β-glucocerebrosidase allosteric modulator, pharmaceutical composition thereof and use thereof

Abstract

Provided are compounds represented by formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, a pharmaceutical composition containing same, and the use thereof as a β-glucocerebrosidase (GCase) allosteric modulator, preferably for treating neurodegenerative diseases.

Description

Beta-glucocerebrosidase allosteric modulators, pharmaceutical compositions thereof, and uses thereof

[0001] Cross-reference to Related Applications

[0002] This disclosure claims the benefit of and priority to the following four Chinese patent applications, the entire contents of which are hereby incorporated by reference in their entirety:

[0003] Chinese Patent Application No. CN202410597300.6, filed May 14, 2024, with the China National Intellectual Property Administration,

[0004] Chinese Patent Application No. CN202411292033.8, filed September 14, 2024, with the China National Intellectual Property Administration,

[0005] Chinese Patent Application No. CN202510024333.6, filed January 07, 2025, with the China National Intellectual Property Administration, and

[0006] Chinese Patent Application No. CN202510285716.9, filed March 11, 2025, with the China National Intellectual Property Administration. TECHNICAL FIELD

[0007] The present disclosure belongs to the technical field of medicine, in particular to compounds as allosteric modulators of beta-glucocerebrosidase (also known as acid beta-glucosidase, D-glucosyl-N-acylsphingosine glucosylhydrolase or GCase), pharmaceutical compositions containing the compounds, and uses thereof in the prevention or treatment of neurodegenerative diseases. BACKGROUND

[0008] Beta-glucocerebrosidase is an enzyme with glucosylceramidase activity that metabolizes the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose. Beta-glucocerebrosidase has maximum activity at pH 5.5, the pH of the lysosomal compartment. Within the lysosome, it remains membrane-associated and degrades its substrate, glucocerebroside (GluCer). It requires activation by the protein Saposin C and negatively charged lipids to exert maximal catalytic activity, ensuring proper cellular protein degradation and cell signaling.

[0009] Mutations in GBA1 (gene encoding lysosomal enzyme glucocerebrosidase) are one of the most common known genetic risk factors for the development of Parkinson's disease and related synucleinopathies, and are causal for the rare autosomal recessive storage disorder, Gaucher disease. GBA1 mutations can lead to disruption of protein degradation, lysosomal targeting and reduced enzyme performance in lysosomes. Gaucher disease has phenotypic diversity, with both neuronopathic and non-neuronopathic forms. Patients and heterozygous carriers of Gaucher disease have an increased risk of developing Parkinson's disease and dementia with Lewy bodies. Reductions in GCase enzyme activity levels have been detected in different brain regions in Parkinson's disease patients, and furthermore, studies have shown that modulators of GCase enzyme can restore lysosomal function, reduce lipid substrate accumulation, and thus inhibit pathological alpha-Syn aggregation, so GCase modulators are considered as a new drug development strategy for alleviating and treating Parkinson's disease.

[0010] Therefore, it is of great significance to study new, potent and highly selective GCase modulators for the treatment of neurodegenerative diseases. SUMMARY

[0011] The present disclosure provides a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0012] wherein, is selected from a single bond or a double bond;

[0013] Q is selected from N or C;

[0014] G is selected from N, CH or C(O);

[0015] ring B is selected from the following groups:

[0016] a) C6-C 14 spiro cycloalkylene, C6-C 14 fused cycloalkylene, C5-C 12 bridge cycloalkylene, 6-14 membered spiro heterocyclylene, 6-14 membered fused heterocyclylene or 5-12 membered bridge heterocyclylene;

[0017] or,

[0018] b)

[0019] W is selected from a bond, -CR a R b -, -CR a R b O-, C(O), O or S;

[0020] R a , R b are independently selected from H, halogen, C1-C6alkyl, C1-C6haloalkyl or C1-C4alkoxy;

[0021] Ring A is selected from C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl;

[0022] each R 1 is independently selected from CN, NH2, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halogen, C1-C6alkyl;

[0023] R 2 is selected from H, C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halogen, C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl;

[0024] R 3 is selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-6 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl optionally substituted with NH2, OH, halogen, or C1-C6alkyl;

[0025] each R 4 is independently selected from deuterium, OH, halogen, =O, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C6cycloalkyl;

[0026] R 5 is selected from H, deuterium, NH2, CN, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-7 membered heterocyclyl;

[0027] p, q are independently selected from 0, 1, or 2.

[0028] In some embodiments, in formula (I),

[0029] is selected from a single or double bond;

[0030] Q is selected from N or C;

[0031] G is selected from N, CH, or C(O);

[0032] Ring B is selected from the following groups:

[0033] a) C6-C 14 spiro cycloalkylene, C6-C14 bridged cycloalkyl, 6-14 membered spiro heterocyclyl, 6-14 membered fused heterocyclyl, or 5-12 membered bridged heterocyclyl; 12 bridged cycloalkyl, 6-14 membered spiro heterocyclyl, 6-14 membered fused heterocyclyl, or 5-12 membered bridged heterocyclyl;

[0034] or,

[0035] b)

[0036] W is selected from a bond, -CR a R b -, -CR a R b O- or C(O);

[0037] R a , R b are independently selected from H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C4alkoxy;

[0038] Ring A is selected from C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl;

[0039] each R 1 is independently selected from CN, NH2, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C3-C6cycloalkyl or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halogen, C1-C6alkyl;

[0040] R 2 is selected from H, C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halogen, or C1-C6alkyl;

[0041] R 3 is selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-6 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl optionally substituted with NH2, OH, halogen, or C1-C6alkyl;

[0042] each R 4 is independently selected from deuterium, OH, halogen, =O, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C6cycloalkyl;

[0043] R 5H, deuterium, NH2, CN, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-7 membered heterocyclyl;

[0044] p, q are independently selected from 0, 1 or 2.

[0045] In some embodiments, in formula (I),

[0046] is selected from a single bond or a double bond;

[0047] Q is selected from N or C;

[0048] G is selected from N, CH or C(O);

[0049] Ring B is selected from the following groups:

[0050] a) C6-C 14 spiro cycloalkylene, C6-C 14 fused cycloalkylene, C5-C 12 bridged cycloalkylene, 6-14 membered spiro heterocyclylene, 6-14 membered fused heterocyclylene, or 5-12 membered bridged heterocyclylene;

[0051] or,

[0052] b)

[0053] W is selected from a bond, -CR a R b - or -CR a R b O-;

[0054] R a , R b are independently selected from H, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C4alkoxy;

[0055] Ring A is selected from C3-C 12 cycloalkyl, or 4-12 membered heterocyclyl;

[0056] each R 1 is independently selected from CN, NH2, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C3-C6cycloalkyl or 4-10 membered heterocyclyl being optionally substituted with NH2, OH, halogen, C1-C6alkyl;

[0057] R 2H, C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halogen, or C1-C6alkyl;

[0058] R 3 H, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-6 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl optionally substituted with NH2, OH, halogen, or C1-C6alkyl;

[0059] each R 4 is independently selected from deuterium, OH, halogen, =O, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C6cycloalkyl;

[0060] R 5 is selected from H, deuterium, NH2, CN, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-7 membered heterocyclyl;

[0061] p, q are independently selected from 0, 1, or 2.

[0062] In some embodiments, when is a double bond, Q is C, G is N, and W is selected from a bond or -CR a R b , ring B is not the following structure: and ring A is selected from C3-C 12 cycloalkyl, or 4-12 membered heterocyclyl.

[0063] In some embodiments, when is a double bond, Q is C, G is N, and W is selected from a bond or -CR a R b , ring B is not the following structure:

[0064] In some embodiments, when W is a bond, ring B is not the following structure:

[0065] In some embodiments, when W is selected from -CR a R b , ring B is not the following structure:

[0066] In some embodiments, when W is selected from a bond or -CR a R b , ring B is not the following structure:

[0067] In some embodiments, when W is selected from a bond or -CR a R b then ring B is not the following structure:

[0068] In some embodiments, is a single bond, Q is N, and G is C(O).

[0069] In some embodiments, is a double bond, Q is C, and G is N.

[0070] In some embodiments, ring B is selected from the following groups:

[0071] a) a 6-14 membered spiro- heterocyclylene, 6-14 membered fused- heterocyclylene, or 5-12 membered bridged- heterocyclylene; or,

[0072] b)

[0073] In some embodiments, ring B is selected from the following groups:

[0074] a) a 6-14 membered spiro- heterocyclylene or 6-14 membered fused- heterocyclylene; or,

[0075] b)

[0076] In some embodiments, ring B is selected from the following groups:

[0077] a) a 6-10 membered spiro- heterocyclylene or 6-10 membered fused- heterocyclylene; or,

[0078] b)

[0079] In some embodiments, ring B is selected from a 6-14 membered spiro- heterocyclylene, 6-14 membered fused- heterocyclylene, or 5-12 membered bridged- heterocyclylene.

[0080] In some embodiments, ring B is a 6-14 membered spiro- heterocyclylene or 6-14 membered fused- heterocyclylene.

[0081] In some embodiments, ring B is a 6-14 membered spiro- heterocyclylene or 6-14 membered fused- heterocyclylene each having at least one N atom as a ring-forming atom.

[0082] In some embodiments, ring B is a 6-14 membered N- spiro- heterocyclylene or 6-14 membered N- fused- heterocyclylene.

[0083] In some embodiments, ring B is a 6-14 membered N- spiro- heterocyclylalkyl or 6-14 membered N- fused- heterocyclylalkyl.

[0084] In some embodiments, Ring B is a 6-10 membered N-spiro heterocycloalkyl or a 6-10 membered N-fused heterocycloalkyl.

[0085] In some embodiments, Ring B is selected from a 6-14 membered bicyclic spiro heterocyclyl.

[0086] In some embodiments, Ring B is selected from a 6-10 membered bicyclic spiro heterocyclyl.

[0087] In some embodiments, Ring B is selected from a 3 / 6 bicyclic spiro heterocyclyl, a 4 / 4 bicyclic spiro heterocyclyl, a 4 / 5 bicyclic spiro heterocyclyl, a 4 / 6 bicyclic spiro heterocyclyl, a 5 / 5 bicyclic spiro heterocyclyl, or a 5 / 6 bicyclic spiro heterocyclyl.

[0088] In some embodiments, Ring B is selected from a 5 / 5 bicyclic spiro heterocyclyl, a 4 / 4 bicyclic spiro heterocyclyl, a 4 / 5 bicyclic spiro heterocyclyl, a 5 / 6 bicyclic spiro heterocyclyl, or a 4 / 6 bicyclic spiro heterocyclyl.

[0089] In some embodiments, Ring B is selected from a 4 / 4 bicyclic spiro heterocyclyl, a 4 / 5 bicyclic spiro heterocyclyl, a 5 / 6 bicyclic spiro heterocyclyl, or a 4 / 6 bicyclic spiro heterocyclyl.

[0090] In some embodiments, Ring B is selected from a 4 / 4 bicyclic spiro heterocyclyl, a 4 / 5 bicyclic spiro heterocyclyl, or a 4 / 6 bicyclic spiro heterocyclyl.

[0091] In some embodiments, Ring B is selected from a 6-14 membered bicyclic fused heterocyclyl.

[0092] In some embodiments, Ring B is selected from a 3 / 5 bicyclic fused heterocyclyl, a 6 / 6 bicyclic fused heterocyclyl, a 5 / 6 bicyclic fused heterocyclyl, or a 5 / 5 bicyclic fused heterocyclyl.

[0093] In some embodiments, Ring B is selected from a 6 / 6 bicyclic fused heterocyclyl, a 5 / 6 bicyclic fused heterocyclyl, or a 5 / 5 bicyclic fused heterocyclyl.

[0094] In some embodiments, Ring B is selected from a 3 / 5 bicyclic fused heterocyclyl, a 5 / 6 bicyclic fused heterocyclyl, or a 5 / 5 bicyclic fused heterocyclyl.

[0095] In some embodiments, Ring B is selected from a 5 / 6 bicyclic fused heterocyclyl or a 5 / 5 bicyclic fused heterocyclyl.

[0096] In some embodiments, Ring B is selected from a 5 / 6 bicyclic fused heterocyclyl.

[0097] In some embodiments, Ring B is a 5-12 membered bicyclic bridged heterocyclyl.

[0098] In some embodiments, Ring B is a 6-9 membered bicyclic bridged heterocyclyl. In some embodiments, Ring B is a 7 membered or 8 membered bicyclic bridged heterocyclyl.

[0099] In some embodiments, the 6-14 membered spiro heterocyclyl, 6-14 membered fused heterocyclyl, or 5-12 membered bridged heterocyclyl each independently contains 1, 2, or 3 heteroatoms independently selected from N, O, or S.

[0100] In some embodiments, the 6-14 membered spiro heterocyclyl, 6-14 membered fused heterocyclyl, or 5-12 membered bridged heterocyclyl each independently contains 1, 2, or 3 heteroatoms independently selected from N or O.

[0101] In some embodiments, the 6-14 membered spiro heterocyclyl, 6-14 membered fused heterocyclyl, or 5-12 membered bridged heterocyclyl each independently contains 1, 2, or 3 heteroatoms independently selected from N or O.

[0102] In some embodiments, the 3 / 6 bicyclic spiro heterocyclyl, 4 / 4 bicyclic spiro heterocyclyl, 4 / 5 bicyclic spiro heterocyclyl, 4 / 6 bicyclic spiro heterocyclyl, 5 / 5 bicyclic spiro heterocyclyl, 5 / 6 bicyclic spiro heterocyclyl, 3 / 5 bicyclic fused heterocyclyl, 6 / 6 bicyclic fused heterocyclyl, 5 / 6 bicyclic fused heterocyclyl, 5 / 5 bicyclic fused heterocyclyl, 6-9 bicyclic bridged heterocyclyl, or 7 membered or 8 membered bicyclic bridged heterocyclyl each independently contains 1, 2, or 3 heteroatoms independently selected from N or O.

[0103] In some embodiments, Ring B is selected from C6-C 14 spiro cycloalkyl.

[0104] In some embodiments, Ring B is selected from C6-C 10 spiro cycloalkyl.

[0105] In some embodiments, Ring B is selected from C7-C9 spiro cycloalkyl.

[0106] In some embodiments, Ring B is selected from

[0107] In some embodiments, Ring B is selected from:

[0108] In some embodiments, Ring B is selected from:

[0109] In some embodiments, Ring B is selected from:

[0110] In some embodiments, Ring B is selected from:

[0111] In some embodiments, Ring B is selected from

[0112] In some embodiments, Ring B is selected from

[0113] In some embodiments, is selected from the following structures:

[0114] In some embodiments, is selected from the following structures:

[0115] In some embodiments, is selected from the following structures:

[0116] In some embodiments, is selected from the following structures:

[0117] In some embodiments, is selected from the following structures:

[0118] In some embodiments, is selected from the following structures:

[0119] In some embodiments, W is selected from a bond, -CR a R b -, -CR a R b O-, or C(O).

[0120] In some embodiments, W is selected from a bond, -CR a R b -, -CR a R b O-, C(O), or O.

[0121] In some embodiments, W is selected from a bond, -CH2-, -CHCH3-, -CH2O-, C(O), or O.

[0122] In some embodiments, W is selected from a bond, -CH2-, -CH2O-, or C(O). a R b In some embodiments, W is selected from a bond, -CH2-, -CH2O-, or C(O). a R b O-.

[0123] In some embodiments, W is selected from a bond, -CH2-, -CH2O-, or C(O). a R b O-.

[0124] In some embodiments, W is selected from a bond, -CH2-, -CH2O-, or C(O).

[0125] In some embodiments, W is selected from a bond, -CH2-, -CH2O-, or C(O).

[0126] In some embodiments, W is selected from a bond, -CH2-, -CH2O-, or C(O).

[0127] In some embodiments, W is selected from a bond, -CH2-, -CH2O-, or C(O). a R b In some embodiments, W is selected from a bond, -CH2-, -CH2O-, or C(O). a R b O-.

[0128] In some embodiments, W is selected from a bond, -CH2-, -CH2O-, or C(O).

[0129] In some embodiments, W is C(O).

[0130] In some embodiments, R a , R b are each independently selected from H or C1-C6 alkyl.

