Poly(ADP-ribose)glycohydrolase inhibitor and pharmaceutical use thereof

Abstract

The present invention relates to a poly(ADP-ribose)glycohydrolase inhibitor and the pharmaceutical use thereof. Particularly, the present invention relates to a compound as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as a poly(ADP-ribose)glycohydrolase (PARG) inhibitor. The compound and the pharmaceutical composition containing the compound can be used for treating and / or preventing diseases associated with PARG, such as cancer, wherein the definition of each group in general formula (I') is the same as that in the description.

Description

Poly ADP ribose hydrolase inhibitors and medical uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a new class of poly ADP ribose hydrolase (PARG) inhibitors, pharmaceutical compositions containing the same, methods of preparation, and uses thereof as PARG inhibitors for treating diseases associated with PARG activity. BACKGROUND

[0002] Cells can be damaged by various internal and external factors such as replication errors, ionizing radiation, chemotherapy drugs, ultraviolet light, smoking, etc. during normal metabolic processes. DNA damage repair mechanisms can protect the genome from damage. Uncontrolled and unregulated rapid proliferation of cancer cells leads to a higher incidence of DNA damage and DNA repair defects than normal cells, and also relies more on DNA damage repair mechanisms.

[0003] Poly ADP ribosylation is a post-translational modification of proteins, which is widely involved in important biological processes such as DNA damage repair, transcription regulation, chromatin protein remodeling, etc. and plays an important role in maintaining the stability of the genome. In the earliest process of single-stranded DNA repair, poly ADP-ribose polymerase (PARP) binds to the break and undergoes self-poly ADP-ribosylation, which in turn recruits other DNA repair proteins.

[0004] Poly ADP ribosylation is a transient process and is hydrolyzed by poly ADP ribose hydrolase (PARG). PARG, as the main poly ADP ribose hydrolase, plays a role in about 90% of poly ADP ribose in cells (Front Biosci, 2009, 14(5): 1619-1626). When PARP is poly ADP-ribosylated, its catalytic activity is reduced, and PARG helps to restore PARP to its active form (Mol Aspects Med, 2013, 34(6): 1217-1256).

[0005] PARG plays an important role in the damage repair cycle. Studies have shown that PARG can promote DNA double-strand break repair and single-strand break repair (Nucleic Acids Res. 2011, 39(12): 5045-56); PARG knockout can inhibit DNA single-strand break repair and reduce BRCA-2 deficient cell survival (Cell Cycle, 2012, 11(5): 990-997); in human lung, uterine, pancreatic cancer cells, knocking down or deleting PARG increases sensitivity to radiation and DNA damage agents (Biochem Biophys Res Commun, 2013, 441(4): 793-798; J Cell Sci, 2009, 122(Pt 12): 1990-2002; Biochem Biophys Res Commun, 2013, 435(1): 100-106). At the same time, some studies have shown that PARG inhibition can be effective on PARP inhibitor-resistant cells (Mol Cell Biol, 2007, 27(15): 5597-5605). Therefore, PARG inhibitors have great potential in the field of cancer treatment.

[0006] Currently, there is no PARG inhibitor on the market, and IDE161, DAT-2645, and ETX-19477 have entered clinical stage research, and a plurality of compounds are in preclinical research stage. SUMMARY

[0007] The present inventors have designed and synthesized a series of nitrogen-containing bicyclic compounds through painstaking research, and the research results show that the compounds have PARG inhibitory effect, and the compounds and pharmaceutical compositions containing the compounds can be used for treating and / or preventing diseases related to PARG activity, such as cancer, etc.

[0008] Therefore, the present application relates to a compound represented by general formula (I') or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0009] wherein:

[0010] R is selected from ring A, hydrogen or -NR 9 R 10 , ring A is optionally substituted with one or more groups selected from R 11

[0011] ring A is selected from a saturated or partially unsaturated monocyclic heterocyclyl, spirocyclic heterocyclyl, bridged cyclic heterocyclyl, fused cyclic heterocyclyl or heteroaryl;

[0012] ring B is selected from a heteroaryl;​

[0013] R 01 selected from hydrogen, alkyl, said alkyl being optionally substituted with a group selected from -OC(O)R 9 R 10 , -C(O)R 9 , -C(O)OR 9 R 10 ;

[0014] R 02 selected from or hydrogen;

[0015] R 1 selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl being optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0016] R 2 and R 3 are each independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl being optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or

[0017] R 2 and R 3 , together with the atom to which they are attached, form a cycloalkyl or heterocyclyl, said cycloalkyl or heterocyclyl being optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0018] each R 11 is independently selected from hydrogen, halogen, -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -C(O)NR 9 R 10 , -S(O) p R 9-S(O) p NR 9 R 10 -NHC(O)R 9 , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -NR 9 R 10 , nitro, hydroxy, thiol, carboxy, ester, oxo; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from deuterated, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from deuterated, halogen, -NR a R b , -OR a , nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0019] R 4 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from deuterated, halogen, -NR a R b , -OR c , nitro, cyano, oxo, hydroxy, thiol, carboxy, -C(O)R 9 , -C(O)OR 9 , ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from deuterated, halogen, -NR a R b , -OR c , nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl; or

[0020] R 4 and ring A, together with the atoms to which they are attached, further form a fused or bridged heterocyclic ring, said fused or bridged heterocyclic ring is optionally substituted with one or more groups selected from deuterated, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or

[0021] R 4 with ring A and R 11 together form a heterocycle, which is optionally substituted with one or more groups selected from deuterated, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0022] R 6 is selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, thiol, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterated, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0023] R 8 is selected from hydrogen, halogen, cyano, amino, nitro, hydroxy, thiol, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterated, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0024] R 9 and R 10 are each independently selected from hydrogen, halogen, hydroxy, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterated, halogen, -NR a R b , nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)NR a R b , -S(O) p R c , -NHC(O)R c , cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0025] Ra and R b each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,

[0026] R a and R b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl group, said nitrogen-containing heterocyclyl group being optionally substituted with one or more substituents selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0027] R c selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0028] p is 1 or 2;

[0029] n is 0, 1 or 2.

[0030] The present application also relates to a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0031] wherein:

[0032] ring A is selected from monocyclic heterocyclyl, spirocyclic heterocyclyl, bridged cyclic heterocyclyl or fused cyclic heterocyclyl;

[0033] ring B is selected from heteroaryl;

[0034] R 1selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0035] R 2 and R 3 are each independently selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or

[0036] R 2 and R 3 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, said cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0037] R 5 is selected from hydrogen, halogen, -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -C(O)NR 9 R 10 , -S(O) p R 9 , -S(O) p NR 9 R 10 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterium, halogen, -NR a R b , -OR a , nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0038] R4 selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; a R b c , nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl; 9 9 a R b , -OR c , nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl; or

[0039] R 4 and ring A, together with the atom to which they are attached, further form a fused or bridged heterocyclic ring, said fused or bridged heterocyclic ring is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or

[0040] R 4 and ring A, together with R 5 or R 9 form a heterocyclic ring, said heterocyclic ring is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0041] R 6 selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0042] each R 7 ​​​each independently selected from the group consisting of hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0043] R 8 selected from the group consisting of hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0044] R 9 and R 10 each independently selected from the group consisting of hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; c , -C(O)OR c , -OC(O)R c , -C(O)NR a R b , -S(O) p R c , cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0045] R a and R b each independently selected from the group consisting of hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0046] R a and Rb together with the nitrogen atom to which it is attached, form a nitrogen-containing heterocyclyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0047] R c selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0048] p is 1 or 2;

[0049] n is 0, 1 or 2.

[0050] In a particular embodiment, the compound according to the application of general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II-1) or (II-2), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0051] wherein ring A, ring B, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , n are as defined in general formula (I).

[0052] In a preferred embodiment, the compound according to the application of general formula (I), general formula (II-1), general formula (II-2), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 5-10 membered heteroaryl, preferably 5-6 membered heteroaryl, more preferably thiazolyl, imidazolyl, furanyl, thiophenyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, particularly preferably thiazolyl.

[0053] In another particular embodiment, the compound according to the application of general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (IIA-1) or (IIA-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0054] wherein ring A, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , n are as defined in general formula (I).

[0055] In another particular embodiment, the compound according to the application of general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (III-1) or (III-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0056] wherein A is selected from N and CH;

[0057] R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , n are as defined in general formula (I).

[0058] In another particular embodiment, the compound according to the application of general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (IV-1) or (IV-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0059] wherein,

[0060] A is selected from N and CH;

[0061] R 1 , R 4 , R 6 , R7 R 8 R 9 n is defined as in general formula (I).

[0062] In another preferred embodiment, the compound according to the application according to general formula (I’), general formula (I), general formula (II-1), general formula (II-2), general formula (IIA-1), general formula (IIA-2), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl; said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl is optionally substituted with one or more groups selected from hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy.

[0063] In another preferred embodiment, the compound according to the application according to general formula (I’), general formula (I), general formula (II-1), general formula (II-2), general formula (IIA-1), general formula (IIA-2), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy.

[0064] In another preferred embodiment, the compound according to the application according to general formula (I’), general formula (I), general formula (II-1), general formula (II-2), general formula (IIA-1), general formula (IIA-2), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from C 2-6 alkenyl and C2-6 alkynyl, said C 2-6 alkenyl and C 2-6 alkynyl is optionally substituted with C 1-6 alkyl.

[0065] In another preferred embodiment, the compound according to the present application according to Formula (I’), Formula (I), Formula (II-1), Formula (II-2), Formula (IIA-1), Formula (IIA-2), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 9 selected from C 1-6 alkyl, said C 1-6 alkyl is substituted with -OC(O)R c ; R c selected from C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with amino.

[0066] In another preferred embodiment, the compound according to the present application according to Formula (I’), Formula (I), Formula (II-1), Formula (II-2), Formula (IIA-1), Formula (IIA-2), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 9 selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl; said C 3-6 cycloalkyl, 4-6 membered heterocyclyl is optionally substituted with one or more groups selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy.

[0067] In another preferred embodiment, the compound according to the present application according to Formula (I’), Formula (I), Formula (II-1), Formula (II-2), Formula (IIA-1), Formula (IIA-2), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 9selected from the group consisting of deuterated, halogen, amino, cyano, oxo, hydroxyl, thiol, carboxyl, C 1-6 one or more groups of alkyl are substituted.

[0068] In another preferred embodiment, the compound according to the application according to Formula (I), Formula (II-1), Formula (II-2), Formula (IIA-1), Formula (IIA-2) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a 5-6 membered monocyclic heterocyclyl, 6-10 membered spirocyclic heterocyclyl, or 6-10 membered fused ring heterocyclyl, preferably piperazinyl, piperidinyl, tetrahydropyridinyl,

[0069] In another preferred embodiment, the compound according to the application according to Formula (I), Formula (II-1), Formula (II-2), Formula (IIA-1), Formula (IIA-2) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 forms a fused or bridged ring heterocycle with ring A and the atom to which it is attached, preferably the fused or bridged ring heterocycle is

[0070] In another preferred embodiment, the compound according to the application according to Formula (I), Formula (II-1), Formula (II-2), Formula (IIA-1), Formula (IIA-2) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 forms a fused or bridged ring heterocycle with ring A and the atom to which it is attached, preferably the fused or bridged ring heterocycle is 5 or R 9 together with ring A and R 1-6 together form a heterocycle, which is optionally substituted with one or more substituents selected from deuterated, halogen, amino, cyano, oxo, hydroxyl, thiol, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy;

[0071] the fused ring is preferably more preferably which is optionally further substituted with deuterated, halogen, amino, cyano, oxo, hydroxyl, thiol, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6One or more substituents of the haloalkoxy group are used for substitution.

[0072] In another specific embodiment, the compound represented by general formula (I') according to the present invention, or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (V-1) or formula (V-2), or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0073] in,

[0074] Z is either O or CH2;

[0075] Ring E is selected from saturated or partially unsaturated 5-8 member monocyclic heterocyclic groups, 7-12 member spirocyclic heterocyclic groups, 7-10 member bridged ring heterocyclic groups, 8-10 member fused ring heterocyclic groups or 5-10 member heteroaryl groups;

[0076] Each R 12 Each is independently selected from hydrogen, halogen, -C(O)R 9 -C(O)OR 9 -OC(O)R 9 -C(O)NR 9 R 10 -S(O) p R 9 -S(O) p NR 9 R 10 -NHC(O)R 9 Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, halogen, cyano, -NR 9 R 10 The groups are nitro, hydroxy, mercapto, carboxyl, ester, and oxo; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more groups selected from deuterated, halogenated, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more groups selected from deuterated, halogenated, and -NR. a R b -OR a Substitution with one or more groups of nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0077] m is 0, 1, or 2;

[0078] R 1 , R 4 , R 6 , R 8 , R 9 , R 10 , R a , R b , p is as defined in general formula (I’).

[0079] In another particular embodiment, the compound according to the present application of general formula (I’), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (VI-1) or (VI-2), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof,

[0080] wherein,

[0081] Z is O or CH2;

[0082] Y is selected from O, S, NH, or CH2;

[0083] s and t are each independently 0 or 1 ;

[0084] each R 12 is independently selected from hydrogen, -NHC(O)R 9 , C 1-6 alkyl, -NR 9 R 10 , hydroxyl, thiol, oxo, cyano; wherein said C 1-6 alkyl is optionally substituted with one or more groups selected from amino and hydroxyl; or

[0085] any two adjacent R 12 , together with the atoms to which they are attached, form a 4-6 membered heterocyclyl, 4-6 membered cycloalkyl, or 5-6 membered heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxyl, oxo, C 1-6 alkyl;

[0086] R 9 is selected from hydrogen or C 1-6 alkyl;

[0087] R 10 is selected from hydrogen or C 1-6 alkyl;

[0088] m is 0, 1, or 2;

[0089] R 1 , R 4 , R 6 , R 8 as defined in general formula (I’).

[0090] In a preferred embodiment, the compound according to the application as depicted in general formula (I’), general formula (V-1), general formula (V-2), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring E is selected from:

[0091] each R 12 is independently selected from hydrogen, -NHC(O)R 9 , C 1-6 alkyl, -NR 9 R 10 , hydroxy, thiol, oxo, cyano; wherein said C 1-6 alkyl is optionally substituted with one or more groups selected from amino and hydroxy;

[0092] R 9 is selected from hydrogen or C 1-6 alkyl;

[0093] R 10 is selected from hydrogen or C 1-6 alkyl;

[0094] m is 0, 1 or 2.

[0095] In another preferred embodiment, the compound according to the application as depicted in general formula (I’), general formula (I), general formula (II-1), general formula (II-2), general formula (IIA-1), general formula (IIA-2), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2), general formula (VI-1), general formula (VI-2), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl; said C 1-6 alkyl is optionally substituted with deuterium, halogen, hydroxy, -NR a R b , -OR c , C 3-6 cycloalkyl or 4-6 membered heterocyclyl;

[0096] Ra and R b each independently is selected from hydrogen, C 1-6 alkyl; or

[0097] R a and R b together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen containing heterocyclyl group, optionally substituted with one or more substituents selected from halogen, amino, cyano, oxo, hydroxyl, thiol, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl;

[0098] R c is selected from hydrogen, C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with phenyl.

[0099] In another preferred embodiment, the compound according to the application according to Formula (I’), Formula (I), Formula (II-1), Formula (II-2), Formula (IIA-1), Formula (IIA-2), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (V-1), Formula (V-2), Formula (VI-1), Formula (VI-2), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from 4-10 membered heterocyclyl, preferably 4-6 membered heterocyclyl; said heterocyclyl is optionally substituted with one or more groups selected from halogen, hydroxyl, -C(O)R 9 , -C(O)OR 9 , C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl is optionally substituted with one or more groups selected from deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl;

[0100] R 9 is selected from hydrogen and C 1-6 alkyl.

[0101] In another preferred embodiment, the compound according to the application according to Formula (II-1), Formula (II-2), Formula (IIA-1), Formula (IIA-2), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2) is in the form of a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and cyano.

[0102] In another preferred embodiment, the compound according to the application according to Formula (II-1), Formula (II-2), Formula (IIA-1), Formula (IIA-2), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2) is in the form of a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, and cyano.

[0103] In another preferred embodiment, the compound according to the application according to Formula (I’), Formula (I), Formula (II-1), Formula (II-2), Formula (IIA-1), Formula (IIA-2), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (V-1), Formula (V-2), Formula (VI-1), Formula (VI-2) is in the form of a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of C 1-6 alkyl, and cyano, wherein the C 1-6 alkyl is optionally substituted with one or more groups selected from deuterium, halogen, cyano, hydroxy, C 1-6 alkoxy.

[0104] In another preferred embodiment, the compound according to the application according to Formula (I’), Formula (I), Formula (II-1), Formula (II-2), Formula (IIA-1), Formula (IIA-2), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (V-1), Formula (V-2), Formula (VI-1), Formula (VI-2) is in the form of a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of C1-6 alkyl and C 1-6 haloalkyl, preferably C 1-6 haloalkyl.

[0105] In another preferred embodiment, the compound according to the application as depicted in the general formula (I’), general formula (I), general formula (II-1), general formula (II-2), general formula (IIA-1), general formula (IIA-2), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2), general formula (VI-1), general formula (VI-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from C 1-6 alkyl, n is 0, 1 or 2.

[0106] In another preferred embodiment, the compound according to the application as depicted in the general formula (I’), general formula (I), general formula (II-1), general formula (II-2), general formula (IIA-1), general formula (IIA-2), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2), general formula (VI-1), general formula (VI-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, preferably hydrogen.

[0107] In another preferred embodiment, the compound according to the application as depicted in the general formula (I’), general formula (I), general formula (II-1), general formula (II-2), general formula (IIA-1), general formula (IIA-2), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , n are each independently the corresponding group in the compounds of embodiments 1-22.

[0108] Exemplary compounds of the application include, but are not limited to, the compounds in the following table:

[0109] Exemplary compounds of the application also include, but are not limited to, the compounds in the following table:

[0110] or a pharmaceutically acceptable salt thereof.

[0111] The present application further provides a method for preparing a compound according to the present application of general formula (III-1) or a meso, rac-, enantiomeric, diastereomeric isomer or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0112] Compound A7 and compound A8 are reacted under basic conditions by substitution or palladium catalyzed coupling to give a compound of general formula (III-1);

[0113] wherein

[0114] X is halogen, preferably F or CI;

[0115] R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , n are defined as in general formula (III-1).

[0116] The present application further provides a method for preparing a compound according to the present application of general formula (III-2) or a meso, rac-, enantiomeric, diastereomeric isomer or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0117] Compound B7 and compound A8 are reacted under basic conditions by substitution or palladium catalyzed coupling to give a compound of general formula (III-2);

[0118] wherein

[0119] X is halogen, preferably F or CI;

[0120] R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , n are defined as in general formula (III-2).

[0121] The present application further provides a method for preparing a compound according to the present application of general formula (IV-1) or a meso, rac-, enantiomeric, diastereomeric isomer or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0122] Compound A7 and compound C8 are reacted under basic conditions by substitution reaction or palladium catalyzed coupling reaction to obtain a compound represented by general formula (IV-1);

[0123] wherein,

[0124] X is halogen, preferably F or CI;

[0125] R 1 , R 4 , R 6 , R 7 , R 8 , R 9 , n is as defined in general formula (IV-1).

[0126] The present application further provides a method for preparing a compound represented by general formula (IV-2) or its meso, rac, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to the present application, comprising the following steps:

[0127] Compound B7 and compound C8 are reacted under basic conditions by substitution reaction or palladium catalyzed coupling reaction to obtain a compound represented by general formula (IV-2);

[0128] wherein,

[0129] X is halogen, preferably F or CI;

[0130] R 1 , R 4 , R 6 , R 7 , R 8 , R 9 , n is as defined in general formula (IV-2).

