JAK kinase solution diluted with 1-5 μL of kinase buffer (HEPES 50-250 mM, MgCl.sub.2 5-20 mM, etc.) was added to each well. 1-5 μL of kinase buffer was added to the negative control well. 1-5 μL of substrate mixture containing peptide substrate and ATP was added. The plate was incubated at room temperature for 0.5-5 hours. 104, EDTA and detection solution containing labeled antibody was added, and then the plate was incubated at room temperature for another 1-24 hours. The fluorescence signal value at about 620 nm and 665 nm of each well was measured by BioTek Synergy H1 plate reader, and the inhibition rate was calculated by the fluorescence signal value. According to the inhibition rate of different concentrations, the IC.sub.50 of the compound was obtained by curve fitting.
[2374] Experimental Data Processing Method:
[2375] The percentage inhibition data of the wells treated with the compound was calculated with the positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate {% inhibition rate=100-[(test compound value-negative control value)]/(Positive control value-negative control value)×100}. IC.sub.50 value was calculated by using GraphPad prism to fit the data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula.
[2376] Experimental Results:
[2377] According to the above scheme, the biological activities of the embodiment compounds of the present disclosure showed in the JAK1/2/3/TYK2 kinase activity test are as shown in Table 1.
TABLE-US-00001 TABLE 1 Embodiment JAK1, IC.sub.50 JAK2, IC.sub.50 JAK3, IC.sub.50 TYK2, IC.sub.50 No. (nM) (nM) (nM) (nM) 1 0.34 0.69 2.68 0.55 2 0.11 0.53 8.95 2.30 3 0.11 0.29 0.81 0.17 4 0.86 0.55 5.72 0.68 5 0.85 1.39 26.46 4.44 6 4.03 NA NA 10.71 9 30.65 NA NA >100 11 0.30 NA NA 9.13 12 2.71 NA NA 10.09 19 2.23 NA NA 40.70 25 1.63 NA NA 4.57 29 44.20 >100 >100 47.30 31 48.60 NA NA >100 35 5.60 NA NA 22.22 39 2.94 NA NA 9.49 40 0.83 0.77 8.78 1.01 51 0.24 NA NA 0.24 60 0.12 NA NA 0.46 62 0.08 NA NA 0.17 66 3.02 NA NA 1.49 72 4.32 NA NA 15.95 79 2.95 NA NA 5.77 87 35.10 NA NA >100 88 1.75 NA NA 3.53 89 0.65 NA NA 0.15 90 7.23 NA NA 21.61 109 7.85 6.27 25.85 33.89 111 5.69 NA NA 1.63 132 0.10 0.77 3.43 0.42 160 11.68 NA NA 6.15 161 20.81 NA NA 35.04 163 0.45 NA NA 24.41 164 0.85 NA NA 16.57 165 4.92 NA NA >100 166 0.19 NA NA 9.31 167 2.55 NA NA 7.28 169 0.63 1.07 28.84 0.50 170 0.66 NA NA 0.225 171 0.85 0.67 23.32 0.60 173 1.07 1.15 26.26 0.84 174 2.73 NA NA 1.88 175 >100 NA NA 42.82 176 4.18 NA NA 2.36 177 3.36 NA NA 1.58 178 10.60 NA NA >100 179 0.44 NA NA 0.47 180 0.35 NA NA 0.56 182 0.37 NA NA 0.25 183 0.18 NA NA 0.1 184 0.14 NA NA 0.48 185 0.29 NA NA 0.6 186 0.12 0.73 14.72 0.2 191 0.41 NA NA 0.94 203 0.23 NA NA 0.19 213 0.20 0.30 12.64 0.46 214 0.35 0.82 133.20 0.455 215 0.12 NA NA 0.27 216 0.04 NA NA 0.48 217 0.04 1.61 1.92 0.1 218 0.27 1.05 19.58 0.4 219 0.09 0.76 2.61 0.13 220 0.67 NA NA 4.27 221 0.79 NA NA 1.26 224 1.76 NA NA >100 225 9.16 NA NA 0.94 226 13.12 NA NA 0.3 227 5.17 NA NA 4.77 228 2.63 NA NA 9.99 231 11.33 NA NA 3.78 232 7.20 NA NA 2.00 233 3.55 NA NA 2.09 234 111.90 NA NA 7.11 235 3.33 NA NA 2.71 236 8.81 NA NA 4.77 237 0.07 0.79 3.62 0.32 238 0.03 0.44 0.71 0.12 239 0.13 1.25 3.11 0.22 240 0.49 NA NA 0.68 241 0.15 1.39 7.35 0.22 242 0.21 0.85 6.58 0.89 243 0.53 2.42 147.80 1.48 244 1.15 NA NA 2.45 245 2.77 NA NA 2.76 246 0.22 0.71 6.87 1.88 247 0.10 0.73 2.40 0.12 248 0.44 NA NA 0.36 249 1.88 NA NA 0.28 250 0.04 NA NA 0.07 255 1.17 NA NA 2.38 257 0.07 0.83 19.95 0.2 258 0.27 NA NA 0.61 260 0.19 0.36 3.83 0.225 261 0.04 NA NA 5.58 262 0.07 NA NA 1.35 263 0.11 NA NA 0.22 264 