[0131] In some embodiments, R a , R b are each H.

[0132] In some embodiments, ring A is selected from C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

[0133] In some embodiments, ring A is selected from C3-C 12 cycloalkyl, 5-10 membered heteroaryl, or phenyl.

[0134] In some embodiments, ring A is selected from C3-C 12 cycloalkyl, or 5-10 membered heteroaryl.

[0135] In some embodiments, ring A is selected from C5-C10 Bridged cycloalkyl or 5-6 membered heteroaryl.

[0136] In some implementations, ring A is selected from C3-C 12 Cycloalkyl or 4-12 membered heterocyclic groups.

[0137] In some embodiments, ring A is selected from C3-C6 cycloalkyl, 4-9 membered heterocyclic, 5-6 membered heteroaryl, or phenyl.

[0138] In some embodiments, ring A is selected from C3-C6 cycloalkyl, 4-9 membered heterocyclic or 5-6 membered heteroaryl.

[0139] In some implementations, ring A is selected from C5-C. 10 Bridged cycloalkyl, C5-C 10 Spirocycloalkyl or 4-9 membered heterocyclic groups.

[0140] In some implementations, ring A is selected from C3-C 12 Cycloalkyl.

[0141] In some implementations, ring A is selected from C5-C. 10 Bridged cycloalkyl groups.

[0142] In some embodiments, ring A is selected from C5-C6 bridged cycloalkyl groups.

[0143] In some implementations, ring A is

[0144] In some implementations, ring A is selected from 5-7 membered heterocyclic groups.

[0145] In some implementations, ring A is selected from 5-7 quinary bicyclic bridged heterocyclic groups or 5-7 quinary monocyclic heterocyclic groups.

[0146] In some implementations, ring A is selected from 5-7 quinary bicyclic bridged heterocyclic groups.

[0147] In some implementations, ring A is selected from a 6-membered heterocyclic group.

[0148] In some implementations, ring A is selected from a 6-membered monocyclic heterocyclic group.

[0149] In some implementations, ring A is selected from...

[0150] In some implementations, ring A is a 5-10 membered heteroaryl group.

[0151] In some implementations, ring A is a 5-6 membered heteroaryl group.

[0152] In some embodiments, ring A is pyridinyl, thiazolyl, pyrazolyl, or pyrimidinyl.

[0153] In some embodiments, ring A is pyridyl, thiazolyl, or pyrazolyl.

[0154] In some embodiments, ring A is pyridyl.

[0155] In some embodiments, ring A is

[0156] In some embodiments, ring A is

[0157] In some embodiments, ring A is phenyl.

[0158] In some embodiments, ring A is selected from

[0159] In some embodiments, ring A is selected from

[0160] In some embodiments, ring A is selected from

[0161] In some embodiments, ring A is selected from

[0162] In some embodiments, ring A is selected from

[0163] In some embodiments, ring A is selected from

[0164] In some embodiments, ring A is selected from

[0165] In some embodiments, ring A is selected from

[0166] In some embodiments, ring A is selected from

[0167] In some embodiments, each R 1 is independently selected from CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halogen, C1-C6 alkyl.

[0168] In some embodiments, each R 1independently selected from CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6 alkyl or C1-C6 alkoxy optionally substituted with OH or halogen.

[0169] In some embodiments, each R 1 independently selected from CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6 alkyl or C1-C6 alkoxy optionally substituted with OH or halogen.

[0170] In some embodiments, each R 1 independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, said C1-C6 alkoxy optionally substituted with halogen.

[0171] In some embodiments, each R 1 independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, said C1-C6 alkoxy optionally substituted with halogen.

[0172] In some embodiments, each R 1 independently selected from CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl, said C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl optionally substituted with OH or halogen.

[0173] In some embodiments, each R 1 independently selected from CN, NH2, OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl, said C3-C6 cycloalkyl or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halogen, or C1-C6 alkyl.

[0174] In some embodiments, R 1 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, said C1-C6 alkyl, C1-C6 alkoxy optionally substituted with NH2, OH, halogen, or C1-C6 alkyl.

[0175] In some embodiments, R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0176] In some embodiments, R1 halogen, C1-C6alkyl, or C1-C6haloalkyl.

[0177] In some embodiments, R 1 is C1-C6alkyl.

[0178] In some embodiments, R 1 is C1-C6haloalkyl.

[0179] In some embodiments, R 1 is selected from F, CH3, CF3, CH2CF3, OCHF2, CN, cyclopropyl, or morpholinyl.

[0180] In some embodiments, R 1 is selected from F, CH3, CF3, CH2CF3, or OCHF2.

[0181] In some embodiments, R 1 is selected from CH3, CF3, or OCHF2.

[0182] In some embodiments, R 1 is selected from F, CH3, or CF3.

[0183] In some embodiments, R 1 is CH3.

[0184] In some embodiments, R 1 is CF3.

[0185] [Rule 26 Correction 10.12.2025] In some embodiments, is selected from the following structures:

[0186] [Rule 26 Correction 10.12.2025] In some embodiments, is selected from the following structures:

[0187] In some embodiments, is selected from the following structures:

[0188] In some embodiments, is selected from the following structures:

[0189] In some embodiments, is selected from the following structures:

[0190] In some embodiments, is selected from the following structures:

[0191] In some embodiments, is selected from the following structures:

[0192] In some embodiments, is selected from the following structures:

[0193] In some embodiments, R 2 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl, optionally substituted with NH2, OH, halogen, or C1-C6 alkyl.

[0194] In some embodiments, R 2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl, optionally substituted with NH2, OH, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl.

[0195] In some embodiments, R 2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl, optionally substituted with NH2, OH, halogen, or C1-C6 alkyl.

[0196] In some embodiments, R 2 is selected from C1-C6 alkyl, or 4-10 membered heterocyclyl, optionally substituted with halogen.

[0197] In some embodiments, R 2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl, optionally substituted with NH2, OH, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl.

[0198] In some embodiments, R 2C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl, optionally substituted with NH2, OH, halo, or C1-C6alkyl.

[0199] In some embodiments, R 2 is C1-C6alkyl substituted with halo.

[0200] In some embodiments, R 2 is C1-C6alkyl substituted with F.

[0201] In some embodiments, R 2 is selected from CF3, CHF2, CH2CHF2, cyclobutyl, or oxetanyl. In some embodiments, R 2 is selected from CH2CHF2, cyclobutyl, oxetanyl, or -CH2-oxetanyl.

[0202] In some embodiments, R 2 is selected from CH2CHF2or oxetanyl.

[0203] In some embodiments, R 2 is selected from CH2CHF2, cyclobutyl, or oxetanyl.

[0204] In some embodiments, R 2 is CH2CHF2.

[0205] In some embodiments, R 3 is selected from H, C1-C6alkyl, or C1-C6alkoxy.

[0206] In some embodiments, R 3 is H.

[0207] In some embodiments, R 4 is selected from deuterium, OH, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C6cycloalkyl.

[0208] In some embodiments, R 4 is selected from deuterium, OH, halo, =O, C1-C6alkyl, or C1-C6haloalkyl.

[0209] In some embodiments, R 4 is selected from deuterium, =O, or C1-C6alkyl.

[0210] In some embodiments, R 4 is selected from =O or C1-C6alkyl.

[0211] In some embodiments, R 4selected from deuterium, =0, or CH3.

[0212] In some embodiments, R 4 selected from =0 or CH3.

[0213] In some embodiments, R 4 selected from deuterium or =0.

[0214] In some embodiments, R 4 is =0.

[0215] In some embodiments, R 5 selected from H, deuterium, halogen, C1-C6alkyl, or C3-C6cycloalkyl.

[0216] In some embodiments, R 5 selected from H, halogen, C1-C6alkyl, or C3-C6cycloalkyl.

[0217] In some embodiments, R 5 selected from H, deuterium, halogen, or C3-C6cycloalkyl.

[0218] In some embodiments, R 5 selected from H or C1-C6alkyl.

[0219] In some embodiments, R 5 selected from H, F, Cl, CH3, or cyclopropyl.

[0220] In some embodiments, R 5 selected from H, F, Cl, or cyclopropyl.

[0221] In some embodiments, R 5 selected from H, Cl, CH3, or cyclopropyl.

[0222] In some embodiments, R 5 selected from H or CH3.

[0223] In some embodiments, R 5 is H.

[0224] In some embodiments, p is selected from 0 or 1.

[0225] In some embodiments, q is selected from 0 or 1.

[0226] In some embodiments, the compound of Formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (I-1) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0227] Ring A is selected from C3-C 12cycloalkyl or 4-12 membered heterocyclyl;

[0228] when W is selected from a bond or -CR a R b , ring B is not the following structure:

[0229] ring B, R 1 , R 2 , R 3 , R 4 , R 5 , p, q, W are as defined above.

[0230] In some embodiments of formula (I-1), ring A is selected from C3-C 12 cycloalkyl or 5-10 membered heterocyclyl.

[0231] In some embodiments of formula (I-1), ring A is selected from C5-C7 cycloalkyl or 5-7 membered heterocyclyl.

[0232] In some embodiments, the compound of formula (I) or formula (I-1), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound represented by formula (II-1), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0233] X1is selected from O, S, or CR 6 R 7 ;

[0234] X2is selected from CR 8 or N;

[0235] X3is selected from C, CR 9 or N;

[0236] R 6 , R 7 , R 8 , R 9 are independently selected from H, deuterium, NH2, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C6cycloalkyl;

[0237] s, m, n are independently selected from 0, 1, or 2;

[0238] q' is selected from 0 or 1;

[0239] q" is selected from 0 or 1;

[0240] ring A is selected from C3-C 12 cycloalkyl or 4-12 membered heterocyclyl;

[0241] when W is selected from a bond or -CR a R b- at the time, ring B is not the following structure:

[0242] R 1 R 2 R 3 R 4 R 5 p, W are as defined above.

[0243] In some embodiments of formula (II-1), R 6 R 7 R 8 R 9 are independently selected from H or C1-C6 alkyl.

[0244] In some embodiments, the compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula (V-1) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0245] ring A is selected from C3-C6 cycloalkyl, 4-9 membered heterocyclyl, or 5-6 membered heteroaryl;

[0246] R 1 R 2 R 3 R 4 R 5 p, q, W are as defined above.

[0247] In some embodiments, the compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula (I-2) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0248] ring A, ring B, R 1 R 2 R 3 R 4 R 5 p, q, W are as defined above.

[0249] In some embodiments of formula (I-2), ring B is selected from C6-C 14 spiro cycloalkylene, 6-14 membered spiro heterocyclylene, or 6-14 membered fused heterocyclylene;

[0250] W is selected from a bond, -CR a R b -, -CR a R b O-, C(O), or O;

[0251] R a, R b is independently selected from H or C1-C6alkyl;

[0252] Ring A is selected from C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl;

[0253] each R 1 is independently selected from CN, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6alkyl and C1-C6alkoxy optionally substituted with OH or halogen;

[0254] R 2 is selected from C1-C6alkyl or 4-10 membered heterocyclyl, said C1-C6alkyl optionally substituted with halogen;

[0255] R 3 is selected from H, C1-C6alkyl, or C1-C6alkoxy;

[0256] R 4 is selected from =O or C1-C6alkyl;

[0257] R 5 is selected from H or C1-C6alkyl.

[0258] In some embodiments of formula (I-2), ring B is selected from 6-14 membered spiro- or fused- heterocyclyl;

[0259] In some embodiments, the compound of formula (I) or formula (I-2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound represented by formula (II-2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0260] X1is selected from O, S, or CR 6 R 7 ;

[0261] X2is selected from CR 8 or N;

[0262] X3is selected from C, CR 9 or N;

[0263] R 6 , R 7 , R 8 , R 9 is independently selected from H, deuterium, NH2, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C6cycloalkyl;

[0264] s, m, n are independently selected from 0, 1, or 2;

[0265] q' is selected from 0 or 1 ;

[0266] q" is selected from 0 or 1 ;

[0267] Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , p, W are as defined above.

[0268] In some embodiments, X1is selected from O or CR 6 R 7 .

[0269] In some embodiments, X2is selected from CH or N.

[0270] In some embodiments, is a single bond, X3is selected from CR 9 or N.

[0271] In some embodiments, at least one of X2and X3is N.

[0272] In some embodiments, R 6 , R 7 , R 8 , R 9 are each independently selected from H, deuterium, or C1-C6alkyl.

[0273] In some embodiments, R 6 , R 7 , R 8 , R 9 are each independently H.

[0274] In some embodiments, s, m, n are each independently selected from 0 or 1.

[0275] In some embodiments, q' is 0; q" is 0.

[0276] In some embodiments, is a single bond.

[0277] In some embodiments, the compound of Formula (I) or Formula (I-2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (III-2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0278] T is selected from N or CH;

[0279] Ring A, R 1 , R 2R 3 R 4 R 5 p, q, W are as defined above.

[0280] In some embodiments, T is N.

[0281] In some embodiments, the compound of Formula (I) or Formula (I-2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (V-2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0282] Ring A, R 1 R 2 R 3 R 4 R 5 p, q, W are as defined above.

[0283] In some embodiments, the compound of Formula (I) or Formula (I-2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (VI-2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0284] Z1is selected from CR 10 or N;

[0285] Z2is selected from CR 10 or N;

[0286] R 10 is selected from H, deuterium, NH2, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C6cycloalkyl;

[0287] t, f, g, k are independently selected from 0, 1, or 2;

[0288] q' is selected from 0 or 1;

[0289] q" is selected from 0 or 1;

[0290] Ring A, R 1 R 2 R 3 R 4 R 5 p, W are as defined above.

[0291] In some embodiments, R 10 is selected from H, deuterium, or C1-C6alkyl.

[0292] In some embodiments, R 10 is H.

[0293] In some embodiments, Z1is N, Z2is selected from CH or N.

[0294] In some embodiments, Z1is CH or N, Z2is selected from N.

[0295] In some embodiments, Z1is N, Z2is CH. In some embodiments, Z1is CH, Z2is selected from N. In some embodiments, Z1is N, Z2is N.

[0296] In some embodiments, at least one of Z1and Z2is N.

[0297] In some embodiments, t is 1.

[0298] In some embodiments, k is 1.

[0299] In some embodiments, f, g are selected from 0 or 1.

[0300] In some embodiments, f, g are both 0.

[0301] In some embodiments, f, g are both 1.

[0302] In some embodiments, q' is 0, q" is 0.

[0303] In some embodiments, the compound of Formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from a compound of Formula (II) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0304] X1is selected from O, S, or CR 6 R 7 ;

[0305] X2is selected from CR 8 or N;

[0306] X3is selected from C, CR 9 or N;

[0307] R 6 , R 7 , R 8 , R 9 are independently selected from H, deuterium, NH2, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C6cycloalkyl;

[0308] s, m, n are independently selected from 0, 1, or 2;

[0309] q' is selected from 0 or 1;

[0310] q" is selected from 0 or 1;

[0311] Rings A and R 1 R 2 R 3 R 4 R 5 p, W, Q, and G are defined as above.

[0312] In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III) or its stereoisomer or a pharmaceutically acceptable salt thereof:

[0313] T is selected from N or CH;

[0314] Rings A and R 1 R 2 R 3 R 4 R 5 p, q, W, Q, G are as defined above.

[0315] In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (IV) or its stereoisomer or a pharmaceutically acceptable salt thereof:

[0316] Y1 and Y2 are independently selected from N or CH;

[0317] Z is selected from CH2 or CH2CH2;

[0318] Rings A and R 1 R 2 R 3 R 4 R 5 p, q, W, Q, G are as defined above.

[0319] In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (V) or its stereoisomer or a pharmaceutically acceptable salt thereof:

[0320] Rings A and R 1 R 2 R 3 R 4 R 5 p, q, W, Q, G are as defined above.

[0321] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (VI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0322] Z1is selected from CR 10 or N;

[0323] Z2is selected from CR 10 or N;

[0324] R 10 is selected from H, deuterium, NH2, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C6cycloalkyl;

[0325] t, f, g, k are independently selected from 0, 1, or 2;

[0326] q' is selected from 0 or 1;

[0327] q" is selected from 0 or 1;

[0328] Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , p, W, Q, G are as defined above.