[0131] Another aspect of the present application provides a pharmaceutical composition comprising a compound according to the present application or its tautomer, meso, rac, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0132] The present application further provides the use of a compound according to the present application or its tautomer, meso, rac, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a poly ADP ribose glycohydrolase (PARG) inhibitor.

[0133] The present application further provides the use of a compound according to the present application or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a medicament for the prevention and / or treatment of a disease associated with the activity of poly ADP ribose glycohydrolase (PARG).

[0134] The present application further provides a compound according to the present application or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use as a medicament.

[0135] The present application further provides a compound according to the present application or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use as a poly ADP ribose glycohydrolase (PARG) inhibitor.

[0136] The present application further provides a compound according to the present application or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the prevention and / or treatment of a disease associated with the activity of poly ADP ribose glycohydrolase (PARG).

[0137] The present application further provides a method of inhibiting the activity of poly ADP ribose glycohydrolase (PARG), comprising administering to a subject in need thereof an effective amount of a compound according to the present application or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0138] The present application further provides a method of preventing and / or treating a disease associated with the activity of poly ADP ribose glycohydrolase (PARG), comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound according to the present application or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0139] In a preferred embodiment of the present application, the disease associated with the activity of poly ADP ribose glycohydrolase (PARG) according to the present application is cancer, such as ovarian cancer, uterine serous carcinoma, breast cancer, prostate cancer, bladder cancer, pancreatic cancer, gastric cancer, colorectal cancer, and the like.

[0140] The compounds of the present application can form pharmaceutically acceptable acid addition salts with acids in accordance with conventional methods in the art of pharmacy. Such acids include inorganic acids and organic acids, with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid and the like being particularly preferred.

[0141] The compounds of the present application can form pharmaceutically acceptable base addition salts with bases in accordance with conventional methods in the art of pharmacy. Such bases include inorganic bases and organic bases, with diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like being acceptable organic bases, and aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide and the like being acceptable inorganic bases.

[0142] The pharmaceutical compositions containing the active ingredient can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art of pharmacy. Such compositions can contain one or more ingredients selected from the following: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, cros Carmellose sodium, corn starch or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques in order to mask the unpleasant taste of the drug or delay the release of the drug in the gastrointestinal tract and thereby provide a sustained release of the drug. For example, a water soluble taste masking material such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate butyrate can be used.

[0143] Oral preparations can also be provided as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water soluble carrier such as polyethylene glycol or an oil such as peanut oil, liquid paraffin or olive oil.

[0144] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and gum tragacanth; dispersing or wetting agents, for example a naturally occurring phosphatide, for example soy lecithin, or an ester or partial ester of a fatty acid, for example polyoxyethylene sorbitan monooleate, or a condensation product of an alkylene oxide with a fatty acid, for example polyoxyethylene stearate, or a condensation product of an alkylene oxide with partial esters of fatty acids, for example polyoxyethylene sorbitan monooleate, or a condensation product of an alkylene oxide with partial esters of fatty acid anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0145] Oil suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, for example liquid paraffin. The oil suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, for example aspartame and flavoring agents, for example peppermint, methyl salicylate or orange flavoring, can be added to provide a palatable vehicle for the active ingredients. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0146] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition thereto of water can provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are as described above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0147] The pharmaceutical compositions of this application can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents can be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters of fatty acids, for example sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening, flavoring and preservative agents. Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose, and flavoring agents, for example peppermint, methyl salicylate or orange flavoring.

[0148] The pharmaceutical compositions of this application can be in the form of a sterile injectable aqueous or oleaginous suspension. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient can be dissolved in a mixture of soybean oil and lecithin. The oil solution then is treated with a high-speed homogenizer. The oil solution is then injected into a water and glycerol mixture to form the microemulsion. The injectable oil-in-water microemulsion can be injected intravenously, or can be injected into a muscle or subcutaneously. Alternatively, the solution or microemulsion can be administered in a manner so as to maintain a constant circulating concentration of the compound of this application. To maintain such a constant concentration, a continuous intravenous delivery device can be used.

[0149] The pharmaceutical compositions of this application can be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular and subcutaneous administration. This suspension can be formulated according to known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0150] The compounds of this application can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and other glycerides.

[0151] It is well within the skill of the art to determine the appropriate dosage of a drug depending on a variety of factors, including but not limited to the following: the activity of the particular compound employed, the age of the patient, the body weight of the patient, the health status of the patient, the sex of the patient, the diet of the patient, the time of administration, the route of administration, the rate of excretion, the combination of drugs employed, etc. In addition, the optimal mode of treatment, such as the mode of therapy, the daily amount of the compound of general formula or the kind of the pharmaceutically acceptable salt can be verified according to the conventional therapeutic regimen.

[0152] The present application can contain a compound represented by the general formula (I), and pharmaceutically acceptable salts, hydrates or solvates thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form. The derivatives of the present application can be used in combination with other active ingredients, provided that they do not produce other adverse effects, such as allergic reactions, etc. The compound of the present application can be used as the only active ingredient, or in combination with other drugs for treating diseases associated with poly ADP ribose glycohydrolase (PARG) activity. The combination therapy is achieved by administering each therapeutic component simultaneously, separately or sequentially.

[0153] Definitions of terms

[0154] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0155] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds described in the present application include their isotopes, i.e., the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds described in the present application are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, the isotopes of bromine include 79 Br and 81 Br.

[0156] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which are straight-chain or branched groups, preferably alkyl groups containing 1 to 12 carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms, alkyl groups containing 1 to 4 carbon atoms, or alkyl groups containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. Alkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, which can be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0157] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 alkylene). The alkylene preferably has 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably 1 to 6 carbon atoms (i.e., C 1-6 alkylene), further preferably 1 to 4 carbon atoms (i.e., C 1-6Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylidene (-CH(CH3)-), 1,2-ethylidene (-CH2CH2)-, 1,1- propylidene (-CH(CH2CH3)-), 1,2-propylidene (-CH2CH(CH3)-), 1,3-propylidene (- CH2CH2CH2-), and 1,4-butylidene (-CH2CH2CH2CH2-), and the like. Alkylene groups can be substituted or unsubstituted, and when substituted, can be substituted at any available point of attachment with one or more substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0158] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group containing 2 to 4 carbon atoms, such as ethenyl, 1 -propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituents can be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0159] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group containing 2 to 4 carbon atoms or preferably an alkynyl group containing 3 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, and the like. Alkynyl groups can be substituted or unsubstituted, and when substituted, the substituents can be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0160] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

[0161] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 members sharing one carbon atom (referred to as a spiro atom) between single rings, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified as a single-, bi- or polyspirocycloalkyl group, preferably a single- and bi-spirocycloalkyl group, depending on the number of spiro atoms shared between the rings. More preferably, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered single spirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0162] The term "fused ring alkyl" refers to a full carbon polycyclic group of 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, 6 to 14 members, more preferably 7 to 10 members. It can be classified as a bi-, tri-, tetra- or polycyclic fused ring alkyl group, preferably a bi- or tri-cyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bi-cyclic alkyl group, depending on the number of rings comprising the ring system. Non-limiting examples of fused ring alkyl groups include:

[0163] The term "bridged ring alkyl" refers to a full carbon polycyclic group of 5 to 20 members, in which any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, 6 to 14 members, more preferably 7 to 10 members. It can be classified as a bi-, tri-, tetra- or polycyclic bridged ring alkyl group, preferably a bi-, tri- or tetra-cyclic, more preferably a bi- or tri-cyclic, depending on the number of rings comprising the ring system. Non-limiting examples of bridged ring alkyl groups include:

[0164] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, in which the ring that is attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, tetrahydrobenzofuranyl, tetrahydrobenzoxazolyl, tetrahydrobenzisoxazolyl, cyclopentathienyl, tetrahydrobenzothiazolyl and the like. The cycloalkyl group can be optionally substituted or unsubstituted, when substituted, the substituents can be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0165] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, in which one or more ring atoms are selected from nitrogen, oxygen or S(O) mring members are carbon. Preferably, 4 to 12 ring atoms are present, of which 1 to 4 are heteroatoms; more preferably, 7 to 12 ring atoms are present, of which 1 to 4 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolinyl, imidazolinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably 1,2,5-oxadiazolyl, pyranyl, or morpholinyl. Polycyclic heterocyclyl groups include spiro, fused, and bridged ring heterocyclyl groups.

[0166] The term "spirocyclic heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members sharing one atom (referred to as a spiro atom) between single rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m ring atoms are carbon. They can contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably, 6 to 14 ring members are present, more preferably 7 to 12 ring members are present. Spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups depending on the number of spiro atoms shared between rings, preferably mono- and bispiroheterocyclyl groups. More preferably, 4 membered / 4 membered, 4 membered / 5 membered, 4 membered / 6 membered, 5 membered / 5 membered, or 5 membered / 6 membered monospiroheterocyclyl groups. Non-limiting examples of spiroheterocyclyl groups include:

[0167] The term "fused ring heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings can contain one or more double bonds, but no ring has a completely conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m ring atoms are carbon. Preferably, 6 to 14 ring members are present, more preferably 7 to 12 ring members are present. Fused heterocyclyl groups are classified as bi-, tri-, tetra-, or polycyclic fused heterocyclyl groups depending on the number of rings comprising the ring system, preferably bi- or tri-, more preferably 5 membered / 5 membered or 5 membered / 6 membered bicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups include:

[0168] The term "bridged ring heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, wherein any two rings share two non-adjacent atoms, which can contain one or more double bonds, but no ring has a completely conjugated pi-electlectron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) mheteroatoms, the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 12 membered. Depending on the number of rings comprising the ring, the bridged heterocyclyl group can be bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0169] The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl ring.

[0170] The heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituents can be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0171] The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0172] The aryl group can be substituted or unsubstituted, and when substituted, the substituents can be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0173] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 membered or 6 membered, containing 1 to 2 heteroatoms; preferably for example imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0174] Heteroaryl can be optionally substituted or unsubstituted, and when substituted, the substituents can be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0175] The term "alkoxy" refers to an -O-(alkyl) group, wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propyloxy, butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents can be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0176] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0177] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0178] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group, wherein alkyl is as defined above.

[0179] The term "hydroxyl" refers to an -OH group.

[0180] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0181] The term "amino" refers to -NH2.

[0182] The term "cyano" refers to -CN.

[0183] The term "nitro" refers to -NO2.

[0184] The term "oxo" refers to =O.

[0185] The term "carboxyl" refers to -C(O)OH.

[0186] The term "thiol" refers to -SH.

[0187] The term "ester" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0188] "Optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclic group optionally substituted with alkyl" means that alkyl can or can not be present, and the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

[0189] "Substituted" means that one or more hydrogen atoms, preferably up to five, more preferably one to three, of the group are independently of each other replaced with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions and can be determined (experimentally or theoretically) by a person skilled in the art without undue effort as to their possibility or impossibility. For example, an amino or hydroxy group with a free hydrogen can be unstable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0190] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism and to facilitate absorption of the active ingredient to thereby elicit the biological activity.

[0191] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" means a salt of a compound of the present application which is safe and effective for use in a mammal and possesses the desirable biological activity.

[0192] "Carrier" means a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. DETAILED DESCRIPTION

[0193] The compounds of the present application and their preparation are further understood by the examples, which illustrate some of the methods of making or using the compounds. It is to be understood, however, that these examples do not limit the scope of the application. Variations of the present application now known or further developed are considered to fall within the scope of the present application described and claimed herein.

[0194] The compounds of the present application are prepared using convenient starting materials and reagents under appropriate reaction conditions. Typical or envisioned reaction conditions, such as reaction temperatures, times, solvents, pressures, and molar ratios of reactants are described herein. However, unless otherwise specified, other reaction conditions can be employed. Optimized reaction conditions can vary depending on the particular reactants or solvents employed, but in general, reaction optimization procedures and conditions are determined.

[0195] In addition, protecting groups can be used in the present application to protect certain functional groups from unwanted reactions. Suitable protecting groups for a variety of functional groups and their protecting or deprotecting conditions are well known to those skilled in the art. For example, a large number of protecting groups and their protection or deprotection are described in detail in T. W. Greene and G. M. Wuts, Protective Groups in Organic Synthesis, 3rdedition, Wiley, New York, 1999 and references therein.

[0196] The isolation and purification of the compounds and intermediates are carried out by appropriate methods and steps according to the specific requirements, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer chromatography, preparative high performance liquid chromatography or a combination of the above methods. The specific methods of use can be found in the examples described in the present application. Of course, other similar isolation and purification means can also be used. They can be characterized using conventional methods (including physical constants and spectral data).

[0197] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift is given in units of 10 -6 (ppm). The NMR is measured by a Oxford NMR-I-400MHz nuclear magnetic resonance instrument, and the measuring solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0198] MS measurement uses a 1260 Infinity II 6125B single quadrupole liquid chromatograph-mass spectrometer (manufacturer: Agilent), the chromatographic column is kinetex XB-C18 100A 1.7μm (30×3mm) (manufacturer: Finnignt), the mobile phase is acetonitrile / water (0.1% FA). The preparative liquid chromatography uses a 1260 Infinity II preparative liquid chromatograph (manufacturer: Agilent), the chromatographic column is Xtimate C18 5μm (21.2×250mm) (manufacturer: Yantai Ocean Tech), the mobile phase is acetonitrile / water. Thin layer chromatography (TLC) uses Qingdao Haoyang Chemical GF254 silica gel plate, the silica gel plate used for reaction monitoring has a specification of 0.20mm-0.25mm, and the silica gel plate used for separation and purification has a specification of 0.5mm.

[0199] Silica gel column chromatography uses Qingdao Haoyang silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0200] The known starting materials of the present application can be synthesized by using or following the methods known in the art, or can be purchased from the commercial sources such as the internet, the exploration platform, the book city, the viewing net, the Beijing coupling, Sigma, Bailingwei, Yisheming, Shanghai Shuya, Shanghai Ino Kai, An'ajie Chemical, Shanghai Bede, Shanghai Le Yan, Nanjing Yushi, etc.

[0201] Unless otherwise specified, the reactions in the examples can be carried out under nitrogen atmosphere.

[0202] The argon atmosphere, nitrogen atmosphere or hydrogen atmosphere means that the reaction bottle is connected with an argon, nitrogen or hydrogen balloon with a volume of about 1 L.

[0203] The reaction solvent, organic solvent or inert solvent each means that the solvent used does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane (DCM), diethyl ether, methanol (MeOH), ethanol (EtOH), dimethyl sulfoxide (DMSO), 1,4-dioxane, N-methyl pyrrolidone (NMP), pyridine, water, etc. Unless otherwise specified in the examples, the solution means an aqueous solution.

[0204] The chemical reactions described in the present application are generally carried out under normal pressure. The reaction time and conditions are, for example, completed in about 1 to 24 hours at one atmosphere, between -78°C and 200°C. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.

[0205] The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), and the developing agent system used in the reaction includes: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: acetone, and the volume ratio of the solvents is adjusted according to the different polarity of the compounds.

[0206] The eluent system of column chromatography and the developing agent system of thin layer chromatography used for purifying the compounds include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and the volume ratio of the solvents is adjusted according to the different polarity of the compounds, or a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid can be added for adjustment.

[0207] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as familiar to those skilled in the art. In addition, any method and material similar or equivalent to those described can be applied to the method of the present application.

[0208] Example 1: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4- isobutyrylpiperazin-1-yl)-3-methoxy-N-(1-methylcyclopropyl)-1H-indazole-6- sulfonamide (1) and 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-hydroxy-4-(4- isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (2)

[0209] Step 1: Synthesis of 6-bromo-4-fluoro-1H-indazol-3-ol (1-2)

[0210] Methyl 4-bromo-2,6-difluorobenzoate (1-1, 12.0 g, 47.8 mmol), hydrazine hydrate (60%, 7.66 g, 143 mmol) were dissolved in ethanol (100 mL) at room temperature, and the reaction was carried out at 90 °C for 3 h, and then cooled to 30-50 °C. The solvent was removed by concentration, and THF (50 mL) and water (200 mL) were added, and the mixture was stirred for 2 h, and then filtered to obtain the white solid product 1-2 (10.0 g, 91% yield).

[0211] LC-MS (ESI+): 231, 233.0 m / z [M+H] + .

[0212] Step 2: Synthesis of isobutyl 6-bromo-4-fluoro-3-hydroxy-1H-indazole-1-carboxylate (1-3)

[0213] Compound 1-2 (11.2 g, 48.5 mmol) was added to a mixture of 80 mL of pyridine and 100 mL of water at room temperature, and isobutyl chloroformate (66.2 g, 485 mmol) was slowly added dropwise at 10 °C for 30 min, and then the mixture was stirred at 25-35 °C for 18 h. Solid was generated in the system, and the crude product was obtained by filtration. The solid was then stirred in 30 mL of acetic acid and 100 mL of water at room temperature for 4 h, and then filtered to obtain compound 1-3 (14.0 g, 87% yield).

[0214] LC-MS (ESI+): 331, 333 m / z [M+H] + .

[0215] Step 3: Synthesis of isobutyl 6-bromo-4-fluoro-3-methoxy-1H-indazole-1-carboxylate (1-4)

[0216] Compound 1-3 (8 g, 24.2 mmol), anhydrous methanol (1.55 g, 48.3 mmol), triphenylphosphine (10.1 g, 38.6 mmol) were dissolved in anhydrous THF (100 mL), DIAD (8.8 g, 43.5 mmol) was added within 5 min, and the reaction was allowed to proceed at room temperature for 1 h. THF was removed under reduced pressure, DCM (150 mL) was added to dissolve the product, and water (100 mL x 3) was used for washing. The crude product was concentrated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1). The system had an oxygen methyl product 1-4 (Rf = 0.8, PE / EA = 4:1) and a byproduct N-methyl product (Rf = 0.6, PE / EA = 4:1). Compound 1-4 (4.5 g, yield 54%) was separated by purification.

[0217] LC-MS (ESI+): 345, 347 m / z [M+H] + .

[0218] Step 4: Synthesis of isobutyl 6-(benzylthio)-4-fluoro-3-methoxy-1H-indazole-1-carboxylate (1-5)

[0219] Compound 1-4 (4.0 g, 11.6 mmol), benzyl mercaptan (2.9 g, 23.2 mmol), DIPEA (6.0 g, 46.3 mmol), Pd2dba3 (265 mg, 0.29 mmol), Xantphos (402 mg, 0.69 mmol) were added to dioxane (100 mL) and heated to 100 °C under a nitrogen atmosphere for 3 h. The temperature was lowered to room temperature, the solvent was removed, and the product was extracted with DCM / H2O. The product was concentrated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 1-5 (4.2 g, yield 94%).

[0220] LC-MS (ESI+): 389 m / z [M+H] + .

[0221] Step 5: Synthesis of 6-(benzylthio)-4-fluoro-3-methoxy-1H-indazole (1-6)

[0222] Compound 1-5 (3.0 g, 7.7 mmol) was added to 50 mL of methanol, and sodium methoxide (1.05 g, 19.3 mmol) was added with stirring at room temperature. The reaction was stirred for 20 min. 5% citric acid aqueous solution (30 mL) was added, and the product was extracted with ethyl acetate (100 mL). The organic phase was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 1-6 (2.11 g, yield 95%).

[0223] LC-MS (ESI+): 289 m / z [M+H] + .