0.19 NA NA 0.48 265 1.29 1.81 170.10 1.00 266 10.51 NA NA 10.24 267 0.13 NA NA 0.39 268 0.21 NA NA 0.19 269 3.22 NA NA 3.08 270 1.22 NA NA 5.78 271 0.05 NA NA 4.91 272 0.60 NA NA 24.73 273 1.28 2.96 >200 2.19 277 0.61 1.01 8.26 0.58 278 0.71 1.34 7.05 0.98 279 0.24 NA NA 0.66 285 0.17 NA NA 0.51 286 0.06 NA NA 14.02 287 0.58 NA NA 4.21 288 0.27 NA NA 8.09 293 3.97 NA NA 10.83 294 0.64 NA NA 0.23 295 0.30 NA NA 10.83 298 0.67 NA NA 22.81 299 0.28 NA NA 0.56 300 5.11 NA NA 14.73 301 1.64 NA NA 0.45 302 1.89 NA NA 0.34 310 8.67 NA NA 0.26 311 7.50 NA NA 1.44 315 13.10 NA NA >100
[2378] It can be seen from the above table that the compounds of the above embodiments can significantly inhibit the enzymatic activity of JAK1/2/3/TYK2 kinase, and some compounds have a strong inhibitory effect on JAK1/2/3/TYK2 kinase (NA refers to not being tested).
Test Embodiment 2. Determination of the Inhibitory Effect of the Compound of the Present Disclosure on the Cellular JAK-STAT Signal Pathway
[2379] Experimental Objective:
[2380] The objective of the test is to test the inhibitory activity of the compound on the cellular JAK-STAT signaling pathway.
[2381] Experimental Instrument:
[2382] Microplate shaker (88880024) purchased from Thermo Scientific™
[2383] Centrifuge (5702R) purchased from Eppendorf
[2384] Pipette purchased from Eppendorf
[2385] Microplate reader purchased from BioTek, the model of which was SynergyH1 full-function microplate reader.
[2386] Experimental Method:
[2387] U266 cell line was used in this experiment, by activating the JAK-STAT signaling pathway through INF-a stimulation, the inhibitory activity of the compound on its downstream STAT3 phosphorylation was detected, and the half inhibitory concentration IC.sub.50 of the compound on the JAK-STAT signaling pathway activity was obtained.
[2388] The specific experimental procedures are as follows:
[2389] 3-12 μL of U266 cell line was spread into the 384-well detection plate, and the number of cells in each well was 100-300 K, followed by addition of 2 μL of the compound solution serially diluted. The plate was incubated for 2 hours with shaking at 350 rpm at room temperature. After 2 hours, 2 μL of INF-a with a final concentration of 1000 U/mL was added. The plate was shaken at room temperature for 15 minutes. 2-5 μL (5×) LANCE Ultra Lysis Buffer 2 solution was added and the plate was shaken at room temperature for 2 hours. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 0.5 nM and LANCE Ultra ULight-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 5 nM were added, and the plate was incubated overnight at room temperature. The fluorescence signal value at 665 nm of each well was measured with the microplate reader, and the inhibition rate was calculated from the fluorescence signal value. According to the inhibition rate of different concentrations, the IC.sub.50 of the compound was obtained by curve fitting.
[2390] Experimental Data Processing Method:
[2391] The percentage inhibition data of the wells treated with the compound was calculated with the positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate {% inhibition rate=100-[(test compound value-negative control value)]/(Positive control value-negative control value)×100}. IC.sub.50 value was calculated by using GraphPad prism to fit the data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula.
[2392] Experimental Results:
[2393] According to the above scheme, the biological activities of the embodiment compounds of the present disclosure showed in JAK-STAT signal pathway of U266 cells are as shown in Table 2.