[0329] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0330] In some embodiments, the compound of Formula (I) or Formula (I-2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0331] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), Formula (I-l), Formula (II-l), Formula (V-l), Formula (I-2), Formula (II-2), Formula (III-2), Formula (V-2), Formula (VI-2), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0332] In another aspect, the present disclosure provides a method of preventing or treating a disease mediated by GCase in a subject (e.g., a mammal), comprising administering to a subject, preferably a mammal, more preferably a human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I), Formula (I-l), Formula (II-l), Formula (V-l), Formula (I-2), Formula (II-2), Formula (III-2), Formula (V-2), Formula (VI-2), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0333] In yet another aspect, the present disclosure provides a method of allosterically modulating GCase, comprising administering to a subject, preferably a mammal, more preferably a human, in need thereof, an effective amount of a compound of Formula (I), Formula (I-l), Formula (II-l), Formula (V-l), Formula (I-2), Formula (II-2), Formula (III-2), Formula (V-2), Formula (VI-2), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0334] In another aspect, the present disclosure provides the use of a compound of Formula (I), Formula (I-l), Formula (II-l), Formula (V-l), Formula (I-2), Formula (II-2), Formula (III-2), Formula (V-2), Formula (VI-2), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing or treating a disease mediated by GCase.

[0335] In yet another aspect, the present disclosure provides the use of a compound of Formula (I), Formula (I-l), Formula (II-l), Formula (V-l), Formula (I-2), Formula (II-2), Formula (III-2), Formula (V-2), Formula (VI-2), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for allosterically modulating GCase.

[0336] In another aspect, the present disclosure provides use of a compound of Formula (I), Formula (I-1), Formula (II-1), Formula (V-1), Formula (I-2), Formula (II-2), Formula (III-2), Formula (V-2), Formula (VI-2), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of a GCase-mediated disease.

[0337] In another aspect, the present disclosure provides use of a compound of Formula (I), Formula (I-1), Formula (II-1), Formula (V-1), Formula (I-2), Formula (II-2), Formula (III-2), Formula (V-2), Formula (VI-2), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of a GCase-mediated disease.

[0338] In another aspect, the present disclosure provides use of a compound of Formula (I), Formula (I-1), Formula (II-1), Formula (V-1), Formula (I-2), Formula (II-2), Formula (III-2), Formula (V-2), Formula (VI-2), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of a GCase-mediated disease.

[0339] In another aspect, the present disclosure provides use of a compound of Formula (I), Formula (I-1), Formula (II-1), Formula (V-1), Formula (I-2), Formula (II-2), Formula (III-2), Formula (V-2), Formula (VI-2), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of a GCase-mediated disease.

[0340] In some embodiments, the GCase-mediated disease is a disease that benefits from allosteric modulation of GCase. In some embodiments, the GCase-mediated disease is a disease that benefits from activation of GCase.

[0341] In some embodiments, the GCase-mediated disease is selected from neurodegenerative diseases.

[0342] In some embodiments, the neurodegenerative disease is Alzheimer’s disease or Parkinson’s disease.

[0343] Any embodiment of any aspect of the present disclosure can be combined with any other embodiment of the same aspect or other aspects. Moreover, any embodiment of any aspect of the present disclosure can be applied to other embodiments of the same aspect or other aspects without departing from the scope of the present disclosure.

[0344] Definitions and explanations of terms

[0345] Unless otherwise indicated, the terms used in the present disclosure have the following meanings. The definitions of the groups and terms described in the present disclosure, including the definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in examples, etc., can be combined and integrated with each other as appropriate. A particular term should not be considered indefinite or unclear in the absence of a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0346] Herein represents a point of attachment.

[0347] The term "stereoisomer" refers to isomers that have the same structure except for the arrangement of atoms in space, including cis-trans isomers, enantiomers, and diastereomers.

[0348] The compounds of the present disclosure can have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and thus the compounds of the present disclosure can exist in specific geometric or stereoisomeric forms. The specific geometric or stereoisomeric forms can be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic mixtures or other mixtures thereof, such as enantiomeric or diastereomeric enrich mixtures, all of which are within the scope of the compounds of the present disclosure. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms can be present in a substituent group, and all such isomers and mixtures thereof are included within the scope of the compounds of the present disclosure. The compounds of the present disclosure containing an asymmetric atom can be isolated in optically active form or as racemic mixtures, and the optically active forms can be obtained either by separation of a racemic mixture or by synthesis using an optically active starting material or reagent.

[0349] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, provided that the valence of the particular atom is normal and the resulting compound is stable. When the substituent group is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo cannot be on an aromatic group.

[0350] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that the ethyl group can be unsubstituted (CH2CH3), mono-substituted (CH2CH2F, CH2CH2C1, etc.), multi-substituted (CHFCH2F, CH2CHF2, CHFCH2C1, CH2CHC12, etc.), or fully substituted (CF2CF3, CF2CC13, CC12CC13, etc.). It will be understood by those skilled in the art that, for any group containing one or more substituents, such group does not include any substitution or substitution pattern that is not

[0351] When any variable (e.g., R a , R b ) occurs more than one time in a compound; each occurrence is independent of the others. b For instance, if a group is substituted with 2 R b , each R a is selected independently.

[0352] When a bond to a substituent interposes two atoms of a ring, the substituent can be bonded to either atom of the ring.

[0353] When a linking group referred to herein is not indicated to be in a particular direction, the linking group is in either direction. For example, when W in structural unit ring A-W-ring B is selected from "-CR a R b O-" then W can be connected in the left-to-right direction to form the unit "ring A-CR a R b O-ring B" or in the right-to-left direction to form the unit "ring A-OCR a R b -ring B".

[0354] Herein, a bond depicted by a solid line and a dashed line represents a single or double bond. For example, the structural unit contains

[0355] Herein, "bond" in "W is selected from a bond" means a direct bond.

[0356] Herein, C m -C n means an integer number of carbon atoms in the range of m-n. For example, "C1-C 10" is intended to mean that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0357] The term "alkyl" refers to a hydrocarbon group of formula C n H 2n+1 The term "C1-C6alkyl" can be understood to mean an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like. The term "C1-C3alkyl" can be understood to mean a straight or branched chain saturated alkyl group having 1, 2, or 3 carbon atoms. The "C1-C3alkyl" group can include the "C1-C6alkyl" group, which can further include the "C1-C3alkyl" group. 10 The term "C1-C6alkyl" can be understood to mean an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like. The term "C1-C3alkyl" can be understood to mean a straight or branched chain saturated alkyl group having 1, 2, or 3 carbon atoms. The "C1-C 10 The term "C1-C6alkyl" can be understood to mean an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like. The term "C1-C3alkyl" can be understood to mean a straight or branched chain saturated alkyl group having 1, 2, or 3 carbon atoms. The "C1-C

[0358] The term "haloalkyl" is intended to include mono-haloalkyl and poly-haloalkyl groups. For example, the term "C1-C6haloalkyl" means a C1-C6alkyl group as defined above substituted by one or more halogen atoms, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, penta chloroethyl, and the like.

[0359] The term "alkoxy" refers to a straight or branched chain alcohol in which the hydrogen atom on the hydroxyl group is replaced by an alkyl group, and can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C6alkoxy" can be understood as "C1-C6alkyloxy" or "C1-C6alkyl-O-". The "C1-C6alkoxy" group can include the "C1-C3alkyl" group. 10 The term "C1-C6alkoxy" can be understood as "C1-C6alkyloxy" or "C1-C6alkyl-O-". The "C1-C6alkoxy" group can include the "C1-C3alkyl" group. 10 The term "C1-C6alkoxy" can be understood as "C1-C6alkyloxy" or "C1-C6alkyl-O-". The "C1-C6alkoxy" group can include the "C1-C3alkyl" group. 10 The term "C1-C6alkoxy" can be understood as "C1-C6alkyloxy" or "C1-C6alkyl-O-". The "C1-C6alkoxy" group can include the "C1-C3alkyl" group.10 Alkoxy" can include "Ci-C6alkoxy" and "Ci-C3alkoxy" and the like ranges, which "Ci-C6alkoxy" can further include "Ci-C3alkoxy".

[0360] The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and exists as a monocyclic, fused, bridged, or spirocyclic, etc. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 14-membered ring. The term "C3-C 12 Cycloalkyl" can be understood to mean a saturated monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Specific examples of said cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C3-C 12 Cycloalkyl" can include "C3-C6cycloalkyl", the term "C3-C6cycloalkyl" can be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, or 6 carbon atoms, specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.

[0361] The term "spirocycloalkyl" refers to a 6- to 14-membered polycyclic group sharing one carbon atom (termed the spiro atom) between single rings, which can contain one or more double bonds, but does not have a fully conjugated pi-electron system overall. Preferred are 7- to 12- (e.g., 7-, 8-, 9-, 10-, 11-, or 12-membered). More preferred are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic spirocycloalkyl groups, where A-membered / B-membered bicyclic spirocycloalkyl refers to a spirocyclic ring formed by an A-membered monocyclic ring and a B-membered monocyclic ring sharing one carbon atom (termed the spiro atom). Specific examples of spirocycloalkyl groups include, but are not limited to:

[0362] The term "spirocycloalkyl" refers to a 6- to 14-membered polycyclic group sharing one carbon atom (termed the spiro atom) between single rings, which can contain one or more double bonds, but does not have a fully conjugated pi-electron system overall. Preferred are 7- to 12- (e.g., 7-, 8-, 9-, 10-, 11-, or 12-membered). More preferred are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic spirocycloalkyl groups, where A-membered / B-membered bicyclic spirocycloalkyl refers to a spirocyclic ring formed by an A-membered monocyclic ring and a B-membered monocyclic ring sharing one carbon atom (termed the spiro atom). Specific examples of spirocycloalkyl groups include, but are not limited to:

[0363] The term "fused cycloalkyl" refers to a 6- to 14-membered polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or more double bonds, but the group as a whole does not have a fully conjugated π-electron system. Preferably, it is 7- to 12-membered (e.g., 7, 8, 9, 10, 11, or 12-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyl, wherein A-membered / B-membered bicyclic fused cycloalkyl refers to a polycyclic group in which an A-membered monocyclic ring and a B-membered monocyclic ring share an adjacent pair of carbon atoms. Specific examples of fused cycloalkyl groups include, but are not limited to:

[0364] The term “condensed cycloalkyl” refers to a divalent group derived from a “condensed cycloalkyl” group as defined herein.

[0365] The term "bridged cycloalkyl" refers to a 5- to 12-membered, all-carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but does not possess a fully conjugated π-electron system overall. Preferably, it is 5- to 9-membered (e.g., 5, 6, 7, 8, or 9-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Specific examples of bridged cycloalkyl groups include, but are not limited to:

[0366] The term “bridged cycloalkyl” refers to a divalent group derived from a “bridged cycloalkyl” group as defined herein.

[0367] The term "heterocyclyl" refers to a monocyclic, fused, spiro, or bridged ring that is fully saturated or partially saturated (not aromatic overall as a heteroaromatic) having 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups (i.e., groups of atoms containing a heteroatom) in its ring atoms, including but not limited to a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), a phosphorus atom (P), a boron atom (B), -S(=0)2-, -S(=0)-, -P(=0)2-, -P(=0)-, -NH-, -S(=0)(=NH)-, -C(=0)NH-, or -NHC(=0)NH-, etc. The term "4-12 membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, and having 1, 2, 3, 4, or 5 ring atoms independently selected from the heteroatoms or heteroatom groups described above. "3-10 membered heterocyclyl" includes "4-7 membered heterocyclyl", wherein specific examples of 4-membered heterocyclyl include but are not limited to azetidinyl, thietanyl, or oxetanyl; specific examples of 5-membered heterocyclyl include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydro-lH-pyrrolyl; specific examples of 6-membered heterocyclyl include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[l,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl include but are not limited to diazepanyl. The heterocyclyl can also be a bicyclic group, wherein specific examples of 5,5 membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrol-2(lH)-yl or ; specific examples of 5,6 membered bicyclic groups include but are not limited to hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[l,5-a]pyrazinyl. Optionally, the heterocyclyl can be a benzo-fused ring of the above 4-7 membered heterocyclyl, specific examples include but are not limited to dihydroisoquinolinyl, etc. "4-10 membered heterocyclyl" can include "5-10 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", etc. "4-7 membered heterocyclyl" can further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", etc. Although some bicyclic heterocyclyl groups in the present disclosure contain a benzene ring or a heteroaromatic ring partially, the heterocyclyl is still non-aromatic overall.

[0368] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group of 6 to 14 members sharing one atom (referred to as the spiro atom) between single rings, wherein one or more ring atoms are a heteroatom selected from a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), S(O), or S(O)2, with the remaining ring atoms being carbon. It can contain one or more double bonds, but as a whole does not have a fully conjugated pi-electron system. Preferably, it is 7 to 12 members (e.g., 7, 8, 9, 10, 11, or 12 members). More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic spiroheterocyclyl. Wherein A-membered / B-membered bicyclic spiroheterocyclyl refers to a spiro ring formed by an A-membered monocyclic ring and a B-membered monocyclic ring sharing one atom (referred to as the spiro atom). Specific examples of spiroheterocyclyl groups include, but are not limited to:

[0369] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group of 6 to 14 members sharing one atom (referred to as the spiro atom) between single rings, wherein one or more ring atoms are a heteroatom selected from a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), S(O), or S(O)2, with the remaining ring atoms being carbon. It can contain one or more double bonds, but as a whole does not have a fully conjugated pi-electron system. Preferably, it is 7 to 12 members (e.g., 7, 8, 9, 10, 11, or 12 members). More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic spiroheterocyclyl. Wherein A-membered / B-membered bicyclic spiroheterocyclyl refers to a spiro ring formed by an A-membered monocyclic ring and a B-membered monocyclic ring sharing one atom (referred to as the spiro atom). Specific examples of spiroheterocyclyl groups include, but are not limited to:

[0370] The term "N-spiroheterocyclyl" refers to a spiroheterocyclyl group as defined above comprising a nitrogen atom as the point of attachment.

[0371] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 6 to 14 members, each ring in the system sharing an adjacent pair of atoms with other rings in the system, wherein one or more ring atoms are a heteroatom selected from a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), S(O), or S(O)2, with the remaining ring atoms being carbon. It can contain one or more double bonds, but as a whole does not have a fully conjugated pi-electron system. Preferably, it is 7 to 12 members (e.g., 7, 8, 9, 10, 11, or 12 members). It can be a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Wherein A-membered / B-membered bicyclic fused heterocyclyl refers to a fused ring formed by an A-membered monocyclic ring and a B-membered monocyclic ring sharing an adjacent pair of atoms. Specific examples of fused heterocyclyl groups include, but are not limited to:

[0372] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 6 to 14 members, each ring in the system sharing an adjacent pair of atoms with other rings in the system, wherein one or more ring atoms are a heteroatom selected from a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), S(O), or S(O)2, with the remaining ring atoms being carbon. It can contain one or more double bonds, but as a whole does not have a fully conjugated pi-electron system. Preferably, it is 7 to 12 members (e.g., 7, 8, 9, 10, 11, or 12 members). It can be a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Wherein A-membered / B-membered bicyclic fused heterocyclyl refers to a fused ring formed by an A-membered monocyclic ring and a B-membered monocyclic ring sharing an adjacent pair of atoms. Specific examples of fused heterocyclyl groups include, but are not limited to:

[0373] The term "N-fused heterocyclyl" refers to a fused heterocyclyl group as defined above comprising a nitrogen atom as the point of attachment.