[0224] Step 6: Synthesis of 2-(6-(benzylthio)-4-fluoro-3-methoxy-lH-indazol-l-yl)-5- (difluoromethyl)-l,3,4-thiadiazole (1-7)

[0225] Compound 1-6 (1.5 g, 5.2 mmol) was added to 30 mL of DMF at room temperature, Cs2CO3 (3.39 g, 10.4 mmol) was added, and the temperature was raised to 65 °C. 2-Bromo-5-(difluoromethyl)-l,3,4-thiadiazole (1.7 g, 7.8 mmol) was added, and the reaction was stirred for 1 h. The temperature was lowered to room temperature, 5% aqueous citric acid (50 mL) was added, and dichloromethane (100 mL) was added to extract the product. The organic phase was washed with water twice, dried, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 1-7 (1.6 g, yield 73%).

[0226] LC-MS (ESI+): 423 m / z [M+H] + .

[0227] Step 7: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-fluoro-3-methoxy- lH-indazole-6-sulfonyl chloride (1-8)

[0228] Compound 1-7 (0.7 g, 1.65 mmol) was added to 20 mL of CH3CN solvent at room temperature, 12 M concentrated hydrochloric acid (1.4 mL, 16.5 mmol) was added, the temperature was lowered to 0 °C, and N-chlorosuccinimide (881 mg, 6.6 mmol) was added. The reaction was stirred for 20 min. DCM (50 mL) was added, washed with water (50 mL x 2), the organic phase was dried, and concentrated to obtain the crude product, which was used in the next step without purification.

[0229] Step 8: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-fluoro-3-methoxy- N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide (1-9)

[0230] Compound 1-9 (465 mg, yield 65%) was obtained by the following procedures. Step 8: Synthesis of 1-9

[0231] LC-MS (ESI+): 434 m / z [M+H] + .

[0232] Step 9: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-3-methoxy-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (1) and 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-hydroxy-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (2)

[0233] Compound 1 (114 mg, yield 40%) and compound 2 (10 mg, yield 3%) were obtained by the following procedures. Step 9: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-3-methoxy-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (1) and 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-hydroxy-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (2)

[0234] Compound 1:

[0235] LC-MS (ESI+): 570.2 m / z [M+H] + .

[0236] 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 1.2 Hz, 1H), 8.37 (s, 1H), 7.59 (t, J = 53.2 Hz, 1H) 7.17 (d, J = 1.6 Hz, 1H), 4.17 (s, 3H), 3.76-3.72 (m, 4H), 3.25-3.20 (m, 4H), 3.01-2.94 (m, 1H), 1.09 (s, 3H), 1.06 (d, J = 6.8 Hz, 6H), 0.70-0.64 (m, 2H), 0.46-0.40 (m, 2H).

[0237] Compound 2:

[0238] LC-MS (ESI+): 556.1 m / z [M+H] + .

[0239] The following compounds are obtainable according to the procedure of Example 1 using the corresponding starting materials:

[0240] Example 10: Synthesis of 3-(Difluoromethoxy)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4- isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (10)

[0241] Step 1: Synthesis of isobutyl 6-bromo-3-(difluoromethoxy)-4-fluoro-1H-indazole-1-carboxylate (10-1)

[0242] Compound 1-3 (4.0 g, 12.1 mmol) was added to 80 mL CH3CN, and cooled to -30 ~ -20 °C; KOH (13.6 g, 242 mmol) was added to 80 mL water to prepare a KOH solution. The aqueous KOH solution was slowly added to the CH3CN system of the substrate at -10 ~ -30 °C, the temperature was adjusted to -10 ~ -30 °C, and (bromodifluoromethyl)phosphonic acid diethyl ester (6.45 g, 24.0 mmol) was slowly added dropwise. After the addition was completed, the temperature was slowly increased to 0 ~ -10 °C, and the reaction was stirred for 2 h. When the raw material was detected by LCMS to be <5%, 10% citric acid aqueous solution was slowly added dropwise in the range of 5 ~ -5 °C, the pH of the aqueous phase was adjusted to 4-6, 50 mL ethyl acetate was added, the product was extracted into the organic phase, and dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to separate compound 10-1 (2.2 g, yield 43%).

[0243] LC-MS (ESI+): 381, 383 m / z [M+H] + .

[0244] Compound 10 was obtained according to the synthetic method of Example 1, using compound 10-1 instead of compound 1-4.

[0245] LC-MS (ESI+): 606.1 m / z [M+H] + .

[0246] 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.43 (br., 1H), 7.72 (t, J = 71.2 Hz, 1H), 7.61 (t, J = 53.2 Hz, 1H), 7.24 (s, 1H), 3.76-3.72 (m, 4H), 3.26-3.21 (m, 4H), 3.02-2.95 (m, 1H), 1.10 (s, 3H), 1.06 (d, J = 6.8 Hz, 6H), 0.68-0.66 (m, 2H), 0.45-0.42 (m, 2H).

[0247] Example 11: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(4-(1- methoxycyclopropylcarbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6- sulfonamide (11)

[0248] Step 1: Synthesis of 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-methoxy-6-(N-(1- methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)piperazine-1-carboxylic acid tert-butyl ester (11-1)

[0249] To a solution of compound 1-9 (500 mg, 1.15 mmol) in dimethyl sulfoxide (5 mL) was added 1-(tert-butoxycarbonyl)piperazine (644 mg, 3.46 mmol) and diisopropylethylamine (0.3 mL) at room temperature. The reaction was stirred at 120 °C for 0.5 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 11-1 (320 mg, yield 46%).

[0250] LC-MS (ESI+): 600.2 m / z [M+H] + .

[0251] Step 2: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-methoxy-N-(1- methylcyclopropyl)-4-(piperazin-1-yl)-1H-indazole-6-sulfonamide (11-2)

[0252] To a solution of compound 11-1 (320 mg, 0.53 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.3 mL) at room temperature. The reaction was stirred at 25 °C for 1 h. After the reaction was completed, the reaction was concentrated under reduced pressure to give compound 11-2 (TFA salt, 230 mg, yield 86%).

[0253] LC-MS (ESI+): 500.2 m / z [M+H] + .

[0254] Step 3: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-methoxy-4-(4-(1- methoxycyclopropanecarbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6- sulfonamide (11)

[0255] To a solution of compound 11-2 (50 mg, 0.1 mmol) and 1-methoxycyclopropane-1- carboxylic acid (23 mg, 0.2 mmol) in dichloromethane (2 mL) was added Cat’s condensing reagent (88 mg, 0.2 mmol) and diisopropylethylamine (0.1 mL) at room temperature. The reaction was stirred at 25 °C for 12 h. After the reaction was completed, the obtained crude product was isolated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 11 (2 mg, yield 3%).

[0256] LC-MS (ESI+): 598.2 m / z [M+H] + .

[0257] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 1.2 Hz, 1H), 8.34 (s, 1H), 7.57 (t, J = 53.2 Hz, 1H), 7.17 (d, J = 0.8 Hz, 1H), 4.16 (s, 3H), 4.02 - 3.65 (m, 4H), 3.29 - 3.20 (m, 7H), 1.07 (s, 3H), 1.02 - 1.01 (m, 2H), 0.94 - 0.91 (m, 2H), 0.67 - 0.64 (m, 2H), 0.42 - 0.39 (m, 2H).

[0258] The following compounds were obtained according to the procedure of Example 11 using the corresponding starting materials:

[0259] Example 21: Synthesis of 2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9- isobutyryl-N-(1-methylcyclopropyl)-8,9,10,11-tetrahydro-2H,7H-6,10- methenodibenzo[1,4,7]oxadiazocin[10,9,8-cd]indazole-4-sulfonamide (21)

[0260] Step 1: Synthesis of 1-benzyl 4-tert-butyl 2-(hydroxymethyl)piperazine-1,4- dicarboxylate (21-2)

[0261] To a solution of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (21-1, 5 g, 23.1 mmol) in dichloromethane (50 mL) was added diisopropylethylamine (5 mL) under ice-water bath, and benzyl chloroformate (3 mL) was added dropwise slowly. After the addition was completed, the reaction was stirred for 3 hours under ice-water bath. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to give compound 21-2 (8 g, yield 98%).

[0262] LC-MS (ESI+): 351.2 m / z [M+H] + .

[0263] Step 2: Synthesis of 1-benzyl 4-tert-butyl 2-(((6-bromo-4-fluoro-1-(isobutyryl)-1H- indazol-3-yl)oxy)methyl)piperazine-1,4-dicarboxylate (21-3)

[0264] To a solution of 6-bromo-4-fluoro-3-hydroxy-1H-indazole-1-carboxylic acid isobutyl ester (1-3, 900 mg, 2.7 mmol) and compound 21-2 (1.4 g, 4 mmol) in tetrahydrofuran (10 mL) was added triphenylphosphine (1.4 g, 5.4 mmol) and diisopropyl azodicarboxylate (1 mL) was added dropwise slowly under ice-water bath. After the addition was completed, the reaction was stirred at 25 °C for 12 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 21-3 (1.8 g, yield 99%).

[0265] LC-MS (ESI+): 664.2 m / z [M+H] + .

[0266] Step 3: Synthesis of 6-(benzylthio)-3-((1-(tert-butoxycarbonyl)-4-isobutyrylpiperazin-2- yl)methoxy)-4-chloro-1H-indazole-1-carboxylic acid isobutyl ester (21-4)

[0267] To a solution of compound 21-3 (1.8 g, 2.7 mmol) in dioxane (20 mL) was added tris(dibenzylideneacetone)dipalladium (227 mg, 0.27 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (257 mg, 0.54 mmol), diisopropylethylamine (1 mL) and benzyl mercaptan (0.5 mL) at room temperature. The reaction mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 21-4 (1.2 g, yield 62%).

[0268] LC-MS (ESI+): 706.3 m / z [M+H] + .

[0269] Step 4: Synthesis of 1-benzyl 4-tert-butyl 2-((6-(benzylthio)-4-fluoro-1H-indazol-3- yl)oxy)methyl)piperazine-1,4-dicarboxylate (21-5)

[0270] To a solution of compound 21-4 (1.2 g, 1.7 mmol) in methanol (10 mL) was added sodium methoxide (0.8 mL, 30% in methanol) at room temperature. The reaction was stirred at 25 °C for 1 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 2 / 1) to give compound 21-5 (900 mg, yield 87%).

[0271] LC-MS (ESI+): 607.3 m / z [M+H] + .

[0272] Step 5: Synthesis of 1-benzyl-4-tert-butyl 2-(((6-(benzylthio)-1-(5-(difluoromethyl)-1,3,4- thiazol-2-yl)-4-fluoro-1H-indazol-3-yl)oxy)methyl)piperazine-1,4-dicarboxylate (21-6)

[0273] To a solution of compound 21-5 (900 mg, 1.5 mmol) in N,N-dimethylformamide (10 mL) was added 2-bromo-5-(difluoromethyl)-1,3,4-thiazole (478 mg, 2.2 mmol) and cesium carbonate (966 mg, 3 mmol) at room temperature. The reaction was stirred at 60 °C for 1 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 21-6 (700 mg, yield 63%).

[0274] LC-MS (ESI+): 741.4 m / z [M+H] + .

[0275] Step 6: Synthesis of 1-benzyl-4-tert-butyl 2-(((6-(chlorosulfonyl)-1-(5-(difluoromethyl)-1,3,4- thiazol-2-yl)-4-fluoro-1H-indazol-3-yl)oxy)methyl)piperazine-1,4-dicarboxylate (21-7)

[0276] To a solution of compound 21-6 (700 mg, 0.95 mmol) in acetonitrile (10 mL) was added acetic acid (0.2 mL), water (0.2 mL) and dichloroisocyanide (372 mg, 1.9 mmol) under ice water bath. The reaction was stirred at 0 °C for 1 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained compound 21-7 (650 mg, yield 95%) was used directly for the next step.

[0277] LC-MS (ESI+): 678.2 m / z [M+H] + .

[0278] Step 7: Synthesis of 1-benzyl-4-tert-butyl-2-((1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indol-3-yl)oxy)methyl)piperazine-1,4-dicarboxylate (21-8)

[0279] To a solution of compound 21-7 (650 mg, 0.9 mmol) in dichloromethane (10 mL) was added 1-methylcyclopropylamine hydrochloride (195 mg, 1.8 mmol) and diisopropylethylamine (0.4 mL) at room temperature. The reaction was stirred at 25 °C for 12 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to give compound 21-8 (600 mg, yield 88%).

[0280] LC-MS (ESI+): 752.2 m / z [M+H] + .

[0281] Step 8: Synthesis of benzyl 2-(((1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indol-3-yl)oxy)methyl)piperazine-1-carboxylate (21-9)

[0282] To a solution of compound 21-8 (400 mg, 0.53 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.4 mL) at room temperature. The reaction was stirred at 25 °C for 1 h. After the reaction was completed, the reaction was concentrated under reduced pressure to give compound 21-9 (TFA salt, 340 mg, yield 98%).

[0283] LC-MS (ESI+): 652.2 m / z [M+H]+ .

[0284] Step 9: Synthesis of 2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(N-(1- methylcyclopropyl)sulfamoyl)-7,8,10,11-tetrahydro-6,10-methano[1,4,7]oxadiazacyclodeca[10,9,8- cd]indazol-9(2H)-carboxylic acid benzyl ester (21-10)

[0285] To a solution of compound 21-9 (340 mg, 0.52 mmol) in dimethyl sulfoxide (30 mL) was added diisopropylethylamine (0.2 mL) at room temperature. The reaction mixture was stirred at 130 °C for 8 hours under nitrogen atmosphere. After the reaction was completed, it was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel (eluent: methanol / dichloromethane = 1 / 10) to give compound 21-10 (80 mg, yield 24%).

[0286] LC-MS (ESI+): 632.2 m / z [M+H] + .

[0287] Step 10: Synthesis of 2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)-2,7,8,9,10,11-hexahydro-6,10-methano[1,4,7]oxadiazacyclodeca[10,9,8- cd]indazole-4-sulfamide (21-11)

[0288] To a solution of compound 21-10 (80 mg, 0.13 mmol) in acetonitrile (2 mL) was added trimethylsilyl iodide (0.1 mL) at room temperature. The reaction was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction was concentrated under reduced pressure to give compound 21-11 (30 mg, yield 47%).

[0289] LC-MS (ESI+): 498.4 m / z [M+H] + .

[0290] Step 11: Synthesis of 2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9-isobutyryl-N-(1- methylcyclopropyl)-8,9,10,11-tetrahydro-2H,7H-6,10-methano[1,4,7]oxadiazacyclodeca[10,9,8- cd]indazole-4-sulfamide (21)

[0291] To a solution of compound 21-11 (30 mg, 0.06 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (0.05 mL) under ice water bath, isobutyryl chloride (0.03 mL) was added dropwise. After the addition was completed, the reaction was stirred in ice water bath for 1 hour. After the reaction was completed, it was concentrated under reduced pressure. The residue was separated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% - 10% / 90%) to give compound 21 (3.1 mg, yield 9%).

[0292] LC-MS (ESI+): 568.4 m / z [M+H] + .

[0293] Example 22: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-isobutyryl-N-(1- methylcyclopropyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazino[2',1':3,4][1,4]oxazepino[7,6,5- cd]indazole-11-sulfonamide (22)

[0294] Step 1: Synthesis of 2-(hydroxymethyl)-4-isobutyrylpiperazine-1-carboxylic acid tert-butyl ester (22-2)

[0295] To a solution of 1-Boc-2-hydroxymethylpiperazine (22-1, 2 g, 9.2 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (2.5 mL) under ice water bath, isobutyryl chloride (1.1 mL) was added dropwise slowly. After the addition was completed, the reaction was stirred in ice water bath for 3 hours. After the reaction was completed, the reaction was quenched with water (20 mL), extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 22-2 (2.2 g, yield 83%).

[0296] LC-MS (ESI+): 287.2 m / z [M+H] + .

[0297] Step 2: Synthesis of 6-bromo-4-chloro-1H-indazol-3-ol (22-4)

[0298] To a solution of methyl 4-bromo-2-chloro-6-fluorobenzoate (22-3, 4 g, 14.9 mmol) in ethanol (20 mL) was added hydrazine hydrate (3 mL, 85%) at room temperature. The reaction was stirred at 80 °C for 2 hours. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, the residue was diluted with water (20 mL), filtered to give crude compound 22-4 (3.5 g), which was used directly in the next reaction.

[0299] LC-MS (ESI+): 248.2 m / z [M+H] + .

[0300] Step 3: Synthesis of isobutyl 6-bromo-4-chloro-3-hydroxy-lH-indazole-l- carboxylate (22-5)

[0301] To a solution of compound 22-4 (3.5 g, 14.1 mmol) in water (30 mL) was added pyridine (15 mL) under ice-water bath, isobutyl chloroformate (6 mL) was added dropwise. After the addition was completed, the reaction was stirred at 25 °C for 12 h. After the reaction was completed, the reaction was filtered, the filter cake was washed with water (20 mL), and the solid was dried under vacuum for 2 h. The crude compound 22-5 (4 g) was obtained.

[0302] LC-MS (ESI+): 348.3 m / z [M+H] + .

[0303] Step 4: Synthesis of isobutyl 6-bromo-3-((l-(tert-butoxycarbonyl)-4- isobutyrylpiperazin-2-yl)methoxy)-4-chloro-lH-indazole-l-carboxylate (22-6)

[0304] To a solution of compound 22-5 (1 g, 2.8 mmol) and compound 22-2 (1.2 g, 4.3 mmol) in tetrahydrofuran (10 mL) was added triphenylphosphine (1.5 g, 5.7 mmol) under ice-water bath, diisopropyl azodicarboxylate (1 mL) was added dropwise. After the addition was completed, the reaction was stirred at 25 °C for 12 h. After the reaction was completed, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 22-6 (1.7 g, yield 96%).

[0305] LC-MS (ESI+): 616.3 m / z [M+H] + .

[0306] Step 5: Synthesis of isobutyl 6-(benzylthio)-3-((l-(tert-butoxycarbonyl)-4- isobutyrylpiperazin-2-yl)methoxy)-4-chloro-lH-indazole-l-carboxylate (22-7)

[0307] To a solution of compound 22-6 (1.7 g, 2.7 mmol) in dioxane (20 mL) was added tris(dibenzylideneacetone)dipalladium (230 mg, 0.27 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (257 mg, 0.54 mmol), diisopropylethylamine (1 mL) and benzyl mercaptan (0.5 mL) at room temperature. The reaction mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 22-7 (1.7 g, yield 93%).

[0308] LC-MS (ESI+): 660.3 m / z [M+H] + .

[0309] Step 6: Synthesis of tert-butyl 2-(((6-(benzylthio)-4-chloro-1H-indazol-3-yl)oxy)methyl)-4- isobutyrylpiperazine-1-carboxylate (22-8)

[0310] To a solution of compound 22-7 (1.7 g, 2.6 mmol) in methanol (20 mL) was added sodium methoxide (1 mL, 30% in methanol) at room temperature. The reaction was stirred at 25 °C for 1 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether = 2 / 1) to give compound 22-8 (1.2 g, yield 83%).

[0311] LC-MS (ESI+): 560.3 m / z [M+H] + .

[0312] Step 7: Synthesis of tert-butyl 2-(((6-(benzylthio)-4-chloro-1-(5-(difluoromethyl)-1,3,4- thiazol-2-yl)-1H-indazol-3-yl)oxy)methyl)-4-isobutyrylpiperazine-1-carboxylate (22-9)

[0313] To a solution of compound 22-8 (1.2 g, 2.1 mmol) in N,N-dimethylformamide (10 mL) was added 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (677 mg, 3.1 mmol) and cesium carbonate (1.36 g, 4.2 mmol) at room temperature. The reaction was stirred at 60 °C for 1 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 22-9 (1.2 g, yield 81%).

[0314] LC-MS (ESI+): 694.2 m / z [M+H] + .