TABLE-US-00002 TABLE 2 Embodiment U266 IC.sub.50 (nM) Embodiment 1 0.15 Embodiment 3 4.50 Embodiment 4 2.60 Embodiment 5 4.12 Embodiment 11 4.77 Embodiment 40 17.44 Embodiment 60 2.90 Embodiment 62 1.90 Embodiment 66 4.06 Embodiment 72 5.39 Embodiment 88 3.10 Embodiment 111 2.93 Embodiment 132 23.8 Embodiment 163 52.6 Embodiment 166 26.7 Embodiment 167 14.80 Embodiment 169 9.32 Embodiment 170 3.35 Embodiment 171 0.85 Embodiment 174 0.42 Embodiment 179 9.84 Embodiment 191 2.80 Embodiment 213 11.05 Embodiment 214 17.70 Embodiment 215 24.10 Embodiment 217 36.70 Embodiment 218 61.50 Embodiment 219 117.00 Embodiment 220 10.17 Embodiment 235 44.4 Embodiment 237 0.56 Embodiment 238 1.15 Embodiment 239 39.00 Embodiment 240 14.4 Embodiment 241 115.00 Embodiment 242 0.24 Embodiment 243 0.24 Embodiment 244 3.79 Embodiment 245 16.7 Embodiment 246 1.00 Embodiment 247 2.27 Embodiment 248 43.50 Embodiment 250 7.30 Embodiment 255 8.67 Embodiment 257 1.45 Embodiment 258 32.70 Embodiment 260 1.10 Embodiment 261 10.64 Embodiment 262 9.47 Embodiment 263 4.07 Embodiment 264 33.47 Embodiment 265 20.4 Embodiment 267 18.00 Embodiment 268 42.90 Embodiment 270 14.30 Embodiment 271 1.49 Embodiment 272 15.30 Embodiment 273 41.90 Embodiment 277 0.49 Embodiment 278 0.29 Embodiment 279 2.20 Embodiment 285 42.03 Embodiment 287 10.50 Embodiment 288 4.03 Embodiment 293 16.50 Embodiment 294 15.30 Embodiment 295 3.63 Embodiment 298 1.86 Embodiment 299 2.46 Embodiment 301 1.26 Embodiment 310 5.41
[2394] It can be seen from the above table that the compounds of the above embodiments have a significant inhibitory effect on the JAK-STAT signal pathway activity of human myeloma cell U266.
Test Embodiment 3. Determination of Balb/C Mouse Pharmacokinetics
[2395] 1. Research Purpose:
[2396] Balb/C mouse was used as the test animal, the pharmacokinetic behavior in mice (plasma and colon, ileum tissue) was studied after oral administering the embodiment 1, embodiment 60, embodiment 169, embodiment 170, embodiment 171, embodiment 179, embodiment 191, embodiment 213, embodiment 214, embodiment 237, embodiment 238, embodiment 244, embodiment 246, embodiment 247, embodiment 257, embodiment 260, embodiment 262, embodiment 263, embodiment 267, embodiment 277, embodiment 278, embodiment 279, embodiment 288, embodiment 295, embodiment 299 and embodiment 301 at a dose of 5 mg/kg. After analyzing the drug concentration in the colon and ileum, the ratio of the drug concentration in the colon to that in ileum, and the ratio of the drug concentration in the colon to that in the plasma, the compounds with excellent PK were selected for further research.
[2397] 2. Test Scheme
[2398] 2.1 Test Drugs:
[2399] Embodiment 1, embodiment 60, embodiment 169, embodiment 170, embodiment 171, embodiment 179, embodiment 191, embodiment 213, embodiment 214, embodiment 237, embodiment 238, embodiment 244, embodiment 246, embodiment 247, embodiment 257, embodiment 260, embodiment 262, embodiment 263, embodiment 267, embodiment 277, embodiment 278, embodiment 279, embodiment 288, embodiment 295, embodiment 299 and embodiment 301 prepared in the present disclosure.
[2400] 2.2 Test Animals:
[2401] 12 Balb/C mice in each group, male, Shanghai Jiesjie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).
[2402] 2.3 Administration:
[2403] 12 Balb/C mice in each group, male; p.o. after one night fast; the dose was 5 mg/kg; the administration volume was 10 mL/kg.