[0374] The term "bridged heterocyclyl" refers to a 5- to 12-membered, polycyclic heterocyclic radical, sharing any two non-adjacent ring atoms of two rings, which can contain one or more double bonds, but which does not have a fully conjugated pi-electron system overall, wherein one or more ring atoms are heteroatoms selected from nitrogen (N), oxygen (O), S(O), or S(O)2, and the remaining ring atoms are carbon. Preferably 5- to 9-membered, (e.g., 5-, 6-, 7-, 8-, or 9-membered). Depending on the number of rings comprising the ring system, it can be referred to as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Specific examples of bridged heterocyclyl groups include, but are not limited to:

[0375] The term "bridged heterocyclyl" refers to a 5- to 12-membered, polycyclic heterocyclic radical, sharing any two non-adjacent ring atoms of two rings, which can contain one or more double bonds, but which does not have a fully conjugated pi-electron system overall, wherein one or more ring atoms are heteroatoms selected from nitrogen (N), oxygen (O), S(O), or S(O)2, and the remaining ring atoms are carbon. Preferably 5- to 9-membered, (e.g., 5-, 6-, 7-, 8-, or 9-membered). Depending on the number of rings comprising the ring system, it can be referred to as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Specific examples of bridged heterocyclyl groups include, but are not limited to:

[0376] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic ring system that is aromatic. Aryl groups can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 aryl" is understood to mean an aryl group having 6 to 20 carbon atoms. In particular a ring having 6 carbon atoms ("C6aryl"), for example phenyl; or a ring having 9 carbon atoms ("C9aryl"), for example indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms ("C 13 aryl"), for example fluorenyl; or a ring having 14 carbon atoms ("C 14 aryl"), for example anthryl. The term "C6-C 10 aryl" is understood to mean an aryl group having 6 to 10 carbon atoms. In particular a ring having 6 carbon atoms ("C6aryl"), for example phenyl; or a ring having 9 carbon atoms ("C9aryl"), for example indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl. The term "C6-C 20 aryl" can comprise a "C6-C 10 aryl".

[0377] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromaticity, which contains at least one ring atom selected from N, O, S, the remaining ring atoms being C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and which contain 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and the like as well as their benzo derivatives, such as, for example, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl and the like as well as their benzo derivatives, such as, for example, quinolinyl, quinazolinyl or isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like as well as their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl or phenoxazinyl and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and which contain 1, 2 or 3, preferably 1-2 heteroatoms independently selected from N, O and S.

[0378] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0379] The term "treatment" means the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0380] (i) inhibiting the disease or condition, i.e., arresting its development;

[0381] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0382] The term "prevention" means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition, but has not yet been diagnosed as having it.

[0383] The term "therapeutically effective amount" means:

[0384] (i) treating a particular disease, condition or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying the onset of one or more symptoms of a particular disease, condition or disorder described herein, of a compound of the present disclosure.

[0385] The amount of a compound of the present disclosure that will constitute a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the mode of administration, and the age of the mammal to be treated, but will generally be determined by one of skill in the art using his own knowledge and the disclosure herein.

[0386] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0387] The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid or base addition salts, including salts with inorganic acids or organic acids, and salts with inorganic bases or organic bases.

[0388] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.

[0389] The term "pharmaceutically acceptable excipient" refers to those excipients that are not biologically or otherwise undesirable, and that do not interfere with the biological activity of the active compound. Suitable excipients are well known to those skilled in the art, e.g., carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0390] The term "individual" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (such as chimpanzees and other apes and monkey species); farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds and fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0391] The words "comprise" or "comprising" and variations such as "comprises" or "comprising", when used in this document, can be understood to encompass the terms "consisting of" or "consisting of" and variations thereof, such as "consists" or "consisting of".

[0392] The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, and the like.

[0393] Certain isotopically-labeled compounds of the present disclosure (for example, those 3 H and 14 C) can be used in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by

[0394] The pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with a suitable pharmaceutically acceptable excipient, such as can be formulated into solid, semi-solid, liquid, or gaseous dosage forms, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, aerosols, and the like.

[0395] Typical routes of administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0396] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, emulsification, freeze drying, etc.

[0397] In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0398] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, flow aids, or flavoring agents.

[0399] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0400] In all methods of administration of the compounds of general formula (I) or formula (I-1) or formula (V-1) or formula (I-2) or their stereoisomers or pharmaceutically acceptable salts described herein, the daily dose is from 0.01 mg / kg to 1000 mg / kg body weight, in the form of single or separate doses. Detailed Implementation

[0401] The invention will now be described in detail with reference to embodiments, but this does not imply any adverse limitation of the present disclosure. The present disclosure has been described in detail herein, including specific embodiments thereof. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope thereof.

[0402] Unless otherwise specified, all reagents used in this disclosure are commercially available and can be used without further purification.

[0403] Unless otherwise stated, the proportions expressed for mixed solvents are volume-based.

[0404] Unless otherwise stated, % refers to wt%.

[0405] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0406] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR determination is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS). "IC 50 " refers to the half maximal inhibitory concentration, which refers to the concentration at which the effect of the maximum inhibition is halved.

[0407] The eluent below can form a mixed eluent from two or more solvents, and the ratio is the volume ratio of each solvent, such as "0-7% tetrahydrofuran / petroleum ether", which means that during the gradient elution process, the volume ratio of tetrahydrofuran / petroleum ether in the mixed eluent is 0:100-7:93.

[0408] Abbreviations:

[0409] THF: tetrahydrofuran; LiAlH4: lithium aluminum hydride; DCM: dichloromethane; TEA: triethylamine; Ms2O: methanesulfonic anhydride; DMF: N,N- dimethylformamide; TFA: trifluoroacetic acid; Na2CO3: sodium carbonate; MeOH: methanol; NaBH3CN sodium cyanoborohydride; Py: pyridine; EDCI: l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; BOC: tert-butoxycarbonyl; DMSO: dimethylsulfoxide; Pd(dppf)Cl2: [l,l'-bis(diphenylphosphino) ferrocene] palladium dichloride; dioxane: dioxane; ACN: acetonitrile; DBU: 1,8- diazabicyclo[5.4.0]undec-7-ene; EtOH: ethanol; NaIO4: sodium periodate; NaBH3CN: sodium cyanoborohydride; K2OsO4: potassium osmium; EA: ethyl acetate; EPhos Pd G4: (methylsulfonic acid {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[l,l'- biphenyl]-2-yl)phosphane}(2'-methylamino-l,l'-biphenyl-2-yl)palladium(II); EPhos: bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[l,l'-biphenyl]-2-yl)phosphane; HATU: 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DMA: N,N-dimethyl aniline; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; DIPEA or DIEA: N,N-diisopropylethylamine; Rf: ratio of the migration distance of the solute to the migration distance of the mobile phase; LiHDMS: lithium bis(trimethylsilyl)amide; TOSMIC: methyl phenylsulfonyl methyl isocyanide; t-BuOK: potassium tert-butoxide; Gphos G6 Pd: [2-(dicyclohexylphosphino)-3-tert-butoxy-6-methoxy-2',6'- diisopropyl-l,l'-biphenyl](4-((2-(trimethylsilyl)ethoxy)carbonyl)phenyl-l-yl)palladium bromide.

[0410] Example 1: 6-(6-(Bicyclo[l.l.l]pentan-l-ylmethoxy)-2-azaspiro[3.3]heptan-2-yl)-l-(2,2- difluoroethyl)-lH-pyrazolo[3,4-b]pyrazine

[0411] Step 1: Synthesis of Intermediate 1-2

[0412] Compound 1-1 (1.00 g) was dissolved in 15 mL of tetrahydrofuran under nitrogen protection, and a tetrahydroaluminum lithium solution (2.5 M, 5.35 mL) was added dropwise at 0 °C. After stirring at room temperature for 16 hours, the reaction was completed. The reaction solution was quenched by adding water (2 mL), 15% NaOH (2 mL), and H2O (6 mL) at 0 °C, and anhydrous magnesium sulfate was added and stirred for 30 minutes. After filtration, the filtrate was concentrated to obtain intermediate 1-2 (1.03 g).

[0413] 1 H-NMR (400 MHz, DMSO-d6) δ 4.47 (t, J = 5.5 Hz, 1H), 3.36 (d, J = 5.6 Hz, 2H), 2.54 (s, 1H), 1.70 (s, 6H).

[0414] Step 2: Synthesis of intermediate 1-3

[0415] Intermediate 1-2 (0.90 g) was dissolved in 10 mL of dichloromethane under nitrogen protection, and triethylamine (2.78 g) and methanesulfonic anhydride (3.19 g) were added at 0 °C. After stirring at room temperature for 16 hours, the reaction was completed. To the reaction solution was added 20 mL of dichloromethane, which was washed with saturated sodium bicarbonate (10 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 1-3 (1.46 g).

[0416] 1 H-NMR (400 MHz, DMSO-d6) δ 4.47 (t, J = 5.5 Hz, 1H), 3.36 (d, J = 5.6 Hz, 2H), 2.54 (s, 1H), 1.70 (s, 6H).

[0417] Step 3: Synthesis of intermediate 1-4

[0418] tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1.05 g) was dissolved in N,N-dimethylformamide (15 mL) and cooled to 0 °C, and sodium hydride (295 mg, 60% purity) was slowly added under a nitrogen atmosphere. After stirring for 30 minutes, intermediate 1-3 (1.30 g) was added. After stirring at room temperature for 16 hours, the reaction was completed. 15 mL of saturated ammonium chloride solution was slowly added, followed by extraction with ethyl acetate (20 mL*3), and the combined organic phase was washed with saturated brine (10 mL*2). After drying over anhydrous sodium sulfate, the organic phase was concentrated. The crude product was purified by silica gel column chromatography (gradient 0-7% tetrahydrofuran / petroleum ether) to obtain intermediate 1-4 (0.62 g).

[0419] 1H-NMR (400 MHz, DMSO-d6) δ 3.85-3.70 (m, 5H), 3.18 (s, 2H), 2.48 (s, 1H), 2.39-2.37 (m, 2H), 1.98-1.95 (m, 2H), 1.67 (s, 6H), 1.36 (s, 9H).

[0420] Step 4: synthesis of intermediate 1-5

[0421] Intermediate 1-4 (0.62 g) was dissolved in 8 mL of dichloromethane, trifluoroacetic acid (2.24 g) was added, the reaction was completed after the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain intermediate 1-5 (0.43 g), which was directly used in the next step reaction.

[0422] Step 5: synthesis of compound 1

[0423] Intermediate 1-5 (196 mg) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (100 mg) were dissolved in N,N-dimethylformamide (2 mL), and sodium carbonate (145 mg) was added. The reaction was completed after being stirred at 100°C for 16 hours. 10 mL of water was added, and ethyl acetate (10 mL*2) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative high performance liquid chromatography (column: C18 150*40 mm; mobile phase: [acetonitrile-water (0.5‰ ammonia water + 0.01‰ ammonium bicarbonate)]; acetonitrile ratio: 40%-80%) to obtain the title compound 1 (57.2 mg).

[0424] 1 H-NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.88 (s, 1H), 6.43 (tt, J = 3.7, 54.9 Hz, 1H), 4.66 (td, J = 15.0, 3.8 Hz, 2H), 4.17 (s, 2H), 4.12 (m, 2H), 3.91-3.84 (m, 1H), 3.22 (s, 2H), 2.55-2.50 (m, 2H), 2.50 (s, 1H), 2.13-2.04 (m, 2H), 1.70 (s, 6H).

[0425] MS m / z (ESI): 376.1.

[0426] Example 2: 6-(2-(Bicyclo[1.1.1]pentan-1-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine

[0427] Step 1: Synthesis of intermediate 2-2

[0428] Compound 2-1 (500 mg) and bicyclo[l.l.l]-l-pentanamine hydrochloride (228 mg) were added to 5 mL of methanol under nitrogen protection, stirred at 60 °C for 16 hours, then sodium cyanoborohydride (240 mg) was added, the reaction was completed after continuing to stir at 60 °C for 16 hours. The reaction was quenched by adding 10 mL of saturated aqueous sodium bicarbonate solution and 1 mL of 15% aqueous sodium hydroxide solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (fast silica gel column, gradient 0-80% petroleum ether / tetrahydrofuran) to obtain intermediate 2-2 (220 mg). 12g .

[0429] MS m / z (ESI): 237.2 [M-56] +

[0430] Step 2: Synthesis of intermediate 2-3

[0431] Intermediate 2-2 (220 mg) and 1 mL of trifluoroacetic acid were added to 3 mL of dichloromethane under nitrogen protection, and the reaction was completed after stirring at 25 °C for 12 hours. The reaction was concentrated to obtain the crude product of intermediate 2-3 (250 mg), which was directly used in the next reaction.

[0432] MS m / z (ESI): 193.3 [M+H] + .

[0433] Step 3: Synthesis of compound 2

[0434] Intermediate 2-3 (150 mg) and 6-chloro-l-(2,2-difluoroethyl)-lH-pyrazolo[3,4-b]pyrazine (221 mg) were dissolved in N,N-dimethylformamide (2 mL), and sodium carbonate (413 mg) was added. The reaction was completed after stirring at 100 °C for 12 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative high performance liquid chromatography (Phenomenex Gemini NX 150*30 mm, 5 μm; mobile phase: [acetonitrile-water (2.25% formic acid)]; acetonitrile ratio: 27%-67%) to obtain the title compound 2 (25.5 mg).

[0435] MS m / z (ESI): 375.2 [M+H] + .

[0436] 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.11 (s, 1H), 6.43 (tt, J = 54.9, 3.8 Hz, 1H), 4.68 (td, J = 15.0, 3.8 Hz, 2H), 3.77 - 3.61 (m, 4H), 2.98 (s, 4H), 2.39 (s, 1H), 1.75 - 1.69 (m, 4H), 1.66 (s, 6H).

[0437] Example 3: 6-(2-(Bicyclo[l. l. l ]pentan- l -ylmethyl)-2,7-diazaspiro[3.5]nonan-7-yl)- l -(2,2- difluoroethyl)- lH-pyrazolo[3,4-b]pyrazine

[0438] Step 1: Synthesis of Intermediate 3-2

[0439] Compound 3-1 (1.00 g), 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (2.02 g) were dissolved in 30 mL of pyridine, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.42 g) was added at 0 °C, the reaction was stirred at 25 °C for 16 hours. The reaction was concentrated to get the crude product, which was purified by silica gel column chromatography (gradient 0-12% tetrahydrofuran / petroleum ether) to give Intermediate 3-2 (2.40 g).

[0440] MS m / z (ESI): 321.1 [M+H] +

[0441] 1 H NMR (400 MHz, DMSO-d6) δ 3.93 (s, 2H), 3.55 (s, 2H), 3.30 - 3.22 (m, 4H), 2.42 (s, 1H), 2.00 (s, 6H), 1.64 - 1.58 (m, 4H), 1.39 (s, 9H).

[0442] Step 2: Synthesis of Intermediate 3-3

[0443] Intermediate 3-2 (370 mg) was dissolved in 5 mL of tetrahydrofuran, under nitrogen atmosphere, borane / tetrahydrofuran solution (1 M, 3.46 mL) was added slowly dropwise. After the addition was completed, the reaction was warmed to 65 °C and stirred for 16 hours. LCMS showed the reaction was complete. The reaction was quenched by slowly adding 10 mL of methanol, the reaction was concentrated to get the crude product (350 mg), which was used directly in the next step.

[0444] Step 3: Synthesis of Intermediate 3-4

[0445] Intermediate 3-3 (350 mg) was dissolved in 6 mL of dichloromethane, trifluoroacetic acid (2.30 g) was added, and the reaction was completed after stirring at 25 °C for 16 hours. The reaction solution was concentrated to obtain the target crude product (285 mg), which was directly used in the next step.

[0446] MS m / z (ESI): 207.1 [M+H] +

[0447] Step 4: Synthesis of compound 3

[0448] Intermediate 3-4 (94.4 mg) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4- b]pyrazine (100 mg) were dissolved in N,N-dimethylformamide (2 mL), and sodium carbonate (146 mg) was added. The reaction was completed after stirring at 100 °C for 16 hours. 10 mL of water was added, and extraction was performed with ethyl acetate (10 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative high-performance liquid chromatography (C18 150*40 mm; mobile phase: [acetonitrile-water (0.5‰ ammonia water + 0.01‰ ammonium bicarbonate)]; acetonitrile ratio: 12%-52%) to obtain the title compound 3 (65.5 mg).

[0449] MS m / z (ESI): 389.1 [M+H] +

[0450] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.12 (s, 1H), 6.43 (tt, J = 54.9, 3.8 Hz, 1H), 4.68 (td, J = 15.0, 3.8 Hz, 2H), 3.79-3.63 (m, 4H), 2.98 (s, 4H), 2.45 (s, 1H), 2.42 (s, 2H), 1.79-1.70 (m, 4H), 1.66 (s, 6H).