[0315] Step 8: Synthesis of tert-butyl 2-(((4-chloro-6-(chlorosulfonyl)-1-(5-(difluoromethyl)- 1,3,4-thiadiazol-2-yl)-1H-indazol-3-yl)oxy)methyl)-4-isobutyrylpiperazine-1-carboxylate (22-10)

[0316] To a solution of compound 22-9 (1.2 g, 1.7 mmol) in acetonitrile (10 mL) was added acetic acid (0.3 mL), water (0.3 mL) and dichloroisonicotinic acid (682 mg, 3.4 mmol) under ice water bath. The reaction was stirred at 0 °C for 1 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product 22-10 (1.1 g, yield 95%) was used directly for the next step.

[0317] LC-MS (ESI+): 670.2 m / z [M+H] + .

[0318] Step 9: Synthesis of tert-butyl 2-(((4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)- 6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-3-yl)oxy)methyl)-4-isobutyrylpiperazine-1- carboxylate (22-11)

[0319] To a solution of compound 22-10 (1.1 g, 1.6 mmol) in dichloromethane (10 mL) was added 1-methylcyclopropylamine hydrochloride (353 mg, 3.3 mmol) and diisopropylethylamine (0.6 mL) at room temperature. The reaction was stirred at 25 °C for 12 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to give compound 22-11 (700 mg, yield 60%).

[0320] LC-MS (ESI+): 705.2 m / z [M+H] + .

[0321] Step 10: Synthesis of 4-chloro-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-((4- isobutyrylpiperazin-2-yl)methoxy)-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide (22-12)

[0322] To a solution of compound 22-11 (700 mg, 1 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.5 mL) at room temperature. The reaction was stirred at 25 °C for 1 h. After the reaction was completed, the reaction was concentrated under reduced pressure to give compound 22-12 (TFA salt, 500 mg, yield 83%).

[0323] LC-MS (ESI+): 605.2 m / z [M+H] + .

[0324] Step 11: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-6-isobutyryl-N-(l- methylcyclopropyl)-4,4a,5,6,7,8-hexahydro-lH-pyrazino[2',l':3,4][l,4]oxazepino[7,6,5- cd]indazole-l l-sulfonamide (22)

[0325] To a solution of compound 22-12 (100 mg, 0.16 mmol) in dioxane (15 mL) was added Pd-PEPPSI-IHEPT (28 mg, 0.03 mmol) and cesium carbonate (107 mg, 0.33 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. After the reaction was completed, it was concentrated under reduced pressure. The residue was separated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 22 (6.9 mg, yield 7%).

[0326] LC-MS (ESI+): 568.4 m / z [M+H] + .

[0327] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.22 (s, 1H), 7.56 (t, J = 53.2 Hz, 1H), 7.18 (s, 1H), 4.67 - 4.53 (m, 2H), 4.36 - 3.89 (m, 4H), 3.50 - 3.41 (m, 1H), 3.22 - 3.19 (m, 1H), 3.00 - 2.90 (m, 2H), 1.13 (s, 3H), 1.02 (s, 6H), 0.71 - 0.65 (m, 2H), 0.44 - 0.40 (m, 2H).

[0328] Example 48 and 49: Synthesis of 3-(azetidin-3-yloxy)-1-(5-(difluoromethyl)-1,3,4- thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6- sulfonamide (48) and 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin- 1-yl)-3-((1-methylazetidin-3-yl)oxy)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (49)

[0329] Step 1: Synthesis of 3-(azetidin-3-yloxy)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4- (4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (48)

[0330] To 3-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)-1H-indazol-3-yloxy)azetidine-1-carboxylate (prepared according to the procedure of Example 1, replacing anhydrous methanol with 3-hydroxyazetidine-1- carboxylic acid tert-butyl ester) (48-1, 90 mg, 0.13 mmol) in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added at room temperature. The reaction was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction was concentrated under reduced pressure. The crude product was separated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% - 10% / 90%) to give compound 48 (70 mg, yield 90%).

[0331] LC-MS (ESI+): 611.1 m / z [M+H] + .

[0332] Step 2: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-(4- isobutyrylpiperazin-l-yl)-3-((l-methylazetidin-3-yl)oxy)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (49)

[0333] To compound 48 (90 mg, 0.13 mmol) and aqueous formaldehyde (98 mg, 1.6 mmol, 50% w / w) was added methanol (2 mL) and acetic acid (0.5 mL) at room temperature. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (35 mg, 0.16 mmol) was added to the reaction, and stirring was continued for 1 h. After the reaction was completed, saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction, which was then extracted with ethyl acetate (30 mL). The organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound 49 (21 mg, 41% yield) was obtained as a white solid after the crude product was separated by reverse-phase high-performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%).

[0334] LC-MS (ESI + ): 625.1 [M+H] + .

[0335] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 1.2 Hz, 1H), 8.38 (s, 1H), 7.58 (t, J = 53.2 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H), 5.25 - 5.20 (m, 1H), 3.85 - 3.72 (m, 6H), 3.28 - 3.21 (m, 6H), 3.03 - 2.96 (m, 1H), 2.37 (s, 3H), 1.10 - 1.06 (m, 9H), 0.69 - 0.66 (m, 2H), 0.46 - 0.41 (m, 2H).

[0336] The following compounds were obtained according to the procedure of Example 48 using the corresponding starting materials:

[0337] Example 88: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- (fluoromethyl)cyclopropyl)-4-((R)-4-isobutyryl-3-methylpiperazin-l-yl)-3-(((2R,3S)- 2-methylazetidin-3-yl)oxy)-lH-indazole-6-sulfonamide (88)

[0338] Step 1: Synthesis of (R)-4-isobutyryl-3-methylpiperazine-l-carboxylic acid tert-butyl ester (88-2)

[0339] Isobutyryl chloride (399 mg, 3.74 mmol) was added to a solution of (R)-3- methylpiperazine-l-carboxylic acid tert-butyl ester (88-1, 500 mg, 2.50 mmol) and N,N- diisopropylethylamine (644 mg, 4.99 mmol) in dichloromethane (10 mL) at room temperature, and stirred for 2 h. After the reaction was completed, water (30 mL) was added to the reaction solution, which was then extracted with dichloromethane (40 mL x 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 2 / 10) to give compound 88-2 (400 mg, yield 59%). LC-MS (ESI+): 271.1 [M+H] + .

[0340] Step 2: Synthesis of (R)-2-methyl-l-(2-methylpiperazin-l-yl)propan-l-one hydrochloride (88-3)

[0341] Compound 88-2 (200 mg, 0.74 mmol) was added to hydrochloric acid dioxane (5 mL, 4 M) at room temperature, and stirred for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 88-3 (crude, 120 mg, yield 95%).

[0342] LC-MS (ESI+): 171.1 [M+H] + .

[0343] Compound 88 was synthesized according to the method of Example 48, by replacing 2-methyl-l-(piperazin-l-yl)propan-l-one with compound 88-3.

[0344] LC-MS (ESI+): 657.2 [M+H] + .、

[0345] Example 89 and 90: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3- ((3S,4R)-3-hydroxypiperidin-4-yl)oxy)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (89) and l-(5-(difluoromethyl)-l,3,4- thiadiazol-2-yl)-3-(((3R,4S)-3-hydroxy-l-methylpiperidin-4-yl)oxy)-4-(4- isobutyrylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide (90)

[0346] Step 1: Synthesis of trans-3,4-dihydroxypiperidine-l-carboxylic acid tert-butyl ester (89-2)

[0347] To a solution of racemic tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (89-1, 10 g, 50.2 mmol) in dioxane (100 mL) was added a solution of KOH (4.22 g, 75.3 mmol) in 30 mL of water at room temperature. The mixture was heated to 85-90 °C and stirred for 5-6 h. The reaction was monitored by LCMS. The mixture was cooled to 20-30 °C and concentrated. Ethyl acetate (200 mL) and 5% w / w aqueous citric acid solution (200 mL) were added. The organic phase was dried and concentrated to give an oil. The compound 89-2 (8.0 g, 73% yield) was obtained by purification on a silica gel column (eluent: petroleum ether / ethyl acetate = 5 / 1).

[0348] LC-MS (ESI+): 218.13 m / z [M+H] + , 162.13 m / z [M+H-Boc+CO2] + .

[0349] Following the procedures of Example 48 and 49, compounds 89 and 90 were synthesized by replacing 3-hydroxyazetidine-l-carboxylic acid tert-butyl ester with compound 89-2.

[0350] 89: LC-MS (ESI+): 655.2 [M+H] + .

[0351] 90: LC-MS (ESI+): 669.2 [M+H] + .

[0352] Example 91 : Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4- (1,1-dioxidothiomorpholino)-N-(1-methylcyclopropyl)-3-((1,2,2-trimethylpiperidin-4- yl)oxy)-1H-indazole-6-sulfonamide (91)

[0353] Step 1: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(1,1- dioxidothiomorpholino)-N-(1-methylcyclopropyl)-3-((1,2,2-trimethylpiperidin-4- yl)oxy)-1H-indazole-6-sulfonamide (91)

[0354] Compound 71 (30 mg, 0.047 mmol) was dissolved in dichloromethane (3 mL), and m-chloroperoxybenzoic acid (80%, 31 mg, 0.14 mmol) was added at 0-10 °C, and the reaction was stirred for 30 min. The solvent was removed by concentration, and the product was isolated by reverse-phase high-performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 91 (20 mg, 63% yield).

[0355] LC-MS (ESI+): 660.2 [M+H] + .

[0356] Example 92 and 93: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3- ((2R,3S)-1-(3-hydroxycyclobutyl)-2-methylazetidin-3-yl)oxy)-4-(4-isobutyrylpiperazin- 1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (92) and 1-(5- (difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-((2R,3S)-1-(3-fluorocyclobutyl)-2- methylazetidin-3-yl)oxy)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H- indazole-6-sulfonamide (93)

[0357] Step 1: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-((2R,3S)-1-(3- hydroxycyclobutyl)-2-methylazetidin-3-yl)oxy)-4-(4-isobutyrylpiperazin-1-yl)-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (92)

[0358] To a solution of compound 92 (20 mg, 0.03 mmol) in dry dichloromethane (2 mL) was added diethylamine sulfide trifluoride (7 mg, 0.04 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 h. After completion of the reaction, the reaction was quenched by the addition of water (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 93 (6.9 mg, 34.4% yield).

[0359] LC-MS (ESI+): 695.1 [M+H] + .

[0360] Step 2: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-((2R,3S)-1-(3- fluorocyclobutyl)-2-methylazetidin-3-yl)oxy)-4-(4-isobutyrylpiperazin-1-yl)-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (93)

[0361] To a solution of compound 92 (20 mg, 0.03 mmol) in dry dichloromethane (2 mL) was added diethylamine sulfide trifluoride (7 mg, 0.04 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 h. After completion of the reaction, the reaction was quenched by the addition of water (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 93 (6.9 mg, 34.4% yield).

[0362] LC-MS (ESI+): 697.1 [M+H] + .

[0363] Example 94: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-((2R,3S)-1- (2-hydroxy-2-methylpropyl)-2-methylazetidin-3-yl)oxy)-4-(4-isobutyrylpiperazin-1-yl)-N- (1-methylcyclopropyl)-1H-indazole-6-sulfonamide (94)

[0364] To a solution of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1- yl)-3-((2R,3S)-2-methylazetidin-3-yl)oxy)-N-(1-methylcyclopropyl)-1H-indazole-6- sulfonamide (synthesized according to the procedure of Example 49 using (2R,3R)-3- hydroxy-2-methylazetidine-1-carboxylate instead of 3-hydroxyazetidine-1-carboxylate tert-butyl ester) (94-1, 30 mg, 0.05 mmol), 2,2-dimethyloxirane (7 mg, 0.1 mmol) and N,N- diisopropylethylamine (12 mg, 0.19 mmol) in ethanol (2 mL) was added at room temperature and stirring was continued at 80 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was separated by reverse phase HPLC (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 94 (14.8 mg, 44% yield).

[0365] LC-MS (ESI+): 697.1 [M+H] + .

[0366] Example 95: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-((1- formylazetidin-3-yl)oxy)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H- indazole-6-sulfonamide (95)

[0367] Compound 48 (20 mg, 0.0327 mmol) was dissolved in DIPEA (2 mL) and methyl formate (0.4 mL) was added. The reaction was heated to 50-55 °C and stirred for 30-60 min. The solvent was removed by concentration and compound 95 was isolated by reverse phase HPLC (water / acetonitrile = 95% / 5% to 10% / 90%) (14 mg, 67% yield).

[0368] LC-MS (ESI+): 639.2 [M+H] + .

[0369] Example 96 and 97: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-(((2R,3S)-2- ethylazetidin-3-yl)oxy)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6- sulfonamide (96) and 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-((2R,3S)-2-ethyl-1-(oxetan-3- yl)azetidin-3-yl)oxy)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6- sulfonamide (97)

[0370] Step 1: Synthesis of (S)-tert-butyl 3-((2-(methoxymethyl)pyrrolidin-1-yl)imino)azetidine-1- carboxylate (96-2)

[0371] (S)-2-(methoxymethyl)pyrrolidin-1-amine (96-1, 5.0 g, 38.4 mmol) and tert-butyl 3-oxoazetidine-1- carboxylate (7.89 g, 46.08 mmol) were added to anhydrous THF (20 mL) at room temperature, and the reaction was carried out at 55-60 °C for 3 h. After the solvent was removed by concentration, the product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give compound 96-2 (9.0 g, yield 83%).

[0372] LC-MS (ESI+): 284.1 m / z [M+H] + .

[0373] Step 2: Synthesis of (R,Z)-tert-butyl 2-ethyl-3-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)imino)azetidine-1- carboxylate (96-3)

[0374] Compound 96-2 (2.0 g, 7.06 mmol) was added to anhydrous THF (20 mL) at room temperature, and the reaction was cooled to -70 °C under a nitrogen atmosphere. 1M BuLi n-hexane solution (9.2 mL, 9.2 mmol) was added dropwise over 3-5 min, and the reaction was stirred at -70 °C for 3-4 h. EtI (1.44 g, 9.2 mmol) was added dropwise, and the reaction was stirred at -70 °C for 4-5 h. The temperature was slowly increased to about 0 °C, saturated NH4Cl aqueous solution (40 mL) was added, and the product was extracted with ethyl acetate (40 mL). The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give compound 96-3 (1.14 g, yield 52%).

[0375] LC-MS (ESI+): 311.22, 312.1 m / z [M+H] + .

[0376] Step 3: Synthesis of (R)-tert-butyl 2-ethyl-3-oxoazetidine-l-carboxylate (96-4)

[0377] Compound 96-3 (1.14 g, 3.67 mmol) was added to 10 mL THF, then saturated aqueous oxalic acid (20 mL) was added, and stirred at room temperature for 18 h. Ethyl acetate (100 mL) / water (50 mL) was added, and the ethyl acetate solution was washed with water (50 mL) twice, dried and concentrated to give compound 96-4 (crude, 700 mg) as an oil, which was used directly in the next step without purification.

[0378] Step 4: Synthesis of (2R,3R)-tert-butyl 2-ethyl-3-hydroxyazetidine-l-carboxylate (96-5)

[0379] Compound 96-4 (crude, 700 mg) was added to CH3OH (10 mL), and cooled to 0-5 °C, then NaBH4 (265 mg, 7 mmol) was added, and stirred at 0-10 °C for 3 h. Ethyl acetate (50 mL) / water (30 mL) was added to extract, and the ethyl acetate phase was washed with water (20 mL) twice, dried and concentrated to give the crude as an oil, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give compound 96-5 (580 mg, yield 82%).

[0380] LC-MS (ESI+): 202.1 m / z [M+H] + .

[0381] Following the synthetic method of Example 49, replacing 3-hydroxyazetidine-l- carboxylic acid tert-butyl ester with compound 96-5, compounds 96 and 97 were synthesized.

[0382] 96: LC-MS (ESI+): 639.2 [M+H] + .

[0383] 97: LC-MS (ESI+): 695.2 [M+H] + .

[0384] Example 98: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-(6-isobutyryl- 2,6-diazaspiro[3.3]heptan-2-yl)-3-methoxy-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide (98)

[0385] Step 1: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(6-tert- butoxycarbonyl-2,6-diazaspiro[3.3]heptan-2-yl)-3-methoxy-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (98-2)

[0386] To a solution of 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3- methoxy-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (synthesized according to the method of Example 1 using 4-bromo-2-chloro-6-fluorobenzoic acid methyl ester instead of compound 1-1) (98-1, 70 mg, 0.15 mmol) in dioxane (1 mL) were added Pd-PEPPSI-IHEPT (7 mg, 0.008 mmol) and cesium carbonate (152 mg, 0.46 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. After the reaction was completed, it was concentrated to dryness under reduced pressure. The resulting crude product was isolated by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 98-2 (60 mg, yield 63%).

[0387] LC-MS (ESI+): 612.2 m / z [M+H] + .

[0388] Step 2: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-methoxy-N-(1- methylcyclopropyl)-4-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-indazole-6-sulfonamide (98-3)

[0389] To a solution of compound 98-2 (60 mg, 0.1 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) at room temperature. The reaction was stirred at 25 °C for 1 h until the starting material disappeared. After the reaction was completed, the reaction was concentrated to dryness under reduced pressure to give compound 98-3 (TFA salt, 50 mg, yield 99%).

[0390] LC-MS (ESI+): 512.2 m / z [M+H] + .

[0391] Step 3: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(6-isobutyryl-2,6- diazaspiro[3.3]heptan-2-yl)-3-methoxy-N-(1-methylcyclopropyl)-1H-indazole-6- sulfonamide (98)

[0392] To a solution of compound 98-3 (50 mg, 0.1 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (0.05 mL) under ice water bath, and isobutyryl chloride (0.03 mL) was added dropwise. After the addition was completed, the reaction was stirred in ice water bath for 1 h. After the reaction was completed, it was concentrated under reduced pressure. The resulting residue was separated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% - 10% / 90%) to give compound 98 (3.5 mg, yield 6%).

[0393] LC-MS (ESI+): 582.2 m / z [M+H] + .

[0394] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.16 (s, 1H), 7.57 (t, J = 53.2 Hz, 1H), 6.59 (s, 1H), 4.41 (s, 2H), 4.36 (s, 4H), 4.14 (s, 3H), 4.09 (s, 2H), 2.50 - 2.43 (m, 1H), 1.12 (s, 3H), 1.00 (d, J = 6.8 Hz, 6H), 0.69 - 0.66 (m, 2H), 0.44 - 0.41 (m, 2H).

[0395] Example 99: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(1- isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxy-N-(1-methylcyclopropyl)-1H- indazole-6-sulfonamide (99)

[0396] Step 1: Synthesis of tert-butyl 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3- methoxy-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)-3,6- dihydropyridine-1(2H)-carboxylate (99-1)

[0397] To a solution of compound 98-1 (400 mg, 0.89 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (412 mg, 1.33 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-KN) palladium (76 mg, 0.09 mmol) and potassium carbonate (245 mg, 1.78 mmol) in dioxane (5 mL) and water (0.5 mL) was added at room temperature. The reaction was stirred at 90 °C for 2 h. After completion of the reaction, the reaction was diluted with water (25 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether = 3 / 10) to give compound 99-1 (300 mg, yield 57%).

[0398] LC-MS (ESI+): 597.1 [M+H] + .

[0399] Compound 99 was synthesized according to the procedure of Example 98 by replacing compound 98-2 with compound 99-1.

[0400] LC-MS (ESI+): 567.2 [M+H] + .