[2404] 2.4 Sample Collection:
[2405] At 0, 0.5, 1, 2, 3, 5 and 7 hours before and after the administration, the mice were executed by CO.sub.2 and 0.2 mL of blood was collected from the heart, placed in an EDTA-K.sub.2 test tube, and centrifuged at 6000 rpm at 4° C. for 6 minutes to separate the plasma, which was then stored at −80° C. The ileum was taken close to the cecum end with a length of about 4-5 cm, and the colon was also taken close to the cecum end with a length of about 2-3 cm, weighed and placed in a 2 mL centrifuge tube, then stored at −80° C.
[2406] 2.5 Sample Processing:
[2407] 1) 40 uL of plasma sample was precipitated by adding 160 uL of acetonitrile, mixed and centrifuged at 3500×g for 5-20 minutes.
[2408] 2) 30 μL of plasma and intestinal homogenate sample were precipitated by adding 90 of acetonitrile containing internal standard (100 ng/mL), mixed and centrifuged at 13000 rpm for 8 minutes.
[2409] 3) 70 μL of the supernatant solution after treatment was collected and 70 μL of water was added thereto, vortexed and mixed for 10 minutes, and then 20 μL was collected to analyze the concentration of the test compound by LC/MS/MS. LC/MS/MS analysis instrument: AB Sciex API 4000 Qtrap.
[2410] 2.6 Liquid Phase Analysis
[2411] Liquid phase conditions: Shimadzu LC-20AD Pump
[2412] Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1 mm, 3.5 μm) mobile phase: 0.1% formic acid aqueous solution as A solution, acetonitrile as B solution
[2413] Flow rate: 0.4 mL/min
[2414] Elution time: 0-4.0 minutes, the eluent is as follows:
TABLE-US-00003 Time/min A solution B solution 0.01 90% 10% 0.5 90% 10% 0.8 5% 95% 2.4 5% 95% 2.5 90% 10% 4.0 Stop
[2415] 3. Test Results and Analysis
[2416] The main pharmacokinetic parameters were calculated with WinNonlin 6.1, and the results of mouse pharmacokinetic experiments are shown in Table 3:
TABLE-US-00004 TABLE 3 Pharmacokinetic experiment (5 mg/kg) Half Mean Time Blood life detention to peak concentration Curve area Curve area period time Embodiment t.sub.max C.sub.max AUC.sub.0-t AUC.sub.0-∞ t.sub.1/2 MRT No. (h) (ng/mL) (ng/mL × h) (ng/mL × h) (h) (h) 1 blood 0.50 25.57 58.10 61.50 1.75 2.03 1 colon 3.00 2717.33 8322.33 NA NA 3.68 1 ileum 3.00 27066.67 90470.00 93698.05 1.08 2.84 60 blood 2.00 10.32 31.14 32.85 1.41 2.58 60 colon 5.00 2313.33 9131.17 NA NA 3.83 60 ileum 1.00 26133.33 97959.67 102735.06 1.26 2.49 169 blood 0.50 2.21 3.04 NA NA 1.08 169 colon 5.00 9010.00 23168.33 NA NA 2.29 169 ileum 1.00 23306.67 68927.27 NA NA 4.64 170 blood 7.00 15.98 36.70 NA NA 4.13 170 colon 3.00 4323.33 12952.50 NA NA 3.36 170 ileum 1.00 49935.33 118039.13 172293.32 5.48 2.19 171 blood 2.00 8.91 23.40 26.70 1.93 3.05 171 colon 3.00 438.00 2007.00 NA NA 4.24 171 ileum 3.00 17037.00 79777.00 NA NA 3.35 179 blood 0.50 3.80 6.76 NA NA 1.66 179 colon 1.00 484.97 2044.08 2182.71 1.49 2.83 179 ileum 3.00 2332.67 10335.83 NA NA 2.88 191 blood 1.00 0.81 NA NA NA NA 191 colon 5.00 3350.00 10573.00 NA NA 4.59 191 ileum 1.00 32600.00 51491.00 51747.00 1.39 1.13 213 blood 3.00 9.69 7.37 NA NA 2.66 213 colon 5.00 1752.00 4933.58 NA NA 4.92 213 ileum 5.00 321.43 1235.32 NA NA 4.26 214 blood 3.00 1.60 3.59 NA NA 1.82 214 colon 5.00 5593.33 19456.33 NA NA 4.4 214 ileum 1.00 24816.67 49326.83 49523.32 0.79 1.52 