[0451] Example 4: 1-(2,2-difluoroethyl)-6-(2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-2,7- diazaspiro[3.5]nonan-7-yl)-1H-pyrazolo[3,4-b]pyrazine

[0452] According to the synthetic method of Reference Example 2, the bicyclo[1.1.1]-1-pentanamine hydrochloride in Step 1 was replaced by (1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride), and the title compound 4 was prepared in the same manner.

[0453] MS m / z (ESI): 405.2 [M+H] + .

[0454] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.12 (s, 1H), 6.43 (tt, J = 54.9, 3.8 Hz, 1H), 4.69 (td, J = 15.0, 3.8 Hz, 2H), 3.80 - 3.67 (m, 4H), 3.40 (s, 2H), 3.25 (br s, 4H), 1.83 - 1.69 (m, 6H), 1.50 - 1.49 (m, 2H), 1.36 (s, 3H).

[0455] Example 5: 7-(Bicyclo[l. l. l ]pentan- l -ylmethoxy)-2-( l -(2,2-difluoroethyl)- lH- pyrazolo[3,4-b]pyrazin-6-yl)-5-oxa-2-azaspiro[3.4]octane

[0456] Reference Example 1, Step 3, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2- carboxylate was replaced by tert-butyl 6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate. (tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate) was prepared in the same manner as Reference Example 1, Step 4 to give Compound 5.

[0457] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.12 (s, 1H), 6.43 (tt, J = 54.9, 3.8 Hz, 1H), 4.69 (td, J = 15.0, 3.8 Hz, 2H), 3.80 - 3.67 (m, 4H), 3.40 (s, 2H), 3.25 (br s, 4H), 1.83 - 1.69 (m, 6H), 1.50 - 1.49 (m, 2H), 1.36 (s, 3H).

[0458] MS m / z (ESI): 405.2 [M+H]

[0459] Example 6: 6-(2-(Bicyclo[l. l. l ]pentan- l -ylmethoxy)-7-azaspiro[3.5]nonan-7-yl)- l -(2,2- difluoroethyl)- lH-pyrazolo[3,4-b]pyrazine

[0460] Reference Example 1, Step 3, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2- carboxylate was replaced by tert-butyl 6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate. (2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester), compound 6 was prepared in the same manner.

[0461] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.11 (s, 1H), 6.43 (tt, J = 54.9, 3.8 Hz, 1H), 4.68 (td, J = 15.0, 3.8 Hz, 2H), 4.11 - 3.88 (m, 1H), 3.78 - 3.57 (m, 4H), 3.21 (s, 2H), 2.49 (s, 1H), 2.26 - 2.13 (m, 2H), 1.70 (s, 6H), 1.69 - 1.54 (m, 6H).

[0462] MS m / z (ESI): 404.3.

[0463] Example 7: 6-(2-(Bicyclo[1.1.1]pentan-1-ylmethoxy)-6-azaspiro[3.4]octan-6-yl)-1-(2,2- difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine

[0464] Reference Example 1 was prepared by the synthetic method of Reference Example 2, replacing 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester in Step 3 with (2-hydroxy-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester), compound 7 was prepared in the same manner.

[0465] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.11 (s, 1H), 6.43 (tt, J = 54.9, 3.8 Hz, 1H), 4.68 (td, J = 15.0, 3.8 Hz, 2H), 4.11 - 3.88 (m, 1H), 3.78 - 3.57 (m, 4H), 3.21 (s, 2H), 2.49 (s, 1H), 2.26 - 2.13 (m, 2H), 1.70 (s, 6H), 1.69 - 1.54 (m, 6H).

[0466] MS m / z (ESI): 404.3.

[0467] Example 8: 6-(2-(Bicyclo[1.1.1]pentan-1-ylmethyl)-2-azaspiro[3.5]non-6-en-7-yl)-1-(2,2- difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine

[0468] Step 1: Synthesis of Intermediate 8-2

[0469] Compound 8-1 (300 mg) and bis(pinacolato)diboron (697 mg) were dissolved in 5 mL of dioxane, potassium acetate (404 mg) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (167 mg) were added. The reaction was stirred at 80 °C for 2 hours under nitrogen protection. The reaction was complete. The reaction was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate gradient elution) to give the title compound 8-2 (425 mg).

[0470] MS m / z (ESI): 229.1 [M+H-82] +

[0471] Step 2: synthesis of intermediate 8-3

[0472] Intermediate 8-2 (425 mg) and 7-((trifluoromethyl)sulfonyl)oxy)-2- azaspiro[3.5]non-6-ene-2-carboxylic acid tert-butyl ester (300 mg) were dissolved in 5 mL of dioxane and 1 mL of water, cesium carbonate (668 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (111 mg) were added. The reaction was stirred at 90 °C for 2 hours under nitrogen protection. The reaction was complete. 15 mL of water was added, extracted with ethyl acetate (15 mL*3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (gradient 0-13% petroleum ether / tetrahydrofuran, flow rate 30 mL / min) to give intermediate 8-3 (270 mg). 4g flash silica gel column, gradient 0-13% petroleum ether / tetrahydrofuran, flow rate 30 mL / min), to give intermediate 8-3 (270 mg).

[0473] MS m / z (ESI): 406.3 [M+H] +

[0474] Step 3: synthesis of intermediate 8-4

[0475] Intermediate 8-3 (218 mg) was dissolved in 3 mL of dichloromethane, trifluoroacetic acid (1.23 g) was added. The reaction was stirred at 30 °C for 2 hours. The reaction was complete by LC-MS monitoring. The reaction was concentrated under reduced pressure to give the target product crude intermediate 8-4 (164 mg).

[0476] MS m / z (ESI): 306.1 [M+H] +

[0477] Step 4: synthesis of compound 8

[0478] The crude intermediate 8-4 (165 mg) obtained in the previous step and bicyclo[1.1.1]pentane-1-ylmethanesulfonate (123 mg) were dissolved in 3 mL of acetonitrile, and potassium carbonate (224 mg) was added. The reaction solution was heated to 80 °C and stirred for 16 hours until the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (Welch Xtimate C18 150*25mm*5um; mobile phase: [acetonitrile-water (0.5‰ ammonia + 0.01‰ ammonium bicarbonate)]; acetonitrile ratio: 60%-80%) to obtain compound 8 (10.6 mg).

[0479] 1 H NMR (400MHz, DMSO-d6) δ8.97(s,1H),8.48(s,1H),7.21-6.81(m,1H),6.51(tt,J=54.7,3.6Hz,1H),4.91(td,J=15. 2,3.7Hz,2H),3.10-2.89(m,4H),2.72-2.58(m,2H),2.43(s,1H),2.41(s,2H),1.88(t,J=6.3Hz,2H),1.64(s,6H).

[0480] MS m / z (ESI): 386.3 [M+H] +

[0481] Example 9: 6-(4-(bicyclo[1.1.1]pentan-1-ylmethyl)piperazin-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine

[0482] Referring to the synthesis method of Example 3, the tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate in step 1 was replaced with (Piperazine-1-carboxylic acid tert-butyl ester), the title compound 9 was prepared by the same method.

[0483] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.14(s,1H),6.44(tt,J=54.9,3.9Hz,1H),4.69(td,J=15. 0,3.9Hz,2H),3.73(t,J=5.1Hz,4H),2.55-2.51(m,4H),2.49(s,1H),2.38(s,2H),1.76(s,6H).

[0484] MS m / z (ESI): 349.1 [M+H] +

[0485] Example 10: 6-(2-(bicyclo[1.1.1]pentan-1-ylmethyl)-2-azaspiro[3.5]nonane-7-yl)-1-(2,2-difluoroethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0486] Step 1: Synthesis of intermediate 10-2

[0487] Compound 10-1 (2.15 g) and 7-amino-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.1 g) were dissolved in 50 mL of tetrahydrofuran. 1,8-diazabicyclo[5.4.0]undec-7-ene (1.39 g) was added at 0 °C. The mixture was heated to 60 °C and stirred for 16 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography. 20g Intermediate 10⁻² (1.9 g) was prepared by rapid silica gel column chromatography with a gradient of 0–14% petroleum ether / tetrahydrofuran at a flow rate of 100 mL / min.

[0488] 1 H NMR (400MHz, DMSO-d6) δ9.00 (d, J = 7.7Hz, 1H), 8.38 (s, 1H), 6.62-6.15 (m, 1H), 4.80-4.60 (m, 2H), 3.85 -3.70(m,1H),3.61-3.49(m,4H),1.90-1.69(m,4H),1.61-1.47(m,2H),1.37(s,9H),1.34-1.21(m,2H).

[0489] MS m / z(ESI): 388.0 [M+H-56] +

[0490] Step 2: Synthesis of intermediate 10-3

[0491] Intermediate 10⁻² (1.9 g) was dissolved in a mixture of 32 mL ethanol and 8 mL water, and iron powder (1.20 g) and ammonium chloride (2.29 g) were added. The reaction mixture was stirred at 80 °C for 1 hour until the reaction was complete. The reaction mixture was filtered, concentrated under reduced pressure, and 20 mL of water was added. It was extracted with ethyl acetate (20 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude intermediate 10⁻³ (1.6 g).

[0492] MS m / z (ESI): 358.4 [M+H-56] +

[0493] Step 3: Synthesis of intermediate 10⁻⁴

[0494] The crude intermediate 10⁻³ (700 mg) obtained in the previous step was dissolved in 3 mL of formamide. The reaction solution was stirred at 120 °C for 16 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then purified by rapid silica gel column chromatography. 40g Intermediate 10⁻⁴ (270 mg) was prepared by rapid silica gel column chromatography with a gradient of 0–25% petroleum ether / tetrahydrofuran at a flow rate of 80 mL / min.

[0495] MS m / z (ESI): 368.3 [M+H-56] +

[0496] Step 4: Synthesis of intermediate 10-5

[0497] Intermediate 10⁻⁴ (210 mg) was dissolved in 3.0 mL of dichloromethane, and then trifluoroacetic acid (1.13 g) was added. The reaction mixture was stirred at 30 °C for 2 hours, and the reaction was monitored by LC-MS until complete. The reaction mixture was concentrated under reduced pressure to obtain intermediate 10⁻⁵ (160 mg).

[0498] MS m / z (ESI): 324.2 [M+H] +

[0499] Step 5: Synthesis of Compound 10

[0500] Intermediate 10-5 (130 mg) and methyl bicyclo[1.1.1]pentane-1-ylmethanesulfonate (92.1 mg) were dissolved in 2 mL of acetonitrile, and potassium carbonate (166 mg) was added. The reaction solution was stirred at 80 °C for 16 hours until the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [acetonitrile-water (0.01‰ ammonium bicarbonate)]; acetonitrile ratio: 50%-70%) to obtain compound 10 (24.5 mg).

[0501] 1H NMR (400MHz, DMSO-d6) δ8.31(s,1H),8.13(s,1H),6.43(tt,J=54.9,3.8Hz,1H),5.03(td,J=14.6,3.8Hz,2H),4.74-4.47(m,1H),3.02(s, 2H),2.87(s,2H),2.45(s,1H),2.41(s,2H),1.99(d,J=13.0Hz,2H),1.92-1.77(m,2H),1.74-1.68(m,2H),1.66(s,6H),1.60-1.47(m,2H).

[0502] MS m / z (ESI): 404.3 [M+H] +

[0503] Example 11: 1-(2,2-difluoroethyl)-6-(6-((3-fluorobicyclo[1.1.1]pentan-1-yl)methoxy)-2-azaspiro[3.3]heptan-2-yl)-1H-pyrazolo[3,4-b]pyrazine

[0504] Referring to the synthesis method of Example 1, compound 1-1 in step 1 was replaced with (3-Fluorobicyclo[1.1.1]pentane-1-carboxylic acid), compound 11 was prepared by the same method.

[0505] 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),7.88(s,1H),6.43(tt,J=54.9,3.8Hz,1H),4.66(td,J=15.0,3.8Hz,2H),4.17 (s,2H),4.12(s,2H),3.97-3.86(m,1H),3.52(s,2H),2.57-2.52(m,2H),2.16-2.04(m,2H),1.97(d,J=2.7Hz,6H).

[0506] MS m / z(ESI): 394.2 [M+H] +

[0507] Example 12: 1-(2,2-difluoroethyl)-6-(4-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyrazine

[0508] Referring to the synthesis method of Example 3, the tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate in step 1 was replaced with (piperazine-1-carboxylic acid tert-butyl ester), while replacing 3-1 with (3-Fluorobicyclo[1.1.1]pentane-1-carboxylic acid), compound 12 was prepared by the same method.

[0509] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.14(s,1H),6.43(tt,J=54.8,3.8Hz,1H),4.69(td,J=15. 0,3.8Hz,2H),3.73(t,J=5.0Hz,4H),2.67(s,2H),2.54(t,J=5.1Hz,4H),2.02(d,J=2.7Hz,6H).

[0510] MS m / z(ESI): 367.2 [M+H] +

[0511] Example 13: 1-(2,2-difluoroethyl)-6-(4-((1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methyl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyrazine

[0512] Referring to the synthesis method of Example 3, the tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate in step 1 was replaced with (piperazine-1-carboxylic acid tert-butyl ester), while replacing compound 3-1 with (1-Methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid), compound 13 was prepared by the same method.

[0513] 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),8.04(s,1H),6.21(tt,J=55.6,4.5Hz,1H),4.65(td,J=1 3.3,4.5Hz,2H),3.81-3.68(m,6H),2.73(s,2H),2.64-2.49(m,4H),1.61(s,4H),1.44(s,3H).

[0514] MS m / z (ESI): 379.3 [M+H] +

[0515] Example 14: 1-(2,2-difluoroethyl)-6-(4-(1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyrazine

[0516] Step 1: Synthesis of intermediate 14-2

[0517] Compound 14-1 (1.00 g), 2,6-dimethylpyridine (1.05 g), and sodium periodate (4.21 g) were dissolved in a mixed solution of ethyl acetate (10 mL) and water (10 mL). Potassium osmium tetroxide (90.6 mg) was added at 0 °C. The reaction was completed after stirring at room temperature for 3 hours. After separation, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude intermediate 14-2 (1.16 g), which was directly used in the next reaction.

[0518] MS m / z(ESI): 236.1 [M+H] +

[0519] Step 2: Synthesis of 14-3

[0520] Intermediate 14-2 (1.16 g) from the previous step, 1-methyl-2-oxabicyclo[2.1.1]hexane-4-amine hydrochloride (885 mg), and triethylamine (2.49 g) were dissolved in 10 mL of ethyl acetate, followed by the addition of sodium cyanoborohydride (1.55 g). The reaction was stirred at 20 °C for 16 hours until complete. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to rapid silica gel column chromatography (…). 40g The intermediate 14-3 (500 mg) was purified by rapid silica column chromatography with a gradient of 0–14% petroleum ether / tetrahydrofuran at a flow rate of 60 mL / min.

[0521] MS m / z (ESI): 317.2 [M+H] +

[0522] Step 3: Synthesis of 14-4

[0523] Intermediate 14-3 (500 mg) was dissolved in 10 mL of tetrahydrofuran, and wet Pd / C (500 mg) was added. The reaction solution was stirred at 20 °C under a hydrogen atmosphere for 16 hours until the reaction was complete. The reaction solution was filtered and concentrated under reduced pressure to obtain crude intermediate 14-4 (280 mg), which was directly used in the next step of the reaction.

[0524] MS m / z (ESI): 183.2 [M+H] +

[0525] Step 4: Synthesis of Compound 14

[0526] Intermediate 14-4 (180 mg) from the previous step and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (215 mg) were dissolved in N,N-dimethylformamide (2 mL), and sodium carbonate (314 mg) was added. The mixture was heated to 100 °C and stirred for 16 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [acetonitrile-water (0.5‰ ammonia + 0.01‰ ammonium bicarbonate)]; acetonitrile ratio: 13%-33%) to obtain compound 14 (25 mg).

[0527] MS m / z (ESI): 365.1 [M+H] + .