[0401] Example 100: Synthesis of (R)-1-(5-(fluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)-3-(oxetan-3-yloxy)-4-(4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl)-1H-indazole-6-sulfonamide (100)

[0402] Step 1: Synthesis of (R)-tert-butyl 4-(2-chloroacetyl)-3-hydroxymethylpiperazine-1- carboxylate (100-2)

[0403] To a solution of (R)-3-hydroxymethylpiperazine-l-carboxylic acid tert-butyl ester (100-1, 1.0 g, 4.62 mmol) and DIPEA (1.4 g, 1.4 mmol) in dichloromethane (15 mL) was added chloroacetyl chloride (1.1 g, 9.24 mmol) dropwise at room temperature. The reaction was stirred for 30 min after the addition was completed. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (50 mL). The organic phase was dried and concentrated to give a crude oil, which was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 5 / 1) to give compound 100-2 (1.1 g, 80% yield).

[0404] LC-MS (ESI+): 293.1 m / z [M+H] + .

[0405] Step 2: Synthesis of (S)-tert-butyl 4-oxohexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-carboxylate (100-3)

[0406] To a solution of compound 100-2 (1.1 g, 3.7 mmol) in THF (10 mL) was added KOt-Bu (830 mg, 7.4 mmol) at room temperature. The reaction was stirred for 2 h at room temperature. The reaction mixture was diluted with dichloromethane (30 mL) and washed with water (30 mL). The organic phase was dried and concentrated to give a crude oil, which was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 5 / 1) to give compound 100-3 (711 mg, 75% yield).

[0407] LC-MS (ESI+): 257.1 m / z [M+H] + , 201.1 m / z [M+H-Boc+CO2] + .

[0408] Step 3: Synthesis of (S)-hexahydropyrazino[2,l-c][l,4]oxazin-4(3H)-one (100-4)

[0409] To a solution of compound 100-3 (711 mg, 2.78 mmol) in 1,4-dioxane (5 mL) was added 4N HC1 / 1,4-dioxane solution (1 mL) at room temperature. The reaction was stirred for 2 h at 60 °C. The reaction mixture was concentrated to give a crude oil, which was dissolved in ethyl acetate (30 mL) and washed with aqueous NaHC03solution (30 mL). The organic phase was dried and concentrated to give a crude oil, which was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 2 / 1) to give compound 100-4 (371 mg, 85% yield).

[0410] LC-MS (ESI+): 157.1 m / z [M+H] + .

[0411] Following the procedure of Example 1, replacing anhydrous methanol with oxetan-3-ol, and replacing 2-methyl-l-(piperazin-l-yl)propan-l-one with compound 100-4, compound 100 was synthesized.

[0412] LC-MS (ESI+): 593.15 [M+H] + .

[0413] The following compounds were prepared according to the procedure of Example 100 using the corresponding starting materials:

[0414] Example 109: Synthesis of (R)-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-(8- methyl-6-oxooctahydro-2H-pyrazino[l,2-a]pyrazin-2-yl)-N-(l-methylcyclopropyl)-3- (oxetan-3-yloxy)-lH-indazole-6-sulfonamide (109)

[0415] Step 1: Synthesis of (R)-tert-butyl 8-methyl-6-oxooctahydro-2H-pyrazino[l,2- a]pyrazine-2-carboxylate (109-2)

[0416] To a solution of (R)-tert-butyl 6-oxooctahydro-2H-pyrazino[l,2-a]pyrazine-2- carboxylate (109-1, 60 mg, 0.24 mmol) and aqueous formaldehyde (101 mg, 1.2 mmol, 35% w / w) in methanol (5 mL) and acetic acid (0.5 mL) was added at room temperature, and stirred for 1 h. Sodium triacetoxyborohydride (100 mg, 0.47 mmol) was added to the reaction mixture, and stirred at 25 °C for another 1 h. After the reaction was completed, saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 109-2 (crude, 60 mg, 95% yield).

[0417] LC-MS (ESI+): 270.1 [M+H] + .

[0418] Following the procedure of Example 100, replacing compound 100-3 with compound 109-2, compound 109 was synthesized.

[0419] LC-MS (ESI+): 625.2 m / z [M+H]+ .

[0420] Example 110: Synthesis of 11-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3- methoxy-4-(5-methyl-6-oxo-8-oxa-2,5-diazaspiro[3.5]non-2-yl)-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (110)

[0421] Step 1: Synthesis of tert-butyl 5-methyl-6-oxo-8-oxa-2,5-diazaspiro[3.5]nonane-2- carboxylate (110-2)

[0422] To a solution of tert-butyl 6-oxo-8-oxa-2,5-diazaspiro[3.5]nonane-2-carboxylate (110-1, 100 mg, 0.4 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (20 mg, 0.8 mmol) under ice-water bath. The reaction was stirred for 30 min. Methyl iodide (0.05 mL) was added and the reaction was stirred at 25 °C for 1 h. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound 110-2 (60 mg, yield 56%).

[0423] LC-MS (ESI+): 257.2 m / z [M+H] + .

[0424] Compound 110 was synthesized according to the procedure of Example 100 by replacing compound 100-3 with compound 110-2.

[0425] LC-MS (ESI+): 570.2 m / z [M+H] + .

[0426] 1 H NMR (400 MHz, DMSO-d6) d 8.30 (s, 1H), 8.19 (s, 1H), 7.55 (t, J = 53.2 Hz, 1H), 6.65 (s, 1H), 4.46 (d, J = 9.6 Hz, 2H), 4.20 (d, J = 9.6 Hz, 2H), 4.22 - 4.11 (m, 7H), 3.05 (s, 3H), 1.11 (s, 3H), 0.69 - 0.66 (m, 2H), 0.42 - 0.40 (m, 2H).

[0427] Example 111: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-((7R,9aR)- 7,8-dimethyl-6-oxooctahydro-2H-pyrazino[l,2-a]pyrazin-2-yl)-N-(l- methylcyclopropyl)-3-(oxetan-3-yloxy)-lH-indazole-6-sulfonamide (111)

[0428] Step 1: Synthesis of (S)-tert-butyl 4-((benzyloxy)carbonyl)-D-alanyl)-3- (hydroxymethyl)piperazine-l-carboxylate (111-2)

[0429] To a solution of (S)-tert-butyl 3-(hydroxymethyl)piperazine-l-carboxylate (111-1, 1000 mg, 4.62 mmol), (benzyloxy carbonyl)-D-alanine (677 mg, 3.24 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1757 mg, 6.94 mmol) and N,N-diisopropyl ethylamine (795 mg, 9.25 mmol) in dichloromethane (20 mL) was stirred at room temperature for 12 h. After the reaction was completed, water (40 mL) was added to the reaction solution, which was then extracted with dichloromethane (60 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) to give compound 111-2 (600 mg, yield 32%).

[0430] LC-MS (ESI+): 422.1 [M+H] + .

[0431] Step 2: Synthesis of (S)-tert-butyl 4-((benzyloxy)carbonyl)-D-alanyl)-3- formylpiperazine-l-carboxylate (111-3)

[0432] To a solution of compound 109-1 (1.0 g, 2.3 mmol) in THF (20 mL) was added 2- methylpropanal (0.2 mL, 2.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then NaBH4(0.1 g, 2.6 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched by the addition of water (0.2 mL). The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (20 mL) and extracted with ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with ethyl acetate / hexane) to give compound 109-2 (0.8 g, yield 80%).

[0433] LC-MS (ESI+): 420.1 [M+H] + .

[0434] Step 3: Synthesis of tert-butyl (7R,9aR)-7-methyl-6-oxooctahydro-2H-pyrazino[l,2- a]pyrazine-2-carboxylate (111-4)

[0435] To a solution of compound 109-1 (1.0 g, 2.3 mmol) in THF (20 mL) was added 2- methylpropanal (0.2 mL, 2.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then NaBH4(0.1 g, 2.6 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched by the addition of water (0.2 mL). The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (20 mL) and extracted with ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with ethyl acetate / hexane) to give compound 109-2 (0.8 g, yield 80%). + .

[0436] Compound 111 was synthesized according to the procedure of Example 109 by replacing compound 109-1 with compound 111-4.

[0437] LC-MS (ESI+): 639.2 [M+H] + .

[0438] Example 112: Synthesis of (R)-1-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-N-(l- methylcyclopropyl)-3-(oxetan-3-yloxy)-4-(6-oxooctahydro-2H-pyrazino[l,2-a]pyrazin-2-yl)- lH-indazole-6-sulfonamide (112)

[0439] Step 1: Synthesis of 2-benzyl 8-(tert-butyl) (S)-4-oxohexahydro-2H-pyrazino[l,2- a]pyrazine-2,8(lH)-dicarboxylate (112-2)

[0440] To a solution of (R)-tert-butyl 6-oxooctahydro-2H-pyrazino[l,2-a]pyrazine-2- carboxylate (synthesized according to the procedure of Example 111 using glycine instead of (benzyloxy carbonyl)-D-alanine) (112-1, 150 mg, 0.59 mmol), benzyl formyl chloride (150 mg, 0.88 mmol) and sodium bicarbonate (99 mg, 1.2 mmol) in tetrahydrofuran (10 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether = 1 / 10) to give compound 112-2 (200 mg, 87% yield).

[0441] LC-MS (ESI+): 390.1 [M+H] + .

[0442] Step 2: Synthesis of (S)-benzyl 4-oxooctahydro-2H-pyrazino[l,2-a]pyrazine-2- carboxylate (112-3)

[0443] To a solution of compound 112-2 (200 mg, 0.51 mmol) in dichloromethane (10 mL) was added hydrochloric acid in dioxane (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give compound 112-2 (crude, 140 mg, 94% yield).

[0444] LC-MS (ESI+): 290.1 [M+H] + .

[0445] Step 3: Synthesis of (S)-benzyl 8-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)-3-(oxetan-3-yloxy)-lH-indazol-4-yl)-4-oxooctahydro-2H- pyrazino[l,2-a]pyrazine-2-carboxylate (112-4)

[0446] To a solution of compound 112-4 (10 mg, 0.01 mmol) in hexafluoroisopropanol (2 mL) was added aluminum trichloride (3 mg, 0.02 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was added with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 112 (0.6 mg, 7.3% yield) as a white solid.

[0447] LC-MS (ESI+): 611.1 [M+H] + .

[0448] Step 4: Synthesis of (R)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)-3-(oxetan-3-yloxy)-4-(6-oxooctahydro-2H-pyrazino[1,2-a]pyrazin- 2-yl)-1H-indazole-6-sulfonamide (112)

[0449] To a solution of compound 112-4 (10 mg, 0.01 mmol) in hexafluoroisopropanol (2 mL) was added aluminum trichloride (3 mg, 0.02 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was added with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was separated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 112 (0.6 mg, 7.3% yield) as a white solid.

[0450] LC-MS (ESI+): 611.1 [M+H] + .

[0451] Example 180, 181 and 182: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-l-yl)-3-(2-hydroxyethoxy)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (180), l-(5-(difluoromethyl)-l,3,4- thiadiazol-2-yl)-4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-3-(2-hydroxyethoxy)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (181), and l-(5-(difluoromethyl)-l,3,4- thiadiazol-2-yl)-3-(2-hydroxyethoxy)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (182)

[0452] Step 1: Synthesis of 2-((6-benzylsulfanyl)-l-(5-difluoromethyl-l,3,4-thiadiazol-2-yl)- 4-fluoro-lH-indazol-3-yl)oxy)ethan-l-ol (180-2)

[0453] To a solution of 2-(6-benzylsulfanyl)-4-fluoro-3-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)-lH-indazol-l-yl)-5-difluoromethyl-l,3,4-thiadiazole (prepared according to the procedure of Example 1, using 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-l-ol instead of anhydrous methanol) (180-1, 2.5 g, 4.66 mmol) in CH3OH (50 mL) was added p-toluenesulfonic acid (0.25 g, 2.33 mmol) at room temperature. The reaction mixture was heated to reflux for 4-5 h. The solvent was removed by concentration. The residue was dissolved in ethyl acetate (100 mL) and washed with aqueous NaHC03solution (100 mL). The organic phase was dried and concentrated to give a crude product, which was purified by column chromatography on silica gel (eluent: dichloromethane / ethyl acetate = 3 / 1) to give compound 180-2 (1.8 g, 85% yield).

[0454] LC-MS (ESI+): 453.1 m / z [M+H] + .

[0455] According to the procedures of Example 1, Step 7 and Step 8, compound 180-2 was used to replace compound 1-7 to give compound 180-3.

[0456] According to the procedure of Example 11, compound 180-3 was used to replace compound 1-9 to synthesize compound 180 and compound 181.

[0457] 180: LC-MS (ESI+): 616.2 [M+H] +.

[0458] 181 : LC-MS (ESI+): 558.2 [M+H] + .

[0459] Compound 182 was synthesized according to the procedure of Example 1, replacing compound 180-3 with 1-7.

[0460] LC-MS (ESI + ): 616.2 [M+H] + .

[0461] Example 183 and 184: Synthesis of cis-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-(4- fluorotetrahydrofuran-3-yl)oxy)-4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (183) and trans-1-(5-(difluoromethyl)-1,3,4- thiadiazol-2-yl)-3-((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-4-(4-(2-hydroxy-2- methylpropanoyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (184)

[0462] Step 1: Synthesis of trans-4-fluorotetrahydrofuran-3-ol (183-2)

[0463] To a 250 mL sealed tube was added 3,4-epoxytetrahydrofuran (183-1, 8.0 g, 92.9 mmol) and 3HF.Et3N (60 mL) at room temperature, heated to 110-120 °C for 4-5 hours. The solvent was removed by concentration, added ethyl acetate (60 mL) / water (200 mL), the organic phase was dried and concentrated to give the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give compound 183-2 (6.7 g, yield 67%).

[0464] LC-MS (ESI+): 107.1 m / z [M+H] + .

[0465] Step 2: Synthesis of cis-4-fluorotetrahydrofuran-3-yl 4-nitrobenzoate (183-3)

[0466] Compound 183-2 (4.0 g, 37.7 mmol) was added to anhydrous THF (100 mL) at room temperature, p-nitrobenzoic acid (7.56 g, 45.2 mmol) was added, triphenylphosphine (12.8 g, 49 mmol) was added, the reaction system was stirred uniformly, and then DIAD (9.76 g, 49 mmol) was added. The reaction system was slightly heated and the temperature rose to 45 °C, and the reaction was stirred for 1 h. The solvent was removed by concentration, dichloromethane (150 mL) / 5% wt citric acid aqueous solution (200 mL) was added, and the organic phase was concentrated to obtain a crude product, which was purified and separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 183-3 (7.24 g, yield 75%).

[0467] LC-MS (ESI+): 256.1 m / z [M+H] + .

[0468] Step 3: Synthesis of cis-4-fluorotetrahydrofuran-3-ol (184-4)

[0469] Compound 183-3 (3.6 g, 14.1 mmol) was added to methanol (30 mL) at room temperature, 15% wt NaOH aqueous solution (5 mL) was added, and the reaction was stirred for 1 h. The solvent was removed by concentration, dichloromethane (50 mL) / 5% wt citric acid aqueous solution (50 mL) was added, the organic phase was separated, washed with water (50 mL), dried, and concentrated to obtain a crude product, which was purified and separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 184-4 (1.04 g, yield 70%).

[0470] LC-MS (ESI+): 107.1 m / z [M+H] + .

[0471] Compound 183 was synthesized according to the method of Example 11 by replacing compound 183-2 with anhydrous methanol.

[0472] LC-MS (ESI+): 660.1 [M+H] + .

[0473] 1H NMR (400 MHz, DMSO) δ 8.47 (s, 1H), 8.39 (s, 1H), 7.60 (t, J = 52.8 Hz, 1H), 7.20 (s, 1H), 5.64 (dm, J = 46 Hz, 1H), 5.55 (m, 1H), 4.30 (m, 1H), 4.16-4.05 (m, 2H), 4.05-3.96 (m, 2H), 3.45-3.20 (m, 7H), 1.38 (s, 6H), 1.09 (s, 3H), 0.67 (m, 2H), 0.43 (m, 2H).

[0474] Following the procedure of Example 11, compound 184 was synthesized by replacing anhydrous methanol with compound 183-4.

[0475] LC-MS (ESI+): 660.1 [M+H] +

[0476] Example 185: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(1-(2- fluoroethyl)-3-methoxyazetidine-3-carbonyl)piperazin-1-yl)-3-formyl-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (185)

[0477] Step 1: Synthesis of methyl 3-methoxyazetidine-3-carboxylate (185-2)

[0478] Methyl 1-(tert-butyl)-3-methyl 3-methoxyazetidine-3-carboxylate (185-1, 500 mg, 2.04 mmol) was added to a hydrochloric acid dioxane solution (4 mol / L, 5 mL) at room temperature, and the reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 185-2 (crude, hydrochloride salt, 290 mg, yield 98%).

[0479] LC-MS (ESI+): 146.1 [M+H] + .

[0480] Step 2: Synthesis of methyl 1-(2-fluoroethyl)-3-methoxyazetidine-3-carboxylate (185-3)

[0481] To a solution of compound 185-2 (150 mg, 1.03 mmol), 1-bromo-2-fluoroethane (194 mg, 1.55 mmol) and potassium carbonate (285 mg, 2.07 mmol) in acetonitrile (5 mL) was added at room temperature. The reaction was stirred at 75 °C for 2 h. After completion of the reaction, the reaction was diluted with water (25 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain compound 185-3 (crude, 100 mg, 51% yield).

[0482] LC-MS (ESI+): 190.1 [M+H] + .

[0483] Step 3: Synthesis of 1-(2-fluoroethyl)-3-methoxyazetidine-3-carboxylic acid (185-4)

[0484] To a solution of compound 185-3 (100 mg, 0.53 mmol) and sodium hydroxide (42.3 mg, 1.06 mmol) in methanol (4 mL) and water (2 mL) was added at room temperature. The reaction was stirred at 25 °C for 2 h. After completion of the reaction, the reaction was diluted with 1 N aqueous hydrochloric acid solution to adjust pH 6-7 and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain compound 185-4 (crude, 60 mg, 64.8% yield).

[0485] LC-MS (ESI+): 176.1 [M+H] + .

[0486] Compound 185 was synthesized according to the procedure of Example 11 by replacing isobutyric acid with compound 185-4.

[0487] LC-MS (ESI+): 659.2 [M+H] + .

[0488] The following compounds were obtained according to the procedure of Example 185 using the corresponding starting materials:

[0489] Example 187: Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4- isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-3-(trans-2-methyloxetan-3-yl)oxy)- 1H-indazole-6-sulfonamide (187)

[0490] Step 1: Preparation of cis-2-methyloxetane-3-ol (187-2)

[0491] 2-methyloxetane-3-one (187-1, 1 g, 11.6 mmol) was dissolved in THF (15 mL), sodium borohydride (882 mg, 11.6 mmol) was added under ice bath, the resulting mixture was stirred at room temperature for 18 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 187-2 (500 mg, yield 48%, colorless oil).

[0492] LC-MS (ESI+): 89.0 m / z [M+H] + .

[0493] Compound 187 was obtained according to the method of Example 1 by replacing anhydrous methanol with compound 187-2.

[0494] LC-MS (ESI+): 626.2 m / z [M+H] + .

[0495] 1 H NMR (400 MHz, DMSO) δ 8.43 (d, J = 1.2 Hz, 1H), 8.36 (s, 1H), 7.56 (t, J = 54.6, 51.7 Hz, 1H), 7.16 (d, J = 1.1 Hz, 1H), 5.33 - 5.21 (m, 1H), 5.04 - 4.94 (m, 1H), 4.90 - 4.80 (m, 1H), 4.68 - 4.57 (m, 1H), 3.75 (d, J = 16.7 Hz, 4H), 3.27 - 3.21 (m, 4H), 3.03 - 2.90 (m, 1H), 1.57 (d, J = 6.3 Hz, 3H), 1.07 (s, 3H), 1.04 (d, J = 6.7 Hz, 6H), 0.66 - 0.62 (m, 2H), 0.42 - 0.39 (m, 2H).