237 blood 2.00 7.12 11.03 NA NA 1.73 237 colon 3.00 2205.33 6459.08 7244.45 1.52 3.43 237 ileum 3.00 4136.67 15340.80 15361.95 0.55 2.43 238 blood 1.00 12.67 19.65 NA NA 1.47 238 colon 3.00 1315.00 5270.95 7376.51 2.89 4.16 238 ileum 1.00 20960.00 36588.13 36609.48 0.58 1.29 244 blood 3.00 12.00 18.01 NA NA 2.12 244 colon 7.00 1190.00 4902.83 NA NA 4.38 244 ileum 1.00 9012.85 22556.48 22618.33 0.66 1.83 246 blood 2.00 5.56 4.76 NA NA 1.46 246 colon 7.00 3256.67 13768.65 NA NA 4.79 246 ileum 1.00 16766.67 27918.73 28435.59 1.81 1.28 247 blood NA NA NA NA NA NA 247 colon 3.00 2274.33 10215.63 NA NA 4.05 247 ileum 1.00 13766.67 24740.60 24856.41 0.92 1.39 257 blood 1.00 33.92 64.70 64.80 1.22 2.18 257 colon 5.00 3993.33 12295.93 NA NA 4.24 257 ileum 3.00 25833.33 104414.82 122516.16 1.98 3.07 260 blood 1.00 24.00 27.26 29.38 1.57 1.37 260 colon 3.00 8876.67 24424.50 NA NA 3.39 260 ileum 1.00 9083.33 18455.27 18667.76 1.01 1.57 262 blood 2.00 8.01 13.42 NA NA 1.77 262 colon 3.00 1236.67 3942.77 4522.81 1.69 3.72 262 ileum 1.00 22335.00 40246.99 40255.23 0.49 1.34 263 blood 3.00 12.74 57.62 NA NA 3.51 263 colon 3.00 5540.00 15486.72 NA NA 3.58 263 ileum 1.00 5490.00 9908.63 9939.86 0.82 1.36 267 blood NA NA NA NA NA NA 267 colon 5.00 1267.00 5609.00 NA NA 4.40 267 ileum 1.00 12170.00 20694.00 20698.00 0.53 1.24 277 blood 2.00 11.96 29.12 31.05 0.96 2.53 277 colon 7.00 649.00 2891.73 NA NA 3.89 277 ileum 1.00 18736.67 42963.67 43348.57 0.92 1.77 278 blood 0.50 1.79 3.62 NA NA 1.50 278 colon 5.00 1297.67 4641.18 NA NA 4.26 278 ileum 1.00 3696.00 6243.00 6263.27 0.95 1.28 288 blood 2.00 11.03 21.50 24.50 2.60 2.5 288 colon 3.00 676.33 2899.00 NA NA 3.91 288 ileum 3.00 7376.67 17648.00 NA NA 2.89 295 blood 2.00 6.54 10.36 NA NA 1.77 295 colon 3.00 1028.00 3394.72 NA NA 3.82 295 ileum 3.00 4302.33 10688.77 NA NA 2.69 299 blood 0.50 6.01 10.59 17.81 3.76 1.92 299 colon 7.00 295.00 948.28 NA NA 4.94 299 ileum 3.00 530.67 1323.01 1353.39 0.89 3.37 301 blood 1.00 69.43 142.73 145.22 1.07 1.65 301 colon 5.00 1497.00 4242.63 NA NA 4.74 301 ileum 1.00 21093.33 35291.01 35304.02 0.60 1.23
[2417] NA refers to none detected or not being tested (the detection limit of blood concentration was 1 ng/mL, when the C.sub.max in the blood test is NA, then NA in the blood test index refers to none detected; when the C.sub.max in the blood test is higher than the quantitative limit 1 ng/mL, then NA in the blood test index refers to not being tested; NA in the tissues (colon and ileum) refers to not being tested).
[2418] Experimental Results:
[2419] From the mouse pharmacokinetics (PK) experimental results in the table, it can be seen that the embodiment compounds of the present disclosure show good exposure levels in the colon and ileum. The area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (C.sub.max) all meet the screening criteria. The ratio of the drug concentration in colon to that in ileum and the ratio of the drug concentration in colon to that in plasma of the compounds are high, which shows good selectivity.
[2420] Test 4. In Vivo Efficacy Test Procedures and Results
[2421] 4.1 Experimental Objective:
[2422] To evaluate the drug efficacy of the embodiment compound on the C57BL/6 mouse colitis model induced by DSS (dextran sulfate sodium).