[0528] 1 H NMR (400MHz, DMSO-d6) δ8.47(s,1H),8.15(s,1H),6.45(tt,J=54.9,3.8Hz,1H),4.70(td,J=15.0,3.8Hz,2H), 3.77(t,J=5.0Hz,4H),3.59(s,2H),2.66(t,J=5.1Hz,4H),1.84-1.66(m,2H),1.57-1.45(m,2H),1.34(s,3H).

[0529] Example 15: 6-(4-(bicyclo[1.1.1]pentan-1-yl)piperazin-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine

[0530] Referring to the synthesis method of Example 14, the 1-methyl-2-oxabicyclo[2.1.1]hexane-4-amine hydrochloride in step 2 was replaced with (Bicyclo[1.1.1]pentane-1-amine hydrochloride), compound 15 was prepared by the same method.

[0531] 1 H NMR (400MHz, DMSO-d6) δ8.46 (s, 1H), 8.14 (s, 1H), 6.44 (tt, J = 54.8, 3.7Hz, 1H), 4.69 (td ,J=15.0,3.8Hz,2H),3.75(t,J=5.1Hz,4H),2.53-2.46(m,4H),2.43(s,1H),1.73(s,6H).

[0532] MS m / z (ESI): 335.2 [M+H] +

[0533] Example 16: 1-(2,2-difluoroethyl)-6-(4-(3-fluorobicyclo[1.1.1]pentan-1-yl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyrazine

[0534] Referring to the synthesis method of Example 14, the 1-methyl-2-oxabicyclo[2.1.1]hexane-4-amine hydrochloride in step 2 was replaced with (3-Fluorobicyclo[1.1.1]pentane-1-amine hydrochloride), compound 16 was prepared by the same method.

[0535] 1 H NMR (400MHz, DMSO-d6) δ8.46 (s, 1H), 8.14 (s, 1H), 6.44 (tt, J = 54.8, 3.7Hz, 1H), 4.69 (td,J=15.0,3.8Hz,2H),3.80-3,60(m,4H),2.53-2.46(m,4H),2.02(d,J=2.7Hz,6H).

[0536] MS m / z (ESI): 353.2 [M+H] +

[0537] Example 17: (4-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperazin-1-yl)(3-fluorobicyclo[1.1.1]pentan-1-yl)methyl ketone

[0538] Step 1: Synthesis of intermediate 17-2

[0539] Compound 17-1 (1.00 g) and piperazine-1-carboxylic acid tert-butyl ester (1.69 g) were dissolved in 20 mL of pyridine. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.42 g) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours until the reaction was complete. The reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (gradient 0–12% tetrahydrofuran / petroleum ether) to obtain intermediate 17-2 (1.80 g).

[0540] Step 2: Synthesis of intermediate 17-3

[0541] Intermediate 17-2 (100 mg) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was slowly added dropwise at 0 °C. The mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain crude intermediate 17-3 of the title compound, which was directly added to the next step of the reaction.

[0542] MS m / z (ESI): 199.2 [M+H]+

[0543] Step 3: Synthesis of Compound 17

[0544] The crude intermediate 17-3 (60 mg) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (77.0 mg) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of sodium carbonate (102 mg). The reaction was carried out after stirring at 100 °C for 2 hours. The reaction solution was cooled to room temperature, and 30 mL of water was added. Ethyl acetate (10 mL * 3) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [acetonitrile-water (0.5‰ ammonia + 0.01‰ ammonium bicarbonate)]; acetonitrile ratio: 45-75%) to obtain compound 17 (108 mg).

[0545] 1 H NMR(400MHz,Chloroform-d)δ8.23(s,1H),8.08(s,1H),6.21(tt,J=55.6,4.5H z,1H),4.67(td,J=13.4,4.4Hz,2H),3.87-3.70(m,8H),2.48(d,J=2.4Hz,6H).

[0546] MS m / z(ESI): 381.2 [M+H] +

[0547] Example 18: 1-(2,2-difluoroethyl)-6-(2-(2-(trifluoromethyl)pyridin-4-yl)-2-azaspiro[3.5]nonane-7-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0548] 4-Bromo-2-(trifluoromethyl)pyridine (56.8 mg), compound 10-5 (100 mg), and potassium carbonate (94.8 mg) were dissolved in N,N-dimethylformamide (2 mL). The reaction solution was stirred at 80 °C for 8 hours until the reaction was complete. After cooling the reaction solution to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by high performance liquid chromatography (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [acetonitrile-water (0.5‰ ammonia + 0.01‰ ammonium bicarbonate)]; acetonitrile ratio: 60-90%) to obtain title compound 18 (26.0 mg).

[0549] H NMR (400MHz, Chloroform-d) δ8.31(d,J=5.6Hz,1H),7.99(s,1H),7.89(s,1H),6.62(d,J=2.3Hz,1H),6.48-6.01(m,2H),5.03( td,J=13.1,4.4Hz,2H),4.85-4.69(m,1H),3.86(s,2H),3.75(s,2H),2.24-2.19(m,2H),2.09-1.99(m,2H),1.96-1.74(m,4H).

[0550] MS m / z (ESI): 469.2 [M+H] +

[0551] Example 19: 1-(bicyclo[1.1.1]pentan-1-yl)-4-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperazin-2-one

[0552] Referring to the synthesis steps of Example 1, intermediates 1-5 in step 5 are replaced with (1-(bicyclo[1.1.1]pentan-1-yl)piperazin-2-one), the title compound 19 was prepared by the same method.

[0553] 1 H NMR(400MHz,Chloroform-d)δ8.15(s,1H),8.09(s,1H),6.21(tt,J=55.6,4.5Hz,1H),4.68(td,J =13.3,4.5Hz,2H),4.29(s,2H),4.13=3.86(m,2H),3.74-3.32(m,2H),2.53(s,1H),2.22(s,6H).

[0554] MS m / z (ESI): 349.1 [M+H] +

[0555] Example 20: 4-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1-(3-fluorobicyclo[1.1.1]pentan-1-yl)piperazin-2-one

[0556] The synthesis method of fragment BB-15 in reference WO2016045587 is used to replace BB-15-3 in synthesis step 2 with... 1-(3-fluorobicyclo[1.1.1]pentane-1-amine hydrochloride) was prepared to yield 1-(3-fluorobicyclo[1.1.1]pentane-1-yl)piperazin-2-one (compound 20-1).

[0557] Referring to the synthesis steps of Example 1, intermediates 1-5 in step 5 were replaced with compound 20-1, and title compound 20 was prepared in the same manner.

[0558] 1 H NMR(400MHz,Chloroform-d)δ8.16(s,1H),8.10(s,1H),6.21(tt,J=55.6,4.4Hz,1H),4.68(td ,J=13.4,4.5Hz,2H),4.33(s,2H),4.18-3.96(m,2H),3.69-3.32(m,2H),2.54(d,J=2.1Hz,6H).

[0559] MS m / z (ESI): 367.1 [M+H] +

[0560] Example 21: 1-(2,2-difluoroethyl)-6-(7-(2-(trifluoromethyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0561] Referring to the synthesis method of Example 10, the 7-amino-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester in step 1 was replaced with (2-Amino-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester), compound 21-5 was prepared by the same method.

[0562] Referring to the synthesis method of Example 18, compound 10-5 was replaced with compound 21-5, and title compound 21 was prepared by the same method.

[0563] 1H NMR (400MHz, DMSO-d6) δ8.34(s,1H),8.24(d,J=5.9Hz,1H),8.15(s,1H),7.22(d,J=2.6Hz,1H),7.12-7.03(m,1H),6.43(tt,J=54 .8,3.8Hz,1H),5.18-4.96(m,3H),3.55-3.47(m,2H),3.44-3.34(m,2H),2.48-2.39(m,2H),2.38-2.28(m,2H),1.91-1.62(m,4H).

[0564] MS m / z (ESI): 469.1 [M+H] +

[0565] Example 22: 1-(2,2-difluoroethyl)-6-(2-(2-(trifluoromethyl)pyridin-4-yl)-2-azaspiro[3.3]heptane-6-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0566] Referring to the synthesis method of Example 10, the 7-amino-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester in step 1 was replaced with (6-amino-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester), compound 22-5 was prepared by the same method.

[0567] Referring to the synthesis method of Example 18, compound 10-5 was replaced with compound 22-5, and title compound 22 was prepared in the same manner.

[0568] 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H),8.23(d,J=5.7Hz,1H),8.15(s,1H),6.74(d,J=2.2Hz ,1H),6.62-6.24(m,2H),5.15-4.85(m,3H),4.18(s,2H),4.03(s,2H),2.86-2.71(m,4H).

[0569] MS m / z(ESI): 441.1 [M+H] +

[0570] Example 23: 1-(2,2-difluoroethyl)-6-(2-(2-(trifluoromethyl)pyridin-4-yl)-2-azaspiro[4.5]decane-8-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0571] Referring to the synthesis method of Example 10, the 7-amino-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester in step 1 was replaced with (8-amino-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester), compound 23-5 was prepared by the same method.

[0572] Referring to the synthesis method of Example 18, compound 10-5 was replaced with compound 23-5, and title compound 23 was prepared in the same manner.

[0573] 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.23(d,J=5.8Hz,1H),8.16(s,1H),6.90(s,1H),6.71(s,1H),6.63-6 .18(m,1H),5.16-4.95(m,2H),4.79-4.73(m,1H),3.48-3.36(m,4H),2.11-1.70(m,8H),1.69-1.51(m,2H).

[0574] MS m / z (ESI): 483.2 [M+H] +

[0575] Example 24: 1-(2,2-difluoroethyl)-6-(6-(2-(trifluoromethyl)pyridin-4-yl)-6-azaspiro[3,4]octane-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0576] Step 1: Synthesis of intermediate 24-2

[0577] Compound 24-1 (250 mg) and methyl 1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole-3-carboxylic acid (390 mg) were dissolved in 5 mL of tetrahydrofuran. Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (336 mg) was added at 0 °C. The reaction mixture was stirred overnight at 60 °C until complete. After cooling to room temperature, 50 mL of water was added, followed by extraction with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate: 2 / 1; Rf: 0.6) to obtain compound 24-2 (400 mg).

[0578] Step 2: Synthesis of intermediate 24-3

[0579] Compound 24-2 (390 mg) was dissolved in an ethanol / water mixture (5 mL; 4:1), followed by the addition of iron powder (253 mg) and ammonium chloride (486 mg). The reaction mixture was stirred at 80 °C for 2 hours until the reaction was complete. After cooling to room temperature, the reaction mixture was filtered. The filtrate was added to 30 mL of water and extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24-3 (350 mg).

[0580] Step 3: Synthesis of intermediate 24-4

[0581] Compound 24-3 (350 mg) was dissolved in 4 mL of formamide, heated to 120 °C, and stirred for 48 hours until the reaction was complete. After cooling the reaction solution to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate: 1 / 1; Rf: 0.5) to obtain compound 24-4 (250 mg).

[0582] Step 4: Synthesis of intermediate 24-5

[0583] Compound 24-4 (250 mg) was dissolved in 10 mL of dichloromethane, and 1.5 mL of trifluoroacetic acid was slowly added dropwise at 0 °C. The reaction was carried out after stirring at room temperature for 2 hours. The reaction solution was then concentrated under reduced pressure to obtain compound 24-5 (250 mg).

[0584] Step 5: Synthesis of Compound 24

[0585] 4-Bromo-2-(trifluoromethyl)pyridine (146 mg), compound 24-5 (250 mg), and potassium carbonate (245 mg) were dissolved in N,N-dimethylformamide (3 mL). The mixture was heated to 80 °C and stirred for 6 hours until the reaction was complete. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography (dichloromethane / methanol: 50 / 1; Rf: 0.6) and high performance liquid chromatography (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [water (0.5‰ ammonia + 0.01‰ ammonium bicarbonate) - acetonitrile]; acetonitrile gradient: 40-70%) to obtain compound 24 (150 mg).

[0586] 1H NMR (400MHz, DMSO-d6) δ8.42-8.19(m,2H),8.15(s,1H),6.93-6.60(m,2H),6.43(tt,J=54. 8,3.7Hz,1H),5.25-4.94(m,3H),3.63-3.36(m,4H),2.74-2.47(m,4H),2.25-2.09(m,2H).

[0587] MS m / z (ESI): 455.2 [M+H] +

[0588] Example 25: 1-(2,2-difluoroethyl)-6-(2-(2-(trifluoromethyl)pyridin-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0589] Referring to the synthesis method of Example 24, replace 24-1 in step 1 with (5-Aminohexahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester), the title compound 25 was prepared by the same method.

[0590] 1 H NMR(400MHz,DMSO-d6)δ8.42-8.13(m,3H),6.96-6.67(m,2H),6.66-6.26(m,1H),5.32-4 .96(m,3H),3.75-3.24(m,4H),3.25-2.80(m,2H),2.39-2.26(m,2H),2.17-1.90(m,2H).

[0591] MS m / z (ESI): 455.2 [M+H] +

[0592] Example 26: 1-(2,2-difluoroethyl)-6-(2-(2-(trifluoromethyl)pyridin-4-yl)octahydro-1H-isoindol-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0593] Referring to the synthesis method of Example 24, replace 24-1 in step 1 with (5-Aminooctahydro-2H-isoindole-2-carboxylic acid tert-butyl ester), the title compound 26 was prepared by the same method.

[0594] 1H NMR (400MHz, DMSO-d6) δ8.40(s,1H),8.21(d,J=5.8Hz,1H),8.12(s,1H),6.81(s,1H),6.65(s,1H),6.43(tt,J=54.9, 3.8Hz,1H),5.04(td,J=14.6,3.9Hz,2H),4.75-4.71(m,1H),3.70-3.36(m,4H),2.59-2.51(m,2H),2.21-1.58(m,6H).

[0595] MS m / z (ESI): 469.2 [M+H] +

[0596] Example 27: 1-(2,2-difluoroethyl)-6-(2-(2-(trifluoromethyl)pyridin-4-yl)-2-azaspiro[3.4]octane-6-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0597] Referring to the synthesis method of Example 24, replace 24-1 in step 1 with (6-amino-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester), the title compound 27 was prepared by the same method.

[0598] 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),8.23(d,J=5.7Hz,1H),8.15(s,1H),6.74(d,J=2.2Hz,1H), 6.65-6.25(m,2H),5.16-4.96(m,3H),4.11-3.98(m,2H),3.98-3.88(m,2H),2.45-1.95(m,6H).

[0599] MS m / z (ESI): 455.2 [M+H] +

[0600] Example 28: 1-(2,2-difluoroethyl)-6-(2-(2-(trifluoromethyl)pyridin-4-yl)-2-azaspiro[4.4]nonane-7-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0601] Referring to the synthesis method of Example 24, replace 24-1 in step 1 with (7-amino-2-azaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester), the title compound 28 was prepared by the same method.

[0602] Example 29: 1-(2,2-difluoroethyl)-6-(6-(2-(trifluoromethyl)pyridin-4-yl)-6-azaspiro[3.5]nonane-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0603] Referring to the synthesis method of Example 24, replace 24-1 in step 1 with (2-Amino-6-azaspiro[3.5]nonane-6-carboxylic acid tert-butyl ester), the title compound 29 was prepared by the same method.

[0604] 1 H NMR (400MHz, CDCl3) δ8.39-8.29(m,1H),8.01-7.88(m,2H),7.13-7.01(m,1H),6.88-6.65(m,1H),6.42-6. 01(m,1H),5.27-4.85(m,3H),3.51-3.43(m,2H),3.41-3.30(m,2H),2.65-2.17(m,4H),1.96-1.70(m,4H).

[0605] MS m / z (ESI): 469.2 [M+H] +

[0606] Example 30: 1-(2,2-difluoroethyl)-6-(8-(2-(trifluoromethyl)pyridin-4-yl)-5-oxa-8-azaspiro[3.5]nonane-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0607] The synthetic route for compound 30 is as follows:

[0608] Example 31: 1-(2,2-difluoroethyl)-6-(7-oxo-6-(2-(trifluoromethyl)pyridin-4-yl)-6-azaspiro[3,4]octane-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0609] Step 1: Synthesis of intermediate 31-2

[0610] 4-Bromo-2-(trifluoromethyl)pyridine (188 mg), compound 31-1 (400 mg), (methanesulfonic acid {bicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphonane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (76.5 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-diphenyl]-2-yl)phosphine (89.2 mg) Compound 31-2 (240 mg) was dissolved in 1,4-dioxane (4 mL) and cesium carbonate (813 mg). The mixture was heated to 100 °C and stirred for 6 hours under nitrogen protection until the reaction was complete. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol: 25 / 1; Rf: 0.5) to obtain compound 31-2 (240 mg).