[0496] Example 188: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(2-hydroxy-2- methylpropanoyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-3-(prop-2-yn-1-yloxy)-1H-indazole- 6-sulfonamide (188)

[0497] Step 1: Preparation of isobutyl 6-(benzylthio)-4-fluoro-3-hydroxy-lH-indazole-l- carboxylate (188-1)

[0498] Compound 188-1 was synthesized according to the procedure of Example 1, Step 4, replacing compound 1-4 with 1-3.

[0499] LC-MS (ESI+): 375.1 m / z [M+H]+.

[0500] Step 2: Preparation of isobutyl 6-(benzylthio)-4-fluoro-3-(prop-2-yn-l-yloxy)-lH- indazole-l-carboxylate (188-2)

[0501] Compound 188-1 (500 mg, 1.3 mmol) was dissolved in DMF (10 mL), followed by the addition of 3-bromopropyne (317 mg, 2.7 mmol) and Ag2CO3 (734 mg, 2.7 mmol). The resulting mixture was stirred at room temperature for 12 h. Water (100 mL) was added to the reaction mixture, which was extracted with ethyl acetate (100 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 188-2 (400 mg, yield 75%, white solid).

[0502] LC-MS (ESI+): 413.1 m / z [M+H] + .

[0503] Compound 188 was synthesized according to the procedure of Example 180, replacing compound 180-2 with 188-2.

[0504] LC-MS (ESI+): 610.2 m / z [M+H] + .

[0505] Example 189: Synthesis of (S)-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-(4-(2- hydroxypropyl)piperazin-l-yl)-3-methoxy-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide (189)

[0506] Step 1: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-methoxy-N-(l- methylcyclopropyl)-4-(piperazin-l-yl)-lH-indazole-6-sulfonamide (189-1)

[0507] Compound 1-9 (400 mg, 0.92 mmol), piperazine (30 mg, 0.24 mmol) and N,N- diisopropylethylamine (318 mg, 3.69 mmol) were added into dioxane (10 mL) and dimethylsulfoxide (2 mL) at room temperature, stirred at 95 °C for 3 hours. After the reaction was completed, water (45 mL) was added to the reaction solution, and then extracted with ethyl acetate (60 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to obtain compound 189-1 (300 mg, yield 65%).

[0508] LC-MS (ESI+): 500.1 [M+H] + .

[0509] Step 2: Synthesis of (S)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(2- hydroxypropyl)piperazin-1-yl)-3-methoxy-N-(1-methylcyclopropyl)-1H-indazole-6- sulfonamide (189-2)

[0510] Compound 189-1 (40 mg, 0.08 mmol), (S)-2-hydroxypropanoic acid (22 mg, 0.24 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (41 mg, 0.16 mmol) and N,N- diisopropylethylamine (31 mg, 0.24 mmol) were added into N,N-dimethylformamide (2 mL) at room temperature, and the reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, water (15 mL) was added to the reaction solution, and then extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to obtain compound 189 (33 mg, yield 73%).

[0511] LC-MS (ESI+): 659.1 [M+H] + .

[0512] 1H NMR (400 MHz, DMSO-d6) δ 8.52 - 8.48 (m, 1H), 8.40 (s, 1H), 7.61 (t, J = 52.8 Hz, 1H), 7.20 (d, J = 1.2 Hz, 1H), 5.06 (d, J = 7.2 Hz, 1H), 4.57 - 4.53 (m, 1H), 4.20 (s, 3H), 3.81 - 3.71 (m, 4H), 3.28 - 3.22 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H), 1.12 (s, 3H), 0.72 - 0.68 (m, 2H), 0.48 - 0.44 (m, 2H).

[0513] The following compounds are obtainable according to the procedure of Example 189 using the corresponding starting materials:

[0514] Synthesis of Example 233: 4-(4-(1H-imidazole-4-carbonyl)piperazin-1-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-3-(oxetan-3-yloxy)-1H-indazole-6-sulfonamide 233

[0515] Step 1: Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)-3-(oxetan-3-yloxy)-4-(4-(1-trityl-1H-imidazole-4-carbonyl)piperazin- 1-yl)-1H-indazole-6-sulfonamide (233-2)

[0516] Compound 233-2 (20 mg, 0.02 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added dropwise under ice-bath, the resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction was concentrated under reduced pressure, the residue was purified by reverse-phase high performance liquid chromatography (water / acetonitrile = 95% / 5% - 10% / 90%) to give compound 233 (5 mg, yield 34%, white solid).

[0517] LC-MS (ESI+): 636.6 m / z [M+H] + .

[0518] Step 2: Preparation of 4-(4-(lH-imidazole-4-carbonyl)piperazin-l-yl)-l-(5-(difluoromethyl)- 1,3,4-thiadiazol-2-yl)-N-(l-methylcyclopropyl)-3-(oxetan-3-yloxy)-lH-indazole-6- sulfonamide (233)

[0519] Compound 233-2 (20 mg, 0.02 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added dropwise under ice-bath, the resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction was concentrated under reduced pressure, the residue was purified by reverse-phase high performance liquid chromatography (water / acetonitrile = 95% / 5% - 10% / 90%) to give compound 233 (5 mg, yield 34%, white solid).

[0520] LC-MS (ESI+): 636.6 m / z [M+H] + .

[0521] Example 234: Synthesis of 3-((l-cyclopropylazetidin-3-yl)oxy)-l-(5-(difluoromethyl)- 1,3,4-thiadiazol-2-yl)-4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (234)

[0522] Step 1: Synthesis of tert-butyl 3-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-6-(N-(1- methylcyclopropyl)sulfamoyl)-1H-indazol-3-yl)oxy)azetidine-1-carboxylate (234-2)

[0523] To a solution of tert-butyl 3-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-6-(N-(1- methylcyclopropyl)sulfamoyl)-1H-indazol-3-yl)oxy)azetidine-1-carboxylate (261-1, 80 mg, 0.14 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (2 mL) was stirred at room temperature for 2 h. The reaction was concentrated to dryness under reduced pressure. The residue was used directly in the next step. LC-MS (ESI+): 475.1 m / z [M+H] + .

[0524] Step 2: Synthesis of 3-((1-cyclopropylazetidin-3-yl)oxy)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (234-3)

[0525] To a solution of compound 234-1 (TFA salt, 80 mg, 0.17 mmol), 3A molecular sieves (5 pieces) and (1-ethoxy cyclopropoxy)trimethylsilane (59 mg, 0.34 mmol) in methanol (2 mL) and acetic acid (0.2 mL) was stirred at 60 °C for 1 h. The reaction was cooled to room temperature. Sodium cyanoborohydride (21 mg, 0.34 mmol) was added to the reaction mixture. The reaction was stirred at 60 °C for 1 h. The reaction was quenched by the addition of saturated aqueous NaHC03solution (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether = 6 / 10) to give compound 234-3 (50 mg, 58% yield). LC-MS (ESI+): 515.1 m / z [M+H] + .

[0526] Compound 234 was synthesized according to the procedure of Example 189 by replacing compound 1-9 with compound 234-3. LC-MS (ESI+): 667.1 [M+H] + .

[0527] The following compounds were obtained according to the procedure of Example 234 using the corresponding starting materials:

[0528] Examples 245 and 246: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3- ((2R,3S)-2-methyl-l-(oxetan-3-yl)azetidin-3-yl)oxy)-4-(4-(3-methylazetidine-3- carbonyl)piperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide (245) and l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-(4-(l,3-dimethylazetidine-3- carbonyl)piperazin-l-yl)-3-((2R,3S)-2-methyl-l-(oxetan-3-yl)azetidin-3-yl)oxy)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (246)

[0529] Step 1: Synthesis of tert-butyl 3-(4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-(((2R,3S)- 2-methyl-l-(oxetan-3-yl)azetidin-3-yl)oxy)-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH- indazol-4-yl)piperazine-l-carboxylate (245-2)

[0530] To a solution of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-(((2R,3S)-2-methyl-l- (oxetan-3-yl)azetidin-3-yl)oxy)-N-(l-methylcyclopropyl)-4-(piperazin-l-yl)-lH-indazole-6- sulfonamide (245-1, 140 mg, 0.22 mmol) in DMF (1 mL) was added l-(tert- butoxycarbonyl)-3-methylazetidine-3-carboxylic acid (74 mg, 0.344 mmol) and DIPEA (144 mg, 1.1 mmol) and stirred for 10 min. HATU (125 mg, 0.33 mmol) was added and stirred for 1 h. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane / ethyl acetate = 2 / 1) to give compound 245-1 (106 mg, 60% yield).

[0531] LC-MS (ESI+): 808.1 m / z [M+H] + .

[0532] Step 2: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-(((2R,3S)-2- methyl-1-(oxetan-3-yl)azetidin-3-yl)oxy)-4-(4-(3-methylazetidine-3-carbonyl)piperazin- 1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (245)

[0533] Compound 245-2 (106 mg, 0.132 mmol) was added to dichloromethane (2 mL) at room temperature, then CF3COOH (3 mL) was added, and the reaction was stirred for 3 h. The reaction was concentrated under reduced pressure to remove the solvent and most of the CF3COOH, and dichloromethane (30 mL) / NaHCO3 (50 mL) aqueous solution was added. The organic phase was dried and concentrated to give a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / CH3OH = 10 / 1) to give compound 245 (65 mg, yield 70%).

[0534] LC-MS (ESI+): 708.1 m / z [M+H] + .

[0535] Step 3: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(1,3-dimethylazetidine- 3-carbonyl)piperazin-1-yl)-3-(((2R,3S)-2-methyl-1-(oxetan-3-yl)azetidin-3-yl)oxy)-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (246)

[0536] Compound 245 (30 mg, 0.042 mmol) was added to CH3OH (2 mL) at room temperature, then 40% wt formaldehyde aqueous solution (0.4 mL) and acetic acid (0.2 mL) were added, and the mixture was stirred uniformly, then NaBH3CN (10.5 mg, 0.168 mmol) was added, and the reaction was stirred for 2-3 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane / CH3OH = 10 / 1) to give compound 246 (16.7 mg, yield 55%).

[0537] LC-MS (ESI+): 722.1 m / z [M+H] + .

[0538] Example 247: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4- isobutyrylpiperazin-1-yl)-3-(2-(methylamino)ethoxy)-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (247)

[0539] Compound 189-1 was prepared according to the procedure of Example 246, using compound 189-1 instead of compound 245-1.

[0540] LC-MS (ESI + ): 611.2 m / z [M+H] + .

[0541] The following compounds were prepared according to the procedure of Example 247, using the corresponding starting materials:

[0542] Example 261: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-((3S,5S)- 3,5-dimethylpiperazin-1-yl)-3-((1-methylazetidin-3-yl)oxy)-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (261)

[0543] Step 1: Synthesis of tert-butyl 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3- methoxy-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)-3,6- dihydropyridine-1(2H)-carboxylate (261-3)

[0544] To a solution of compound 234-2 (TFA salt, 80 mg, 0.14 mmol) and formaldehyde aqueous solution (52.7 mg, 0.53 mmol, 30% w / w) in methanol (2 mL) and acetic acid (0.2 mL) was added sodium triacetoxyborohydride (44.7 mg, 0.21 mmol) at room temperature. The reaction mixture was stirred for 1 h at 25 °C. After the reaction was completed, the reaction mixture was diluted with saturated aqueous NaHC03solution (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to give compound 261-3 (40 mg, 78% yield). LC-MS (ESI+): 489.1 [M+H] +.

[0545] Compound 261 was synthesized according to the procedure of Example 11, replacing Compound 1-9 with Compound 261-3.

[0546] LC-MS (ESI+): 583.2 [M+H] + .

[0547] The following compounds are obtainable according to the procedure of Example 261, using the corresponding starting materials:

[0548] Example 276: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4- isobutyrylpiperazin-1-yl)-3-((2R,3S)-1-isopropyl-2-methylazetidin-3-yl)oxy)-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (276)

[0549] Compound 276-1 was synthesized according to the procedure of Example 49, Step 2, replacing Compound 48 with Compound 261-2.

[0550] Compound 276 was synthesized according to the procedure of Example 1, Step 9, replacing Compound 1-9 with Compound 276-1.

[0551] LC-MS (ESI+): 667.2 [M+H] + .

[0552] The following compounds are obtainable according to the procedure of Example 276, using the corresponding starting materials:

[0553] Example 286: Synthesis of 4-(2,2-difluoro-7-azaspiro[3.5]non-7-yl)-1-(5-(difluoromethyl)- 1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-3-((1,2,2-trimethylpiperidin-4-yl)oxy)-1H- indazole-6-sulfonamide (286)

[0554] Step 1: Synthesis of tert-butyl 2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (286-2)

[0555] Step 2: Synthesis of 2,2-difluoro-7-azaspiro[3.5]nonane (286-3)

[0556] LC-MS (ESI+): 262.1 [M+H] + .

[0557] Step 2: Synthesis of 2,2-difluoro-7-azaspiro[3.5]nonane (286-3)

[0558] Step 2: Synthesis of 2,2-difluoro-7-azaspiro[3.5]nonane (286-3)

[0559] LC-MS (ESI+): 162.1 [M+H] + .

[0560] Step 3: Synthesis of 4-(2,2-difluoro-7-azaspiro[3.5]non-7-yl)-1-(5-(difluoromethyl)- 1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-3-((1,2,2-trimethylpiperidin-4-yl)oxy)-1H- indazole-6-sulfonamide (286)

[0561] To a solution of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1- methylcyclopropyl)-3-((1,2,2-trimethylpiperidin-4-yl)oxy)-1H-indazole-6-sulfonamide (synthesized according to the procedure of Example 261 using 4-hydroxy-2,2-dimethylpiperidine-1- carboxylic acid tert-butyl ester instead of 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester) (286-4, 50 mg, 0.09 mmol), X-2 (30 mg, 0.19 mmol) and N,N-diisopropyl ethylamine (47 mg, 0.37 mmol) in dimethyl sulfoxide (2 mL) was stirred at 120 °C for 2 h. After the reaction was completed, water (45 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (60 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 286 (2.7 mg, 4.3% yield).

[0562] LC-MS (ESI+): 686.1 [M+H] + .

[0563] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 7.2 Hz, 1H), 8.34 (d, J = 3.2 Hz, 1H), 7.57 (t, J = 53.2 Hz, 1H), 7.14 (s, 1H), 5.09-5.04 (m, 1H), 3.18-3.14 (m, 4H), 2.74-2.72 (m, 1H), 2.60-2.58 (m, 1H), 2.50-2.44 (m, 4H), 2.21 (s, 6H), 1.86-1.84 (m, 3H), 1.79-1.76 (m, 1H), 1.55-1.53 (m, 1H), 1.15 (s, 3H), 1.07 (d, J = 11.6 Hz, 6H), 0.68-0.63 (m, 2H), 0.46-0.41 (m, 2H).

[0564] The following compounds were obtained according to the procedure of Example 286 using the corresponding starting materials:

[0565] Example 288: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)-4-(4-(oxetan-3-yl)piperazin-1-yl)-3-((1,2,2-trimethylpiperidin-4- yl)oxy)-1H-indazole-6-sulfonamide (288)

[0566] Step 1: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)-4-(piperazin-1-yl)-3-((1,2,2-trimethylpiperidin-4-yl)oxy)-1H- indazole-6-sulfonamide (288-1)

[0567] Compound 286-4 (80 mg, 0.147 mmol) was added to DMSO (2 mL) at room temperature, and piperazine (38 mg, 0.44 mmol) was added. The reaction was stirred at 110-120 °C for 2 h. The reaction was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give compound 288-1 (51 mg, yield 56%).

[0568] LC-MS (ESI+): 611.1 m / z [M+H] + .

[0569] Step 2: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1- methylcyclopropyl)-4-(4-(oxetan-3-yl)piperazin-1-yl)-3-((1,2,2-trimethylpiperidin-4- yl)oxy)-1H-indazole-6-sulfonamide (288)

[0570] Compound 288-1 (51 mg, 0.083 mmol) was dissolved in CH3OH (2 mL) at room temperature, and 3-oxetanone (18 mg, 0.25 mmol) was added. Acetic acid (0.1 mL) was added, and the reaction was stirred uniformly. NaBH3CN (10 mg, 0.17 mmol) was added, and the reaction was stirred at room temperature for 1 h. The solvent was removed by concentration, and the product was separated by reverse-phase high performance liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to give compound 288 (20 mg, yield 36%).

[0571] LC-MS (ESI+): 667.1 m / z [M+H] + .

[0572] Example 289: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(2- methyl-2,7-diazaspiro[3.5]non-7-yl)-N-(1-methylcyclopropyl)-3-((1,2,2- trimethylpiperidin-4-yl)oxy)-1H-indazole-6-sulfonamide (289)

[0573] Compound 289 was synthesized according to the procedures of Example 11, Steps 1 and 2, and Example 288, Step 2, replacing compound 1-9 with compound 286-4.

[0574] LC-MS (ESI+): 665.2 [M+H] + .

[0575] 1 H NMR (400 MHz, DMSO-d6) d 8.39 (d, J = 1.2 Hz, 1H), 8.34 (s, 1H), 7.57 (t, J = 53.2 Hz, 1H), 7.13 (d, J = 1.2 Hz, 1H), 5.11 - 5.06 (m, 1H), 3.45 (s, 4H), 3.13 (d, J = 6.4 Hz, 4H), 2.80 - 2.71 (m, 1H), 2.65 - 2.58 (m, 1H), 2.23 (s, 6H), 1.96 (t, J = 5.6 Hz, 4H), 1.80 - 1.76 (m, 1H), 1.56 (t, J = 11.6 Hz, 1H), 1.16 (s, 3H), 1.08 (d, J = 5.6 Hz, 6H), 0.69 - 0.64 (m, 2H), 0.45 - 0.41 (m, 2H).

[0576] The following compounds were obtained according to the procedure of Example 289 using the corresponding starting materials:

[0577] Example 297: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-3-((1-(2- fluoroethyl)azetidin-3-yl)oxy)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (297)

[0578] Compound 261-2 (80 mg, 0.17 mmol), 1-fluoro-2-iodoethane (44 mg, 0.25 mmol) and N,N-diisopropyl ethylamine (44 mg, 0.34 mmol) were added into N,N-dimethylformamide (2 mL) at room temperature, and the reaction solution was stirred at 50 °C for 2 hours. After the reaction was completed, water (25 mL) was added to the reaction solution, which was then extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 3 / 10) to obtain compound 197-1 (30 mg, yield 34%). LC-MS (ESI+): 521.1 [M+H] + .

[0579] Compound 297 was synthesized according to the procedure of Example 11 by replacing compound 1-9 with compound 297-1.

[0580] LC-MS (ESI+): 657.2 [M+H] + .

[0581] The following compounds are obtainable following the procedure of Example 297 using the corresponding starting materials:

[0582] Example 306: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-((2R,3S)-l-(2- fluoroethyl)-2-methylazetidin-3-yl)oxy)-4-((R)-4-isobutyryl-3-methylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (306)

[0583] Compound 306 was synthesized following the procedure of Example 11 using compound 297-1 in place of compound 1-9.

[0584] LC-MS (ESI+): 685.2 m / z [M+H] + .