[2423] 4.2. Main Experimental Materials
[2424] 4.2.1 Instruments
[2425] 1. balance Mettler toledo AL104
[2426] 2. balance TP-602
[2427] 4.2.2 Reagents
[2428] 1. Dextran Sodium Sulfate (DSS): MP Biomedicals, LLC, Solon, Ohio, Item No.:160110
[2429] 2. Cyclosporine (CsA): Novartis, Switzerland, batch number: S0033A
[2430] 3. Sodium carboxymethyl cellulose: Sinopharm Chemical Reagent Co., Ltd.
[2431] 4. Twain 80: Sigma, Item No.: 8CBM 513V
[2432] 4.2.3 Experimental Animals
TABLE-US-00005 Animal species and strains: C57BL/6 Gender, age/weight: Female, 6-8 weeks old/18-20 grams supplier: Shanghai Slac Laboratory Animal CO. LTD
[2433] 4.3. Experimental Procedures
[2434] 4.3.1 Grouping
[2435] According to the weight of the animal, BioBook software was used to randomly group the animals on day −1 to ensure that the weight values of each group of animals were similar to reduce deviation, and the grouping and dosing regimen are shown in the following Table.
TABLE-US-00006 Grouping and dosing schedule Test Number Administra- Dosage Dosing Group compound of animals tion route mg/kg regimen 1 Blank .sup.a 10 p.o. N/A BID .sup.b, (Blank control Day 0-9 group) 2 Vehicle .sup.a 10 p.o. N/A BID, (Vehicle control Day 0-9 group) 3 Embodiment 10 p.o. 10 BID, compound .sup.a Day 0-9 .sup.a the vehicle was 0.5% CMC-Na + 1% Tween 80 .sup.b interval of 8 hours
[2436] 4.3.2 Experiment Process
[2437] 1. Formulation of the Reagent
[2438] Drinking water containing DSS: an appropriate amount of DSS powder was dissolved in the autoclaved drinking water to prepare a 2% DSS solution.
[2439] 2. Induction of Enteritis
[2440] On day −1, the animals were equally divided into 12 groups with 10 animals in each group. (Refer to Table 1 for specific grouping scheme)
[2441] From 9:00 on day 0 to 9:00 on day 6, the mice in groups 2 to 9 were given 2% DSS aqueous solution for 6 days (from day 0 to day 6), after which the mice were allowed to freely drink normal water for 3 days (from 9:00 on day 6 to before necropsy on day 9). The day of modeling was counted as day 0. The DSS aqueous solution was wrapped in tin foil to protect it from light. The DSS aqueous solution was replaced every 2 days.
[2442] The mice in group 1 are allowed to drink normal water freely for 9 days (from 9:00 on day 0 to before necropsy on day 9).
[2443] 3. Dosing
[2444] Refer to the above Table for specific dosage, route and time of administration.
[2445] 4.4 Measurement
[2446] 1) Body Weight
[2447] The recording frequency was once a day.
[2448] 2) Daily Disease Index (DAI)
[2449] The recording frequency was once a day, and 4 levels were rated according to the following standards:
[2450] Weight change (0: ≤1%; 1: 1-5%; 2: 5-10%; 3: 10-15%; 4: >15%);
[2451] Bloody stool (0: negative; 4: positive);
[2452] Stool score (0: normal; 2: loose stool; 4: diarrhea)
[2453] Daily Disease Index (DAI) was obtained by dividing the sum the scores of the above 3 parts by 3. DAI-time (day) curve based on the daily DAI score was plotted, and the peak area (AUC) under the curve was calculated. The reduction ratio of DAI AUC was calculated by comparing the administration group with the vehicle group, with a calculation formula of (DAI AUC.sub.administration group-DAI AUC.sub.vehicle)/DAI AUCVehicle×100%
[2454] 4.5. Experimental Results:
TABLE-US-00007 dosage reduction ratio of DAI Embodiment No. (mg/kg) AUC (%) Blank (Blank / / control group) Vehicle (Vehicle / / control group) 60 10 −20.75 62 10 −32.25 169 10 −34.31 170 10 −27.94 213 10 −24.45 214 10 −28.91 246 10 −38.64 247 10 −22.11 260 10 −23.38 278 10 −34.88
[2455] 4.6. Experimental Conclusion
[2456] In the C57BL/6 mouse colitis model induced by DSS, the above embodiment compounds can significantly reduce the daily disease index (DAI) and have obvious pharmacological effects.