[0611] Step 2: Synthesis of compound 31-3

[0612] Compound 31-2 (240 mg) was dissolved in 5 mL of dichloromethane, and trifluoroacetic acid (2.00 mL) was slowly added dropwise at 0 °C. The reaction solution was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain compound 31-3 (170 mg).

[0613] Step 3: Synthesis of intermediate 31-4

[0614] Compound 31-3 (160 mg) and methyl 1-(2,2-difluoroethyl)-4-nitro-pyrazole-3-carboxylic acid (198 mg) were dissolved in 3 mL of tetrahydrofuran, and 1,8-diazabicyclo[5.4.0]undec-7-ene (426 mg) was added at 0 °C. The reaction solution was stirred at 60 °C for 8 hours until the reaction was complete. After cooling the reaction solution to room temperature, 50 mL of water was added, and then the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate: 2 / 1; Rf: 0.6) to obtain compound 31-4 (70.0 mg).

[0615] Step 4: Synthesis of intermediate 31-5

[0616] Compound 31-4 (70.0 mg) was dissolved in an ethanol / water mixture (5 mL; 4:1), followed by the addition of iron powder (40.0 mg) and ammonium chloride (76.7 mg). The reaction was heated to 80 °C and stirred for 2 hours until completion. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Then, 20 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 31-5 (60.0 mg).

[0617] Step 5: Synthesis of Compound 31

[0618] Compound 31-5 (50.0 mg) was dissolved in 1 mL of formamide. The reaction solution was stirred at 150 °C for 4 hours until the reaction was complete. After cooling the reaction solution to room temperature, 20 mL of water was added, and then it was extracted with ethyl acetate (10 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (high performance liquid chromatography) (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [water-acetonitrile]; acetonitrile gradient: 25-45%) to obtain the title compound 31 (25.0 mg).

[0619] 1 H NMR(400MHz, DMSO-d6)δ8.70(d,J=5.6Hz,1H),8.37(d,J=9.3Hz,1H),8.29-8.17(m,1H),8.16(s,1H),7.99-7.77 (m,1H),6.71-6.21(m,1H),5.32-4.86(m,3H),4.12(d,J=55.6Hz,2H),2.90(d,J=52.4Hz,2H),2.80-2.57(m,4H).

[0620] MS m / z (ESI): 469.2 [M+H] +

[0621] [Revised according to Rule 26, 10.12.2025] Synthetic route of intermediate 31-1:

[0622] [Amended according to Rule 26, 10.12.2025] Example 32: 1-(2,2-difluoroethyl)-6-(2-((2-(trifluoromethyl)pyridin-4-yl)methyl)-2-azaspiro[3.5]nonane-7-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0623] 4-(bromomethyl)-2-(trifluoromethyl)pyridine (71.3 mg), compound 10-5 (130 mg), and potassium carbonate (123 mg) were dissolved in N,N-dimethylformamide (2.00 mL). The reaction was stirred at room temperature for 2 hours until the reaction was complete. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [acetonitrile: water (0.5‰ ammonia + 0.01‰ ammonium bicarbonate)]; acetonitrile gradient: 40-70%) to obtain the title compound 32 (40.0 mg).

[0624] 1 H NMR (400MHz, DMSO-d6) δ8.70(d,J=5.0Hz,1H),8.30(s,1H),8.12(s,1H),7.77(s,1H),7.63(d,J=5.0Hz,1H),6.42(tt,J=54.8,3.8Hz,1 H),5.03(td,J=14.6,3.8Hz,2H),4.70-4.53(m,1H),3.77(s,2H),3.10(s,2H),3.00(s,2H),2.05(d,J=13.0Hz,2H),1.93-1.52(m,6H).

[0625] MS m / z (ESI): 483.1 [M+H] +

[0626] Example 33: 2-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-7-((2-(trifluoromethyl)pyridin-4-yl)oxy)-5-oxa-2-azaspiro[3,4]octane

[0627] Step 1: Synthesis of intermediate 33-2

[0628] Under nitrogen protection, compound 33-1 (0.90 g) was dissolved in dimethyl sulfoxide (20 mL), and sodium hydride (314 mg) was added in portions at 0 °C, with stirring at room temperature for 1 hour. Subsequently, 2-trifluoromethyl-4-bromopyridine (0.97 g) was added to the reaction solution, and the reaction was continued for 2 hours until completion. The reaction was quenched with saturated ammonium chloride aqueous solution, and then extracted with ethyl acetate (30 mL * 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol: 10 / 1; Rf: 0.6) to obtain compound 33-2 (1.10 g).

[0629] Step 2: Synthesis of intermediate 33-3

[0630] Under nitrogen protection, compound 33-2 (0.20 g) was added to a solution of hydrogen chloride (10 mL, 4 M ethyl acetate). The reaction mixture was stirred at room temperature for 2 hours under nitrogen protection until the reaction was complete. The reaction mixture was then concentrated under reduced pressure to obtain compound 33-3 (0.15 g).

[0631] Step 3: Synthesis of Compound 33

[0632] Compound 33-3 (100 mg) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (97.7 mg) were dissolved in N,N-dimethylformamide (3.00 mL), followed by the addition of potassium carbonate (115 mg). The reaction was carried out after heating to 90 °C and stirring for 2 hours. The reaction solution was cooled to room temperature, 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether / ethyl acetate: 20 / 1; Rf: 0.6) to give the title compound 33 (56.0 mg).

[0633] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=5.7Hz,1H),8.15(s,1H),7.95(s,1H),7.46(d,J=2.4Hz,1H),7.35-7.29(m,1H),6. 61-6.26(m,1H),5.44-5.37(m,1H),4.74-4.61(m,2H),4.39-4.14(m,5H),4.03(d,J=10.7Hz,1H),2.61-2.52(m,2H).

[0634] MS m / z (ESI): 457.2 [M+H] +

[0635] Example 34: 1-(2,2-difluoroethyl)-6-(5-(2-(trifluoromethyl)pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0636] Referring to the synthesis method of Example 24, replace 24-1 in step 1 with (2-Amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester), the title compound 34 was prepared by the same method.

[0637] Examples 35-43

[0638] Referring to the synthesis method of Example 24, except that 4-bromo-2-(trifluoromethyl)pyridine in step 5 was replaced with the starting materials in the table below, the following compounds 35-43 were synthesized in the same manner:

[0639] Example 44: 1-(2,2-difluoroethyl)-6-(6-(2-(trifluoromethyl)isonicotinyl)-6-azaspiro[3.4]octane-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0640] Compound 24-5 (30.0 mg) and 2-(trifluoromethyl)isonicotinic acid (18.5 mg) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (55.3 mg) and N,N-diisopropylethylamine (37.6 mg) were added. The mixture was stirred at room temperature for 16 hours until the reaction was complete. 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [water-acetonitrile]; acetonitrile gradient: 25-45%) to obtain the title compound 44 (11.7 mg).

[0641] 1 H NMR(400MHz,DMSO-d6)δ8.91-8.87(m,1H),8.38-8.29(m,1H),8.15-8.12(m,1H),8.04-7.98(m 1H),7.91-7.71(m,1H),6.61-6.19(m,1H),5.22-4.91(m,3H),3.60-3.35(m,4H),2.67-2.59(m,2H),2.47-2.30(m,2H),2.15-1.94(m,2H).

[0642] MS m / z (ESI): 483.1 [M+H] +

[0643] Example 45: 2-(1-(2,2-difluoroethyl)-7-oxo-1,7-dihydro-6H-pyrazolo[4,3-d]pyrimidin-6-yl)-7-(2-(trifluoromethyl)pyridin-4-yl)-5-oxa-7-azaspiro[3,4]oct-6-one

[0644] Step 1: Synthesis of intermediate 45-2

[0645] 4-Bromo-2-(trifluoromethyl)pyridine (280 mg), compound 45-1 (200 mg), tris(dibenzylacetone)dipalladium (75.6 mg), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (95.5 mg), and cesium carbonate (807 mg) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to 100 °C and stirred for 6 hours under nitrogen protection until the reaction was complete. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol: 50 / 1; Rf: 0.5) to obtain compound 45-2 (240 mg). Steps 2 to 5 were performed according to steps 2-5 of the synthesis of compound 31, and the title compound 45 was prepared by the same method.

[0646] 1 H NMR(400MHz, DMSO-d6)δ8.71(t,J=6.0Hz,1H),8.31(d,J=2.7Hz,1H),8.17(s,1H),8.14-8.02(m,1H),7.83-7.6 5(m,1H),6.68-6.22(m,1H),5.26-4.69(m,3H),4.44(s,1H),4.31(s,1H),3.24-3.07(m,2H),3.05-2.92(m,2H).

[0647] MS m / z(ESI): 471.0 [M+H] +

[0648] Synthetic route of compound 45-1:

[0649] Example 46: 1-(2,2-difluoroethyl)-6-(6-(2-(trifluoromethyl)thiazolyl-5-yl)-6-azaspiro[3.4]octane-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0650] Compound 24-5 (50.0 mg) and 2-(trifluoromethyl)-5-bromothiazole (30.8 mg) were dissolved in N,N-dimethylformamide (2 mL), and tris(dibenzylacetone)dipalladium (5.0 mg), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (10.0 mg) and cesium carbonate (60.0 mg) were added. The mixture was heated to 80 °C under nitrogen protection, and the reaction was completed after 5 hours. The reaction solution was filtered and concentrated, and purified by preparative high performance liquid chromatography (column: YMC TAR-C18, 30*150 mm, 5 μm; mobile phase: [water-acetonitrile]; acetonitrile gradient: 25-45%) to obtain the title compound 46 (4.00 mg).

[0651] 1 H NMR(400MHz,DMSO-d6)δ8.37(s,1H),8.15(s,1H),6.89(s,1H),6.57-6.29(m,1 H),5.22-4.96(m,3H),3.60-3.30(m,4H),2.81-2.60(m,2H),2.37-1.86(m,4H).

[0652] MS m / z (ESI): 461.2 [M+H] + .

[0653] Example 47: 1-(2,2-difluoroethyl)-6-((3aR,5r,6aS)-2-(2-(trifluoromethyl)pyridin-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0654] Referring to the synthesis steps of Example 24, starting material compound 24-1 was replaced with compound 47-1, and compound 47 was prepared according to the above technical route.

[0655] 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),8.25(d,J=5.9Hz,1H),8.13(s,1H),6.92(s,1H),6.75(d,J=6.0Hz,1H),6. 62-6.27(m,1H),5.14-4.99(m,3H),3.74-3.44(m,4H),2.95-2.85(m,2H),2.33-2.28(m,2H),2.05-1.97(m,2H).

[0656] MS m / z (ESI): 455.5 [M+H] +

[0657] Example 48: 1-(2,2-difluoroethyl)-6-((3aR,5s,6aS)-2-(2-(trifluoromethyl)pyridin-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0658] Referring to the synthesis steps of Example 24, starting material compound 24-1 was replaced with compound 48-1, and compound 48 was prepared according to the above technical route.

[0659] 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),8.25(d,J=5.8Hz,1H),8.14(s,1H),6.89(d,J=2.3Hz,1H),6.82-6.70(m,1H),6.60-6.1 8(m,1H),5.31-5.20(m,1H),5.11-4.97(m,2H),3.70-3.53(m,2H),3.31-3.07(m,4H),2.41-2.27(m,2H),2.22-1.98(m,2H).

[0660] MS m / z (ESI): 455.1 [M+H] +

[0661] Example 49: 1-(2,2-difluoroethyl)-5-methyl-6-(6-(2-(trifluoromethyl)pyridin-4-yl)-6-azaspiro[3,4]octane-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0662] Referring to the synthesis method of Example 24, the formamide in step 3 was... Replace with triethyl orthoformate The title compound 49 was prepared by the same method.

[0663] 1 H NMR (400MHz, MeOD) δ8.20(d,J=6.9Hz,1H),7.85(s,1H),7.18(d,J=2.4Hz,1H),6.93(d,J=5.0Hz,1H),6.28(tt,J=55.4,4.2Hz,1H) ,5.19-4.96(m,3H),3.79(s,2H),3.66(t,J=6.8Hz,2H),3.46-3.32(m,2H),2.64(s,3H),2.56-2.44(m,2H),2.31(t,J=6.8Hz,2H).

[0664] MS m / z (ESI): 469.3 [M+H] +

[0665] Example 50: 1-(oxecyclobutane-3-yl)-6-(6-(2-(trifluoromethyl)pyridin-4-yl)-6-azaspiro[3.4]octane-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0666] Synthesis of intermediate 50-4:

[0667] Step 1: Synthesis of intermediate 50-2:

[0668] 4-Nitropyrazole (2.00 g) and cesium carbonate (11.5 g) were dissolved in N,N-dimethylformamide (15 mL). 3-Iodooxetane (4.88 g) was added dropwise at 0 °C, and the reaction was carried out after stirring at room temperature for 2 hours. 100 mL of water was added, followed by extraction with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate: 10 / 1) to obtain the title compound 50-2 (2.50 g).

[0669] 1 H NMR (400MHz, MeOD) δ9.03 (d, J = 0.7Hz, 1H), 8.41 (s, 1H), 5.65 (s, 1H), 5.00-4.83 (m, 4H).

[0670] MS m / z (ESI): 170.1 [M+H] +

[0671] Step 2: Synthesis of intermediate 50-3:

[0672] Under nitrogen protection, intermediate 50-2 (2.30 g) and n-amyl chloroformate (3.07 g) were dissolved in methyl tert-butyl ether (30 mL). A tetrahydrofuran solution of lithium di(trimethylsilyl)aminoacetate (1 M, 16.2 mL) was added dropwise at -20 °C. The reaction was stirred at -20 °C for 2 hours until completion. The reaction solution was quenched with 30 mL of saturated ammonium chloride, then extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate: 5 / 1) to obtain the title compound 50-3 (3.20 g).

[0673] 1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),5.84-5.76(m,1H),4.98-4.89(m,4H),4. 37(t,J=6.6Hz,2H),1.75-1.65(m,2H),1.40-1.29(m,4H),0.94-0.85(m,3H).

[0674] Step 3: Synthesis of intermediate 50-4:

[0675] Under nitrogen protection, intermediate 50-3 (3.00 g) was added to a mixed solution of tetrahydrofuran (20 mL) and water (10 mL), followed by the addition of lithium hydroxide (1.27 g). The reaction was carried out after stirring at room temperature for 2 hours until completion. The pH was adjusted to 6 with 2 M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was slurried with ethyl acetate to give the target compound 50-4 (1.70 g).

[0676] 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),5.80-5.71(m,1H),4.96-4.90(m,4H).

[0677] Synthesis of Compound 50:

[0678] Step 1: Synthesis of intermediate 50-6:

[0679] Compound 50-5 (600 mg), 4-bromo-2-(trifluoromethyl)pyridine (660 mg), and potassium carbonate (500 mg) were added to N,N-dimethylformamide (5 mL). The mixture was heated to 80 °C and reacted for 2 hours until the reaction was complete. 50 mL of water was added to the reaction mixture, and the mixture was then extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether / ethyl acetate ratio = 10:1 to 5:1) to obtain the title compound 50-6 (600 mg).

[0680] Step 2: Synthesis of intermediate 50-7:

[0681] Compound 50-6 (300 mg) was dissolved in 5 mL of dichloromethane, followed by the addition of 1,4-dioxane (4 M, 3.00 mL) containing hydrogen chloride. The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction mixture was then concentrated under reduced pressure to obtain the title compound 50-7 (200 mg), which was directly added to the next reaction step.