[0585] The following compounds are obtainable following the procedure of Example 306 using the corresponding starting materials:

[0586] Example 312: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-((2R,3S)-l-(2- fluoroethyl)-2-methylazetidin-3-yl)oxy)-N-(l-methylcyclopropyl)-4-(2-oxa-7-azaspiro[3.5]non-7- yl)-lH-indazole-6-sulfonamide (312)

[0587] Step 1: Synthesis of tert-butyl (2R,3S)-3-((l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-6-(N-(l- methylcyclopropyl)sulfamoyl)-4-(2-oxa-7-azaspiro[3.5]non-7-yl)-lH-indazol-3-yl)oxy)-2- methylazetidine-l-carboxylate (312-1)

[0588] Compound 49-1 (70 mg, 0.12 mmol), 2-oxa-7-azaspiro[3.5]nonane (30 mg, 0.24 mmol) and N,N-diisopropylethylamine (31 mg, 0.24 mmol) were added into dimethyl sulfoxide (2 mL) at room temperature, stirred at 100 °C for 2 hours. After the reaction was completed, water (25 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 312-1 (crude, 30 mg, yield 36%).

[0589] LC-MS (ESI+): 696.1 [M+H] + .

[0590] Step 2: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-(((2R,3S)-2- methylazetidin-3-yl)oxy)-N-(1-methylcyclopropyl)-4-(2-oxa-7-azaspiro[3.5]non-7-yl)-1H- indazole-6-sulfonamide (312-2)

[0591] Compound 312-1 (crude, 30 mg, 0.04 mmol) was added into trifluoroacetic acid (2 mL) and dichloromethane (2 mL) at room temperature, and stirring was continued at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 312-2 (crude, 20 mg, yield 78%).

[0592] LC-MS (ESI+): 596.1 [M+H] + .

[0593] Step 3: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-((2R,3S)-1-(2- fluoroethyl)-2-methylazetidin-3-yl)oxy)-N-(1-methylcyclopropyl)-4-(2-oxa-7-azaspiro[3.5]non- 7-yl)-1H-indazole-6-sulfonamide (312)

[0594] To a solution of compound 312-2 (20 mg, 0.03 mmol), 1-fluoro-2-iodoethane (12 mg, 0.07 mmol) and N,N-diisopropylethylamine (9 mg, 0.07 mmol) in dimethyl sulfoxide (2 mL) was added at room temperature. The reaction was stirred at 45 °C for 2 h. After completion of the reaction, the reaction was diluted with water (25 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 312 (1.4 mg, 6.5% yield).

[0595] LC-MS (ESI+): 642.1 [M+H] + .

[0596] The following compounds were prepared according to the procedure of Example 312 using the corresponding starting materials:

[0597] Example 318: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-((2R,3S)-1-(2- fluoroethyl)-2-methylazetidin-3-yl)oxy)-4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)- N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (318)

[0598] Compound 318-1 was synthesized according to the procedure of Example 297 by replacing 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester with (2R,3R)-3-hydroxy-2- methylazetidine-1-carboxylic acid tert-butyl ester. Then, compound 318 was synthesized according to the procedure of Example 189 by replacing compound 1-9 with compound 318-1.

[0599] LC-MS (ESI+): 687.1 [M+H] +

[0600] The following compounds were prepared according to the procedure of Example 318 using the corresponding starting materials:

[0601] Example 323: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(2,2- dimethylbut-3-ynyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-3-((1,2,2-trimethylpiperidin-4- yl)oxy)-1H-indazole-6-sulfonamide (323)

[0602] Step 1: Synthesis of tert-butyl 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4- (4-(2,2-dimethylbut-3-ynyl)piperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H- indazol-3-yl)oxy)-2,2-dimethylpiperidine-1-carboxylate (323-2)

[0603] To a solution of tert-butyl 4-((1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)-4-(piperazin-1-yl)-1H-indazol-3-yl)oxy)-2,2- dimethylpiperidine-1-carboxylate (synthesized according to the procedure of Example 189 using tert-butyl 4-hydroxy-2,2-dimethylpiperidine-1-carboxylate instead of anhydrous methanol) (323-1, 60 mg, 0.09 mmol), 2,2-dimethylbut-3-ynoic acid (19 mg, 0.17 mmol), HATU (49 mg, 0.13 mmol) and N,N-diisopropylethylamine (22 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25 °C for 2 h. After completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / petroleum ether = 6 / 10) to give compound 323-2 (40 mg, 59% yield).

[0604] LC-MS (ESI+): 791.1 [M+H] + .

[0605] Step 2: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(2,2-dimethylbut-3- ynyl)piperazin-1-yl)-3-(2,2-dimethylpiperidin-4-yl)oxy)-N-(1-methylcyclopropyl)-1H- indazole-6-sulfonamide (323-3)

[0606] To a solution of compound 323-2 (40 mg, 0.05 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (2 mL) was stirred at 25 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give compound 323-3 (crude, 30 mg, 86% yield).

[0607] LC-MS (ESI+): 691.1 [M+H] + .

[0608] Step 3: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-(4-(2,2- dimethylbut-3-ynyl)piperazin-l-yl)-N-(l-methylcyclopropyl)-3-((l,2,2- trimethylpiperidin-4-yl)oxy)-lH-indazole-6-sulfonamide (323)

[0609] To a solution of compound 323-3 (crude, 30 mg, 0.06 mmol) and formaldehyde aqueous solution (24 mg, 0.28 mmol, 30% w / w) in methanol (2 mL) and acetic acid (0.2 mL) was added at room temperature. The reaction mixture was stirred for 1 h, and sodium triacetoxyborohydride (24 mg, 0.11 mmol) was added. The reaction mixture was stirred at 25 °C for another 1 h. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by reverse-phase high performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 323 (12.6 mg, 32% yield).

[0610] LC-MS (ESI+): 705.1 [M+H] + .

[0611] The following compounds were prepared according to the procedure of Example 323 using the corresponding starting materials:

[0612] Example 350: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-(4-(2- hydroxy-2-methylpropanoyl)piperazin-l-yl)-N-(l-methylcyclopropyl)-3-((l,2,2- trimethylpiperidin-4-yl-4-d)oxy)-lH-indazole-6-sulfonamide (350)

[0613] Step 1: Synthesis of tert-butyl 4-hydroxy-2,2-dimethylpiperidine-l-carboxylate-4- deuterium (350-2)

[0614] To a solution of compound 350-1 (2.0 g, 8.8 mmol) in CH3OH (60 mL) was added NaBH4(500 mg, 13.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed by concentration. The residue was diluted with CH2Cl2(100 mL) and washed with aqueous NH4Cl solution (100 mL). The organic phase was dried and concentrated to give the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 3 / 1) to give compound 350-2 (1.72 g, yield 85%). LC-MS (ESI+): 231.1 m / z [M+H] + .

[0615] Compound 350 was synthesized according to the procedure of Example 323, using compound 350-2 instead of tert-butyl 4-hydroxy-2,2-dimethylpiperidine-l-carboxylate.

[0616] LC-MS (ESI+): 698.2 [M+H] + .

[0617] Example 351 : Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-((l-(2- fluoroethyl)-2,2-dimethylpiperidin-4-yl)oxy)-4-(4-(2-hydroxy-2-methylpropanoyl)piperazin- 1-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide (351)

[0618] Compound 351-1 was synthesized according to the procedure of Example 323, using 2-hydroxy-2-methylpropanoic acid instead of 2,2-dimethylbut-3-ynoic acid.

[0619] Compound 351 was synthesized according to the procedure of Example 297, using compound 351-1 instead of 261-2. LC-MS (ESI+): 729.1 [M+H] +

[0620] The following compounds were prepared according to the procedure of Example 351 using the corresponding starting materials:

[0621] Example 356: Synthesis of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-3-((l-(2- fluoroethyl)azetidin-3-yl-3-d)oxy)-4-(4-isobutyrylpiperazin-l-yl)-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (356)

[0622] Step 1: Preparation of tert-butyl 3-(hydroxy-d)azetidine-1-carboxylate-3-d (356-2)

[0623] Dissolve 1-Boc-3-azetidinone (356-1, 1 g, 5.8 mmol) in THF (20 mL), add sodium borodeuteride (489 mg, 11.6 mmol) under ice bath, stir the mixture at room temperature for 18 hours. Add water (10 mL) to the reaction, extract with ethyl acetate (50 mL x 3). Combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 356-2 (600 mg, yield 59%, colorless oil).

[0624] LC-MS (ESI+): 176.1 m / z [M+H] + .

[0625] Follow the method of Example 351, replace compound 356-2 with tert-butyl 4- hydroxy-2,2-dimethylpiperidine-1-carboxylate to synthesize compound 356.

[0626] LC-MS (ESI+): 658.2 [M+H] + .

[0627] Example 357: Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-((2R)-1',2- dimethyl-[1,3'-biazetidinyl]-3-yl)oxy)-4-(4-isobutyrylpiperazin-1-yl)-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (357)

[0628] Step 1: Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4- isobutyrylpiperazin-1-yl)-3-((2R)-2-methyl-[1,3'-biazetidinyl]-3-yl)oxy)-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (357-2)

[0629] A solution of (2R)-3-((1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4- isobutyrylpiperazin-1-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-3-yl)oxy)- 2-methyl-[1,3'-biazetidin]-1'-carboxylic acid tert-butyl ester (synthesized according to the procedure of Example 323, replacing 4-hydroxy-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester with (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylic acid tert-butyl ester and 3-oxoazetidine-1-carboxylic acid tert-butyl ester with an aqueous solution of formaldehyde) (100 mg, 0.13 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise while the solution was cooled in an ice bath. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (water / acetonitrile = 95% / 5% to 10% / 90%) to give Compound 357-2 (80 mg, 91% yield, yellow solid).

[0630] LC-MS (ESI+): 680.8 m / z [M+H] + .

[0631] Step 2: Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-((2R)-1',2- dimethyl-[1,3'-biazetidin]-3-yloxy)-4-(4-isobutyrylpiperazin-1-yl)-N-(1- methylcyclopropyl)-1H-indazole-6-sulfonamide (357)

[0632] A solution of Compound 357-2 (60 mg, 0.08 mmol) in methanol (3 mL) was added formaldehyde (26 mg, 0.24 mmol) and sodium cyanoborohydride (18 mg, 0.24 mmol) sequentially. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. Water (20 mL) was added to the reaction and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (water / acetonitrile = 95% / 5% to 10% / 90%) to give Compound 357 (24.7 mg, 40% yield, white solid).

[0633] LC-MS (ESI+): 694.8 m / z [M+H] + .

[0634] 1H NMR (400 MHz, DMSO) δ 8.43 (d, J = 1.0 Hz, 1H), 8.34 (s, 1H), 7.55 (t, J = 53.1 Hz, 1H), 7.15 (s, 1H), 4.78 (q, J = 6.0 Hz, 1H), 3.90 - 3.67 (m, 8H), 3.45 - 3.39 (m, 2H), 3.22 (s, 3H), 3.01 - 2.89 (m, 2H), 2.46 - 2.36 (m, 1H), 1.68 (dd, J = 35.8, 12.4 Hz, 2H), 1.42 (d, J = 6.1 Hz, 3H), 1.34 - 1.16 (m, 2H), 1.08 - 1.02 (m, 9H), 0.65 - 0.63 (m, 2H), 0.41 - 0.39 (m, 2H).

[0635] Example 358: Preparation of 1-(4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)-3-((tetrahydrofuran-3-yl)oxy)-1H-indol-4-yl)piperazin-1- yl)-2-methyl-1-oxopropan-2-yl carbamate (358)

[0636] Step 1: Preparation of 1-(4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)-3-((tetrahydrofuran-3-yl)oxy)-1H-indol-4-yl)piperazin-1- yl)-2-methyl-1-oxopropan-2-yl (tert-butoxycarbonyl) carbamate (358-1)

[0637] Compound 208 (100 mg, 0.16 mmol) was dissolved in DCM (5 mL), N-Boc-glycine (54 mg, 0.31 mmol), DCC (206 mg, 0.31 mmol) and DMAP (5.7 mg, 0.05 mmol) were added successively, and the mixture was stirred at room temperature for 18 hours. Water (50 mL) was added to the reaction solution, which was extracted with DCM (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 358-1 (50 mg, yield 40%, white solid).

[0638] LC-MS (ESI+): 799.8 m / z [M+H] + .

[0639] Step 2: Preparation of 1-(4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)-3-((tetrahydrofuran-3-yl)oxy)-1H-indol-4-yl)piperazin-1- yl)-2-methyl-1-oxopropan-2-yl glycinate (358)

[0640] Compound 358-1 (50 mg, 0.03 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added dropwise under ice-bath, the resulting mixture was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, the residue was purified by reverse-phase high performance liquid chromatography (water / acetonitrile = 95% / 5% - 10% / 90%) to give compound 358 (9.4 mg, yield 35%, white solid).

[0641] LC-MS (ESI+): 740.8 m / z [M+H] + .

[0642] The following compounds were obtained according to the procedure of Example 358 using the corresponding starting materials:

[0643] Example 361: Preparation of 1-(4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)-3-((tetrahydrofuran-3-yl)oxy)-1H-indol-4-yl)piperazin-1- yl)-2-methyl-1-oxopropan-2-yl L-valinate (361)

[0644] Step 1: Preparation of 1-(4-(6-(N-((tert-butoxycarbonyl)-L-valyl)-N-(1- methylcyclopropyl)sulfamoyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-((tetrahydrofuran-3-yl)oxy)-1H-indol-4-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl (tert- butoxycarbonyl) L-valinate (361-1)

[0645] Compound 208 (200 mg, 0.31 mmol) was dissolved in DCM (10 mL), N-tert- butoxycarbonyl-L-alanine (675 mg, 3.1 mmol), DCC (344 mg, 1.5 mmol) were added, and the mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. Water (50 mL) was added to the reaction solution, which was extracted with DCM (50 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether / ethyl acetate = 4 / 1) to give compound 361-1 (200 mg, yield 62%, white solid).

[0646] LC-MS (ESI+): 840.3 m / z [M+H] + .

[0647] Step 2: Preparation of 1-(4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1- methylcyclopropyl)sulfamoyl)-3-((tetrahydrofuran-3-yl)oxy)-1H-indazol-4-yl)piperazin-1- yl)-2-methyl-1-oxopropan-2-yl L-valinate (361)

[0648] Compound 361-1 (200 mg, 0.23 mmol) was dissolved in DCM (3 mL), TFA (1 mL) was added dropwise under ice bath, and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography (water / acetonitrile = 95% / 5% to 10% / 90%) to give compound 361 (136 mg, yield 84%, yellow solid).

[0649] LC-MS (ESI+): 840.3 m / z [M+H] + .

[0650] Example 362: Preparation of methyl (1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4- isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-3-((tetrahydrofuran-3-yl)oxy)-1H- indazol)-6-sulfonamidyl)pentanoate (362)

[0651] Step 1: Preparation of methyl (1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4- isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-3-((tetrahydrofuran-3-yl)oxy)-1H- indazol)-6-sulfonamidyl)pentanoate (362)

[0652] Compound 362 (37.4 mg, yield 31%, white solid) was obtained by the following procedures. Compound 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4- isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-3-((tetrahydrofuran-3- yl)oxy)-1H-indazole-6-sulfonamide (362-1) (synthesized according to the method of Example 1 by replacing anhydrous methanol with tetrahydrofuran-3-ol) (100 mg, 1.15 mmol) was dissolved in DMF (5 mL), NaH (60%, 60 mg, 0.3 mmol) and pivaloyl chloride (48 mg, 0.3 mmol) were added under ice-bath, the mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% - 10% / 90%) to give compound 362 (37.4 mg, yield 31%, white solid).

[0653] LC-MS (ESI+): 740.8 m / z [M+H] + .

[0654] Example 363: Preparation of (1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-(2- hydroxy-2-methylpropanoyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-3-(tetrahydrofuran- 3-yl)oxy)-1H-indazol-6-sulfonamidyl)methyl pivalate (363)

[0655] Compound 363 (40.8 mg, yield 69%, white solid) was obtained by the following procedures. Compound 208 (50 mg, 0.08 mmol) was dissolved in DMF (5 mL), Cs2CO3(75 mg, 0.23 mmol) and pivaloyl chloride (23 mg, 0.16 mmol) were added under ice-bath, the mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (water / acetonitrile = 95% / 5% - 10% / 90%) to give compound 363 (40.8 mg, yield 69%, white solid).

[0656] LC-MS (ESI+): 756.8 m / z [M+H] + .

[0657] 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.56 (t, J = 53.1 Hz, 1H), 7.03 (s, 1H), 5.55 - 5.48 (m, 4H), 4.25 - 3.62 (m, 8H), 3.23 (s, 4H), 2.40 - 2.19 (m, 2H), 1.35 (s, 6H), 1.31 (s, 3H), 0.99 (s, 9H), 0.96 (s, 2H), 0.71 - 0.65 (m, 2H).

[0658] The following compounds were synthesized according to the procedure of Example 363 using the corresponding starting materials:

[0659] Biological testing

[0660] Test Example 1, in vitro enzymatic inhibition of PARG activity of compounds

[0661] 1) Reagents and consumables:

[0662] 2) Experimental method

[0663] 2.1 Test buffer and compound preparation

[0664] 1x Kinase buffer: 50 mM UltraPure Tris-HCl pH 7.5, 5 mM potassium chloride, Triton X-100 0.015%, fatty acid free bovine serum albumin 0.1%, 1 mM dithiothreitol. TM 1 M Tris-HCl pH 7.5, 5 mM potassium chloride, Triton X-100 0.015%, fatty acid free bovine serum albumin 0.1%, 1 mM dithiothreitol.

[0665] Compound preparation: compounds of the application were prepared at 10 mM in DMSO as test stock.

[0666] 2.2 Preparation of the following reagents in 1x Kinase buffer:

[0667] 2.5x PARG His-tag recombinant protein

[0668] 2.5x TFMU-ADPr diammonium

[0669] 3) Experimental procedure

[0670] 3.1 Using a motorized pipette, dilute the compounds in 1x Kinase buffer and transfer 5 μΐ of 5x compound dilution to the assay plate (66PL96025, Perkin Elmer), seal the assay plate and centrifuge the assay plate at 1000 g for 1 minute.

[0671] 3.2 Add 10 μΐ of 2.5x PARG His-tag recombinant protease solution to the assay plate, seal the assay plate, centrifuge the assay plate at 1000 g for 1 min.

[0672] 3.3 Add 10 μΐ of 2.5x TFMU-ADPr diammonium substrate solution to the assay plate, seal the assay plate, centrifuge the assay plate at 1000 g for 1 min, incubate at 23 °C for 1 h, read the plate with a multifunctional microplate reader.

[0673] 4) Data analysis

[0674] The inhibition rate of the compound on PARG protein activity was calculated using the following formula: % inhibition = 100 x (average value of negative control group - average value of compound) / (average value of negative control group - average value of positive control group). The IC 50 curve of the compound was fitted by software Graphpad 8.0 according to the nonlinear regression equation.

[0675] Test Example 2, PARG in vitro enzymatic inhibition activity test of the compound

[0676] This study evaluated the ability of the compound of the present application to inhibit PARG protease activity in vitro. The experiment used the HTRF analysis method.

[0677] 1) Experimental materials and instruments

[0678] PARG, His-tag recombinant protein (bps bioscience)

[0679] UltraPure TM 1M Tris-HCI buffer, pH 7.5 (Invitrogen)

[0680] Triton X-100 (sigma)

[0681] Fatty acid-free bovine serum albumin (Shenguo)

[0682] Potassium chloride (Shanghai)

[0683] MULtilabel Reader (ENVISION)

[0684] Anti-6His-Eu (Nanjing N6)

[0685] Anti-6His-A2 (Nanjin N6)

[0686] HTRF detection buffer (Nanjin N6)

[0687] Parg substrate

[0688] 0.5M ethylenediaminetetraacetic acid, pH 8.0 (Invitrogen)

[0689] Dithiothreitol (sigma)

[0690] 2) Experimental procedure

[0691] PARG kinase was diluted to 37.5 pg / µl using kinase buffer (1X buffer: 50 mM UltraPure TM 1M Tris-Hydroxymethylaminomethane hydrochloride I buffer, hydrogen ion concentration index 7.5, 0.015% triton X-100, 0.1% fatty acid free bovine serum albumin, 5mM potassium chloride, 10 µM dithiothreitol) and added to 384-well microplate at 4 µl / well. Substrate was diluted with kinase buffer to 12 ng / µl and added to microplate at 4 µl / well. Test compounds were gradient diluted with kinase buffer (starting from the highest concentration 3 µM, diluted with 4-fold concentration gradient to 8 concentration points) and added to microplate at 4 µl / well, centrifuged at 1000 rpm for 1 min and incubated at 23°C for 2 hours. Anti-6His-Eu, Anti-6His-A2, 25 µM ethylenediaminetetraacetic acid were added to microplate at 8 µl / well using HTRF detection buffer (detection buffer, Cisbio) and incubated for 1 hour. Wells without PARG enzyme and compounds were used as negative controls and wells with PARG enzyme but without compounds were used as positive controls. Fluorescence values were read using a multi-functional microplate reader at 620 nM and 665 nM emission wavelengths. Compound log concentration versus percentage of inhibition relative to positive control wells was plotted by GraphPad Prism and IC 50 values were calculated. Inhibition percentage (%) = 100 x (average of negative control group - average of compound) / (average of negative control group - average of positive control group) was calculated using the following formula for the inhibition of PARG protein activity and IC 50 curve of compounds was fitted by software Graphpad 8.0 according to non-linear regression equation.

[0692] Test Example 3, Compound Cytological Activity Test 1

[0693] The cell lines used in the following experiments are as follows: HCC1806 (shXRCC1 KD): human breast cancer cells, XRCC1 gene knockdown cells. HCC1806 cells were purchased from American Type Culture Collection (ATCC) with the catalog number: CRL-2335. HCC1806 shXRCC1 KD cells were constructed by a lentivirus infection method.

[0694] Experimental method (CelltiterGlo method)

[0695] Experimental procedure:

[0696] 1) Preparation of cells

[0697] 1.1 Cell culture

[0698] HCC1806 shXRCC1 KD cells were used, and the culture medium was 1640 + 10% FBS + lx PS. The cells were cultured according to the ATCC standard operation, and the cells were in the exponential growth phase for the experiment.

[0699] 1.2 Preparation of cell suspension and plating

[0700] Resuspend the cells with an appropriate amount of cell culture medium, and only cells with a viability of greater than 90% can be used for the experiment.

[0701] HCC1806 shXRCC1 KD cells were inoculated in a 96-well experimental plate at 500 cells per well with a volume of 200 ul per well, and 200 ul of cell culture medium was added to the blank wells. The 96-well experimental plate inoculated with cells was placed in a 37°C, 5% CO2 incubator overnight.

[0702] 2) Preparation of test compounds

[0703] 2.1 Preparation of test compound DMSO stock solution: all compounds were dissolved in 100% DMSO to prepare a 10 mM stock solution.

[0704] 2.2 Preparation of test compound working stock solution: test compound stock solution 10 mM, take 2 ul of compound stock solution and add to 98 ul of complete medium without DMSO, 5 times serial dilution to 10 concentrations in complete medium containing 2% DMSO. The test compound working stock solution (the compound concentration is 20 times the final concentration, and the highest concentration is 200 uM).

[0705] 2.3 Compound treatment

[0706] Add 10 ul of compound working stock solution (20 times release DMSO final concentration 0.1%) to each well of the 96-well plate inoculated with cells.

[0707] 2.4 Control hole setting

[0708] Solvent control: 0.1% DMSO. Blank control: 96-well plate detection reading at 0h when adding drugs

[0709] 2.5 Place the 96-well plate in a 37°C, 5% CO2 cell incubator for 7 days before detection.

[0710] 3) CTG reagent preparation and plate detection

[0711] Mix the substrate and buffer of CTG reagent (Novalign, CellCounting-Lite 2.0 Luminescent Cell Viability Assay, DD1101-02) evenly, take the cell plate with added compound out of the incubator, and place it at room temperature for 30 min. Remove the culture solution containing the drug from the cell plate, dilute the CTG reagent with PBS, dilute 10 ul PBS with 5 ul CTG reagent, and add 150 ul of the diluted CTG reagent (Celltiter Glo assay kit) to each well. Shake for 10 min to mix (avoid light), and equilibrate at room temperature for 5 min (avoid light). Read the light signal value with a multifunctional enzyme label instrument.

[0712] 4) Data processing

[0713] 4.1 Inhibition rate (%) = (DMSO solvent control well reading - test well reading) / (DMSO solvent control well reading - blank control well reading) x 100%;

[0714] 4.2 Fitting curve and calculating IC 50 .

[0715] Test Example 4, Cellulose Activity Test 2 of Compound

[0716] The cell strains used in the following experiments are as follows: HCC1428: human breast cancer cells. HCC1428 cells were purchased from ATCC, item number: CRL-2327.

[0717] Experimental method: (Celltiter Glo assay)

[0718] Experimental process:

[0719] 1) Preparation of cells

[0720] 1.1 Cell culture

[0721] HCC1428 cells were used, and the culture medium was 1640 + 10% FBS + 1x PS. The cells were cultured according to the standard operation provided by ATCC, and the experiment was performed on cells in the exponential growth phase.

[0722] 1.2 Preparation of cell suspension and plating:

[0723] Resuspend the cells with an appropriate amount of cell culture medium, and only cells with a viability of greater than 90% can be used for experiments.

[0724] HCC1428 cells were seeded in 96-well plates at 1000 cells per well in 200ul volume of culture medium, and 200ul of cell culture medium was added to the blank wells. The 96-well plates seeded with cells were incubated in a 37°C, 5% CO2 incubator overnight.

[0725] 2) Preparation of test compounds

[0726] 2.1 Preparation of test compound DMSO stock solution: All compounds were dissolved in 100% DMSO to prepare a 10mM stock solution.

[0727] 2.2 Preparation of test compound working stock solution: 2ul of the test compound stock solution was added to 98ul of complete medium without DMSO to prepare a 4-fold serial dilution to a final concentration of 2% DMSO. The test compound working stock solution was prepared at a concentration of 20 times the final concentration, with a maximum concentration of 200uM.

[0728] 2.3 Compound treatment

[0729] 10ul of the test compound working stock solution was added to each well of the 96-well plate seeded with cells (20 times the final DMSO concentration was 0.1%).

[0730] 2.4 Control well setup

[0731] Solvent control: 0.1% DMSO. Blank control: 96-well plate reading at 0h after drug addition

[0732] 2.5 Detection after incubation of the 96-well plate in a 37°C, 5% CO2 cell incubator for 7 days.

[0733] 3) Preparation of CTG reagents and plate reading

[0734] The substrate and buffer of the CTG reagent were mixed well, and the cell plate with added compound was removed from the incubator and equilibrated at room temperature for 30 minutes. The cell plate was discarded, and the CTG reagent was diluted with PBS at 10ul PBS and 5ul CTG reagent. 150ul of the diluted CTG reagent was added to each well (Celltiter Glo assay kit), and the plate was shaken for 10 minutes, mixed well (avoiding light), and equilibrated at room temperature for 5 minutes (avoiding light). The multifunctional microplate reader was used to read the light signal value

[0735] 4) Data processing

[0736] 4.1, Inhibition rate (%) = (DMSO solvent control well reading - test well reading) / (DMSO solvent control well reading - blank control well reading) x 100%;

[0737] 4.2, Fitting of curves and calculation of IC 50 .

[0738] Table 1, In vitro activity data of the compounds of the present application

[0739] Experimental conclusion:

[0740] As shown in the above table, the compounds of the present application exhibit excellent PARG enzyme activity inhibitory activity, wherein most of the compounds have enzyme inhibitory IC 50 measured value is less than 1 nM, enzyme inhibitory IC 50 measured value is less than 10 nM in test example 2.

[0741] The compounds of the present application exhibit excellent PARG cell growth inhibitory activity, wherein some of the compounds have HCC1806 cell growth inhibitory IC 50 measured value is less than 20 nM, HCC1428 cell growth inhibitory IC 50 measured value is less than 100 nM, which provides a strong candidate drug for the treatment of PARG related diseases.

Claims

A compound of general formula (I') or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R is selected from ring A, hydrogen or -NR 9 R 10 , ring A is optionally substituted with one or more groups selected from R 11 ; Ring A is selected from a saturated or partially unsaturated monocyclic heterocyclyl, spirocyclic heterocyclyl, bridged cyclic heterocyclyl, fused cyclic heterocyclyl, or heteroaryl; Ring B is selected from a heteroaryl; R 01 selected from hydrogen, alkyl, said alkyl being optionally substituted with a group selected from -OC(O)R 9 , -C(O)R 9 , -C(O)OR 9 ; R 02 selected from or hydrogen; R 1 selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 2 and R 3 each independently is selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 2 and R 3 with the atom to which it is attached form a cycloalkyl or heterocyclyl, which is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; each R 11 is independently selected from hydrogen, halogen, -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -C(O)NR 9 R 10 , -S(O) p R 9 , -S(O) p NR 9 R 10 , -NHC(O)R 9 , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -NR 9 R 10 , nitro, hydroxyl, thiol, carboxyl, ester, oxo; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterium, halogen, -NR a R b , -OR a , nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 4 selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from deuterium, halogen, -NR a R b , -OR c , nitro, cyano, oxo, hydroxy, thiol, carboxy, -C(O)R 9 , -C(O)OR 9 , ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from deuterium, halogen, -NR a R b , -OR c , nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl; or R 4 with ring A and the atoms to which it is attached further forming a fused or bridged heterocyclic ring, which is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 4 together with ring A and R 11 form a heterocycle, which is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 6 selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 8 selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 9 and R 10 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from deuterium, halogen, -NR a R b , nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)NR a R b , -S(O) p R c , -NHC(O)R c , cycloalkyl, heterocyclyl, aryl, heteroaryl; R a and R b each is independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or, R a and R b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R c selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; p is 1 or 2; n is 0, 1 or 2. The compound of Formula (I) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein: Ring A is selected from a monocyclic heterocyclyl, spirocyclic heterocyclyl, bridged cyclic heterocyclyl, or fused cyclic heterocyclyl; Ring B is selected from a heteroaryl; R 1 selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 2 and R 3 each independently is selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 2 and R 3 together with the atom to which they are attached form a cycloalkyl or heterocyclyl, optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 5 selected from hydrogen, halogen, -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -C(O)NR 9 R 10 , -S(O) p R 9 , -S(O) p NR 9 R 10 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterium, halogen, -NR a R b , -OR a , nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 4 selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with one or more groups selected from deuterium, halogen, -NR a R b , -OR c , nitro, cyano, oxo, hydroxy, thiol, carboxy, -C(O)R 9 , -C(O)OR 9 , ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more groups selected from deuterium, halogen, -NR a R b , -OR c , nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl; or R 4 with ring A and the atoms to which it is attached further forming a fused or bridged heterocyclic ring, which is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or R 4 with ring A and R 5 or R 9 together form a heterocycle, which is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 6 selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Each R 7 Each group is independently selected from halogen, cyano, amino, nitro, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 8 selected from hydrogen, halogen, cyano, amino, nitro, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 9 and R 10 each independently is selected from the group consisting of hydrogen, halogen, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from the group consisting of deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)NR a R b , -S(O) p R c , cycloalkyl, heterocyclyl, aryl, heteroaryl; R a and R b each is independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or, R a and R b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R c selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; p is 1 or 2; n is 0, 1 or 2. The compound of general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 2, is a compound of general formula (II-1) or (II-2) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , n is as defined in claim 1. The compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein, Ring B is selected from a 5-10 membered heteroaryl, preferably a 5-6 membered heteroaryl, more preferably thiazolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, particularly preferably thiazolyl. The compound of general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound of general formula (IIA-1) or formula (IIA-2) or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , n is as defined in claim 1. The compound of general formula (I’) according to any one of claims 1 to 5, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (III-1) or formula (III-2), or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, A is selected from N and CH; R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , n is as defined in claim 1. The compound of Formula (I) according to any one of claims 1 to 6, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of Formula (IV-1) or (IV-2), or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, A is selected from N and CH; R 1 , R 4 , R 6 , R 7 , R 8 , R 9 , n is as defined in claim 1. The compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein, R 9 selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl; said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl optionally substituted with one or more groups selected from hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy. The compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein, R 9 selected from C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more groups selected from halo, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy. The compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein, R 9 selected from C 2-6 alkenyl and C 2-6 alkynyl, said C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with C 1-6 alkyl. The compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein, R 9 selected from C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with -OC(O)R c R c selected from C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with amino. The compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein, R 9 selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl; said C 3-6 cycloalkyl, 4-6 membered heterocyclyl optionally substituted with one or more groups selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy. The compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein, R 9 selected from 5-6 membered heteroaryl, preferably 5 membered heteroaryl; said heteroaryl is optionally substituted with one or more groups selected from halogen and C 1-6 alkyl. The compound of general formula (I) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein ring A is selected from a 5-6 membered monocyclic heterocyclyl, a 6-10 membered spirocyclic heterocyclyl or a 6-10 membered fused ring heterocyclyl, preferably piperazinyl, piperidinyl, tetrahydropyridinyl, The compound of general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 4 forms a fused or bridged heterocyclic ring with ring A and the atoms to which they are attached, preferably the fused or bridged heterocyclic ring is The compound of Formula (I) according to any one of claims 1 to 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 forms a heterocycle with ring A and R 5 or R 9 together, which heterocycle is optionally substituted with one or more substituents selected from deuterium, halo, amino, cyano, oxo, hydroxyl, thiol, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy; The heterocycle is preferably more preferably optionally further substituted by deuterium, halogen, amino, cyano, oxo, hydroxy, thio, carboxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 one or more substituents of haloalkoxy. The compound of Formula (I) according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of Formula (V-1) or (V-2), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Z is O or CH2; Ring E is selected from a saturated or partially unsaturated 5-8 membered monocyclic heterocyclyl, 7-12 membered spirocyclic heterocyclyl, 7-10 membered bridged cyclic heterocyclyl, 8-10 membered fused cyclic heterocyclyl, or 5-10 membered heteroaryl; each R 12 is independently selected from hydrogen, halogen, -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -C(O)NR 9 R 10 , -S(O) p R 9 , -S(O) p NR 9 R 10 , -NHC(O)R 9 , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -NR 9 R 10 , nitro, hydroxyl, thiol, carboxyl, ester, oxo; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally substituted with one or more groups selected from deuterium, halogen, -NR a R b , -OR a , nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; m is 0, 1 or 2; R 1 , R 4 , R 6 , R 8 , R 9 , R 10 , R a , R b , p is as defined in claim 1. The compound of Formula (I’), or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 17, is a compound of Formula (VI-1) or (VI-2), or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Z is O or CH2; Y is selected from O, S, NH or CH2; s and t are each independently 0 or 1; each R 12 is independently selected from the group consisting of hydrogen, -NHC(O)R 9 , C 1-6 1-6alkyl, -NR 9 R 10 , hydroxyl, thiol, oxo, cyano; wherein said C 1-6 1-6alkyl is optionally substituted with one or more groups selected from the group consisting of amino and hydroxyl; or any two adjacent R 12 with the atom to which it is attached to form a 4-6 membered heterocyclyl, 4-6 membered cycloalkyl, or 5-6 membered heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxyl, oxo, C 1-6 one or more groups of alkyl substituted; R 9 selected from hydrogen or C 1-6 alkyl; R 10 selected from hydrogen or C 1-6 alkyl; m is 0, 1 or 2; R 1 , R 4 , R 6 , R 8 As defined in claim 1. The compound of Formula (I) according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring E is selected from: each R 12 is independently selected from the group consisting of hydrogen, -NHC(O)R 9 , C 1-6 1-6alkyl, -NR 9 R 10 , hydroxyl, thiol, oxo, cyano; wherein said C 1-6 1-6alkyl is optionally substituted with one or more groups selected from the group consisting of amino and hydroxyl; R 9 selected from hydrogen or C 1-6 alkyl; R 10 selected from hydrogen or C 1-6 alkyl; m is 0, 1 or 2. The compound of Formula (I) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 19, wherein R 4 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl; said C 1-6 alkyl is optionally substituted with deuterium, halogen, hydroxyl, -NR a R b , -OR c , C 3-6 cycloalkyl, or 4-6 membered heterocyclyl; R a and R b are each independently selected from hydrogen, C 1-6 alkyl; or R a and R b together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclyl group, optionally substituted with one or more substituents selected from halogen, amino, cyano, oxo, hydroxyl, thiol, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl; R c selected from hydrogen, C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with phenyl. The compound of general formula (I) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R 4 is selected from 4-10 membered heterocyclyl, preferably 4-6 membered heterocyclyl; said heterocyclyl is optionally substituted with one or more groups selected from halogen, hydroxyl, -C(O)R 9 , -C(O)OR 9 , C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl is optionally substituted with one or more groups selected from deuterated, halogen, cyano, hydroxyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl; R 9 selected from hydrogen and C 1-6 alkyl. The compound of general formula (I') according to any one of claims 1 to 19, or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from C 1-6 Alkyl, wherein the C 1-6 Alkyl groups are C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, -NR a R b Replaced by 5-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl, 4-10-membered heterocyclic or 5-6-membered heterocyclic groups may be optionally replaced by halogens or C1-6 alkyl groups; R a and R b are each independently selected from hydrogen, C 1-6 alkyl; or R a and R b together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclyl group, optionally substituted with one or more substituents selected from halogen, hydroxyl, thiol, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 4-6 membered heterocyclyl. The compound of general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt according to any one of claims 2 to 6, 11 to 14, wherein R 5 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl. The compound of Formula (I) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 23, wherein R 1 is selected from C 1-6 alkyl and cyano, wherein the C 1-6 alkyl is optionally substituted with one or more groups selected from deuterium, halogen, cyano, hydroxyl, C 1-6 alkoxy. The compound of general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein R 6 is selected from C 1-6 alkyl and C 1-6 haloalkyl, preferably C 1-6 haloalkyl. The compound of Formula (I) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 2 to 25, wherein R 7 is selected from C 1-6 alkyl, and n is 0, 1, or 2. The compound of general formula (I’) according to any one of claims 1 to 26, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, preferably hydrogen. The compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 27, wherein the compound is selected from: A process for preparing a compound of the general formula (III-1) or its meso, racemic, enantiomeric, diastereomeric forms, or mixtures thereof, or a pharmaceutically acceptable salt thereof, said process comprising the steps of: Compound A7 is reacted with compound A8 under basic conditions by substitution reaction or palladium catalyzed coupling reaction to obtain a compound represented by general formula (III-1); wherein, X is halogen, preferably F or Cl; R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , n is as defined in claim 6. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 28, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Use of a compound represented by general formula (I) according to any one of claims 1 to 28, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30, for the manufacture of a poly ADP ribose glycohydrolase (PARG) inhibitor. Use of a compound represented by general formula (I) according to any one of claims 1 to 28, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30, for the manufacture of a medicament for the prevention or / and treatment of a disease associated with the activity of poly ADP ribose glycohydrolase (PARG), preferably a cancer, such as ovarian cancer, serous membrane cancer of uterus, breast cancer, prostate cancer, bladder cancer, pancreatic cancer, gastric cancer, colorectal cancer, etc.

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