[0682] Step 3: Synthesis of intermediate 50-8:

[0683] Under nitrogen protection, compounds 50-4 (200 mg), 50-7 (188 mg), and N,N-diisopropylethylamine (285 mg) were added to N,N-dimethylformamide (5 mL). At 0 °C, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (420 mg) was added, and the reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. Then, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol: 10 / 1) to obtain the title compound 50-8 (240 mg).

[0684] 1 H NMR (400MHz, DMSO-d6) δ9.46-9.34(m,1H),8.49(s,1H),8.28-8.16(m,1H),6.88-6.74(m,1H),6.73-6.60(m,1H),5.62-5. 44(m,1H),4.91(d,J=6.7Hz,4H),4.49-4.36(m,1H),3.48(s,1H),3.42-3.33(m,3H),2.47-2.35(m,2H),2.13-2.00(m,4H).

[0685] MS m / z (ESI): 466.9 [M+H] +

[0686] Step 4: Synthesis of intermediate 50-9:

[0687] Under nitrogen protection, compound 50-8 (200 mg) was added to a mixed solution of ethanol (8.0 mL) and water (2.0 mL), followed by the addition of iron powder (119 mg) and ammonium chloride (229 mg). The mixture was heated to 70 °C and stirred for 2 hours until the reaction was complete. The reaction solution was cooled to room temperature, filtered to remove the iron powder, and the filtrate was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol: 10 / 1) to obtain the title compound 50-9 (130 mg).

[0688] 1H NMR(400MHz,DMSO-d6)δ8.24-8.19(m,1H),8.19-8.10(m,1H),7.25(s,1H),6.88-6.75(m,1H),6.72-6.58(m,1H),5.89-5.80(m,1H), 4.88-4.77(m,4H),4.53-4.47(m,2H),4.47-4.38(m,1H),3.50-3.44(m,1H),3.44-3.34(m,2H),2.39-2.29(m,2H),2.16-2.00(m,4H).

[0689] MS m / z(ESI): 437.0 [M+H] +

[0690] Step 5: Synthesis of Compound 50:

[0691] Under nitrogen protection, compound 50-9 (120 mg) was added to 10 mL of formamide. The reaction solution was stirred at 150 °C for 2 hours until the reaction was complete. The reaction solution was cooled to room temperature, 10 mL was added, and then extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol: 10 / 1) and preparative high performance liquid chromatography (column: Phenomenex Gemini NX 150 × 30 mm, 5 μm; mobile phase: [water (containing 7 mmol / L ammonium bicarbonate) - acetonitrile]; acetonitrile gradient: 60%-90%) to obtain compound 50 (33.8 mg).

[0692] 1 H NMR(400MHz, DMSO-d6)δ8.35(d,J=5.8Hz,1H),8.26-8.18(m,2H),7.08-6.53(m,2H),6.37-6.18(m,1H ),5.27-5.05(m,1H),4.97(d,J=6.9Hz,4H),3.65-3.35(m,6H),2.71-2.55(m,2H),2.31-2.08(m,2H).

[0693] MS m / z (ESI): 446.9 [M+H] +

[0694] Example 51: 1-(oxetane-3-yl)-6-((3aR,5r,6aS)-2-(2-(trifluoromethyl)pyridin-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0695] Referring to the synthesis method of Example 50, compound 50-5 in step 1 was replaced with compound 51-1. The title compound 51 was prepared by the same method.

[0696] 1 H NMR (400MHz, DMSO-d6) δ8.34(s,1H),8.24(d,J=5.8Hz,1H),8.19(s,1H),6.88(d,J=2.4Hz,1H),6.81-6.68(m,1H),6.37-6.21(m,1H),5 .19-5.02(m,1H),4.97(d,J=6.9Hz,4H),3.69-3.54(m,2H),3.54-3.44(m,2H),3.03-2.83(m,2H),2.44-2.22(m,2H),2.08-1.93(m,2H).

[0697] MS m / z (ESI): 447.1 [M+H] +

[0698] Example 52: 1-(oxecyclobutane-3-yl)-6-(7-(2-(trifluoromethyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0699] Referring to the synthesis method of Example 50, compound 50-5 in step 1 was replaced with compound 52-1. The title compound 52 was prepared by the same method.

[0700] 1 H NMR(400MHz, DMSO-d6)δ8.24(s,1H),8.17(d,J=6.0Hz,1H),8.12(s,1H),7.15( d,J=2.6Hz,1H),7.07-6.92(m,1H),6.24-6.13(m,1H),5.07-4.86(m,5H),3.51 -3.30(m,4H),2.40-2.17(m,4H),1.83-1.49(m,4H).

[0701] MS m / z (ESI): 461.2 [M+H] +

[0702] Example 53: 1-(2,2-difluoroethyl)-6-(4-((6-(trifluoromethyl)pyridin-2-yl)methyl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyrazine

[0703] Step 1: Synthesis of intermediate 53-2

[0704] Piperazine-1-carboxylic acid tert-butyl ester (2.00 g) and 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (2.35 g) were dissolved in N,N-dimethylformamide (25 mL), and sodium carbonate (3.41 g) was added. The mixture was heated to 100 °C and stirred for 2 hours until the reaction was complete. The reaction solution was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate: 10 / 1; Rf: 0.6) to obtain the title compound 53-2 (3.90 g).

[0705] Step 2: Synthesis of intermediate 53-3

[0706] Compound 53-2 (3.90 g) was dissolved in 20 mL of dichloromethane, followed by the addition of 1,4-dioxane (4 M, 26.47 mL) of hydrogen chloride. The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction mixture was concentrated under reduced pressure, slurried with ethyl acetate, filtered, and the filter cake was washed with ethyl acetate and then dried to obtain the title compound 53-3 (3.20 g).

[0707] Step 3: Synthesis of Compound 53

[0708] Compound 53-3 (60.0 mg), 2-(bromomethyl)-6-(trifluoromethyl)pyridine (47.3 mg), and potassium carbonate (81.6 mg) were added to N,N-dimethylformamide (1.00 mL). The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol: 50 / 1; Rf: 0.6) and high performance liquid chromatography (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [water (containing 7 mmol / L ammonium bicarbonate) - acetonitrile]; acetonitrile gradient: 45-80%) to obtain compound 53 (38.0 mg).

[0709] 1H NMR (400MHz, DMSO-d6) δ8.46 (s, 1H), 8.27-8.01 (m, 2H), 7.83 (t, J = 8.0Hz, 2H), 6.44 (tt, J=54.9,3.9Hz,1H),4.70(td,J=15.0,3.8Hz,2H),3.85-3.75(m,6H),2.75-2.56(m,4H).

[0710] MS m / z (ESI): 428.1 [M+H] +

[0711] Examples 54-62

[0712] Referring to the synthesis method of Example 53, 2-(bromomethyl)-6-(trifluoromethyl)pyridine in step 3 was replaced with the starting materials in the table below, and the following compounds 54-62 were synthesized in the same manner.

[0713] Example 63: 1-(2,2-difluoroethyl)-6-((3aR,5r,6aS)-2-(1-methyl-1H-pyrazol-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0714] Compound 47-5 (100 mg), 4-bromo-1-methyl-1H-pyrazole (104 mg), Gphos G6 Pd (30.5 mg), and sodium trimethylsilicate (95.4 mg) were dissolved in tetrahydrofuran (2 mL). The reaction solution was purged with nitrogen three times, and the reaction was carried out at 90 °C with stirring for 10 hours until completion. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol: 10 / 1; Rf: 0.6) and high performance liquid chromatography (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [water (containing 7 mmol / L ammonium bicarbonate) - acetonitrile]; acetonitrile gradient: 45-75%) to obtain compound 63 (25.0 mg).

[0715] 1H NMR (400MHz, DMSO-d6) δ8.28(s,1H),8.13(s,1H),7.17(s,1H),7.05(s,1H),6.44(tt,J=54.8,3.8Hz,1H),5.29-4.96( m,2H),4.94-4.75(m,1H),3.73(s,3H),3.05(d,J=8.8Hz,2H),2.89-2.68(m,4H),2.42-2.22(m,2H),2.10-1.78(m,2H).

[0716] MS m / z(ESI): 390.1 [M+H] +

[0717] Example 64: 1-(2,2-difluoroethyl)-6-((3aR,5r,6aS)-2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0718] The synthesis method of Example 63 was used, except that 4-bromo-1-methyl-1H-pyrazole in the step was replaced with 4-bromo-1-methylpyridin-2(1H)-one, and compound 64 was prepared by the same method.

[0719] 1 H NMR (400MHz, DMSO-d6) δ8.35(s,1H),8.13(s,1H),7.41(d,J=7.6Hz,1H),6.70-6.23(m,1H),5.84(dd,J=7.6,2.4Hz,1H),5.18(d,J=2.3 Hz,1H),5.11-4.93(m,3H),3.61-3.43(m,2H),3.39-3.29(m,2H),3.27(s,3H),2.90-2.84(m,2H),2.40-2.23(m,2H),2.03-1.93(m,2H).

[0720] Example 65: 1-(2,2-difluoroethyl)-6-((3aR,5r,6aS)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0721] Referring to the synthesis method of Example 63, 4-bromo-1-methyl-1H-pyrazole in the step was replaced with 4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole, and compound 65 was prepared by the same method.

[0722] 1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.13(s,1H),7.39-7.17(m,2H),6.44(tt,J=54.8,3.8Hz,1H ),5.15-4.75(m,5H),3.19-3.05(m,2H),2.97-2.67(m,4H),2.43-2.19(m,2H),2.01-1.80(m,2H).

[0723] MS m / z (ESI): 458.1 [M+H] +

[0724] Example 66: 1-(2,2-difluoroethyl)-6-((3aR,5r,6aS)-2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0725] Referring to the synthesis method of Example 63, 4-bromo-1-methyl-1H-pyrazole in the step was replaced with 4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazole, and compound 66 was prepared by the same method.

[0726] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,1H),8.14(s,1H),7.55(d,J=1.3Hz,1H),6.44(tt,J=54.8,3.8Hz,1H),5.14-4.98(m,2H),4. 96-4.79(m,1H),3.83(s,3H),3.08-2.98(m,2H),2.98-2.86(m,2H),2.85-2.65(m,2H),2.43-2.27(m,2H),1.98-1.75(m,2H).

[0727] MS m / z (ESI): 458.1 [M+H] +

[0728] Example 67: 1-(2,2-difluoroethyl)-6-((3aR,5r,6aS)-2-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0729] Referring to the synthesis method of Example 63, 4-bromo-1-methyl-1H-pyrazole in the step was replaced with 4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole, and compound 67 was prepared by the same method.

[0730] 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),8.09(s,1H),7.36(s,1H),6.38(tt,J=54.8,3.8Hz,1H),5.05-4.92(m,2H),4. 92-4.77(m,1H),3.85(d,J=1.3Hz,3H),3.07-2.90(m,4H),2.68-2.65(m,2H),2.37-2.18(m,2H),1.92-1.69(m,2H).

[0731] MS m / z(ESI): 458.0 [M+H] +

[0732] Example 68: 1-(2,2-difluoroethyl)-6-(7-((6-(trifluoromethyl)pyridin-2-yl)methyl)-7-azaspiro[3.5]nonane-2-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0733] Compound 21-5 (100 mg), 2-(bromomethyl)-6-(trifluoromethyl)pyridine (60.0 mg), and potassium carbonate (200 mg) were added to N,N-dimethylformamide (4.00 mL). The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [water (containing 7 mmol / L ammonium bicarbonate) - acetonitrile]; acetonitrile gradient: 50-80%) to obtain compound 68 (38.0 mg).

[0734] 1H NMR (400MHz, DMSO-d6) δ8.31 (s, 1H), 8.14 (s, 1H), 8.07 (t, J = 7.8Hz, 1H), 7.86-7.72 (m, 2H), 6.4 2(tt,J=54.8,3.8Hz,1H),5.15-4.95(m,3H),3.65(s,2H),2.46-2.18(m,8H),1.81-1.54(m,4H).

[0735] MS m / z (ESI): 483.1 [M+H] +

[0736] Examples 69-77

[0737] Referring to the synthesis method of Example 68, 2-(bromomethyl)-6-(trifluoromethyl)pyridine in the reaction was replaced with the starting materials in the table below, and the following compounds 69-77 were synthesized in the same manner.

[0738] Example 78: 1-(2,2-difluoroethyl)-6-((3aR,5r,6aS)-2-((6-(trifluoromethyl)pyridin-2-yl)methyl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0739] Compound 47-5 (70.5 mg), 2-(bromomethyl)-6-(trifluoromethyl)pyridine (40.0 mg), and potassium carbonate (150 mg) were added to N,N-dimethylformamide (2.00 mL). The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [water (containing 7 mmol / L ammonium bicarbonate) - acetonitrile]; acetonitrile gradient: 50-80%) to obtain compound 78 (20.0 mg).

[0740] 1H NMR (400MHz, DMSO-d6) δ8.33(s,1H),8.15(s,1H),8.09(t,J=7.8Hz,1H),7.96(d,J=7.9Hz,1H),7.78(d,J=7.6Hz,1H),6.44(tt,J=54. 8,3.8Hz,1H),5.05(td,J=14.6,3.8Hz,2H),4.96-4.73(m,1H),3.83(s,2H),2.77-2.56(m,4H),2.41-2.19(m,4H),1.96-1.78(m,2H).

[0741] MS m / z(ESI): 469.0 [M+H] +

[0742] Examples 79-89

[0743] Referring to the synthesis method of Example 78, 2-(bromomethyl)-6-(trifluoromethyl)pyridine was replaced with the starting materials in the table below, and the following compounds 79-89 were synthesized in the same manner.

[0744] Example 90: 4-(2-(1-(2,2-difluoroethyl)-7-oxo-1,7-dihydro-6H-pyrazolo[4,3-d]pyrimidin-6-yl)-6-azaspiro[3,4]octane-6-yl)-2-(trifluoromethyl)benzonitrile:

[0745] Compound 24-5 (100 mg), 4-bromo-2-(trifluoromethyl)benzonitrile (100 mg), Xphos Pd G4 (20.0 mg), and cesium carbonate (200 mg) were dissolved in 1,4-dioxane (2 mL). The reaction solution was purged with nitrogen three times, and the mixture was stirred at 80 °C for 16 hours until the reaction was complete. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol: 10 / 1; Rf: 0.6) and high performance liquid chromatography (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [water (containing 7 mmol / L ammonium bicarbonate) - acetonitrile]; acetonitrile gradient: 45-75%) to obtain compound 90 (20.6 mg).

[0746] 1H NMR (400MHz, DMSO-d6) δ8.38(d,J=6.7Hz,1H),8.15(s,1H),7.80(d,J=8.3Hz,1H),7.04-6.72(m,2 H),6.57-6.29(m,1H),5.23-4.95(m,3H),3.73-3.36(m,4H),2.74-2.57(m,4H),2.26-2.07(m,2H).

[0747] MS m / z (ESI): 479.3 [M+H] +

[0748] Example 91: 1-(2,2-difluoroethyl)-6-((3aR,5r,6aS)-2-(2-(2-hydroxypropyl-2-yl)pyridin-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0749] Referring to the synthesis method of Example 63, 4-bromo-1-methyl-1H-pyrazole in the step was replaced with 2-(4-bromopyridin-2-yl)prop-2-ol, and compound 91 was prepared by the same method.

[0750] 1H NMR(400MHz,MeOD-d4)δ8.56(br s,1H),8.21(s,1H),8.02(d,J=7.0Hz,1H),7.98(s,1H),6.90-6.71(m,2H),6.27(tt,J=55.4,4.1Hz,1H),5 .27-4.96(m,3H),4.09-3.62(m,4H),3.18-2.95(m,2H),2.59-2.37(m,2H),2.34-2.17(m,2H),1.62(s,6H).

[0751] MS m / z (ESI): 445.2 [M+H] +

[0752] Example 92: 6-((3aR,5r,6aS)-2-(2-cyclopropylpyridin-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1-(2,2-difluoroethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0753] Referring to the synthesis method of Example 63, 4-bromo-1-methyl-1H-pyrazole in the step was replaced with 4-bromo-2-cyclopropylpyridine, and compound 92 was prepared by the same method.

[0754] 1 H NMR (400MHz, DMSO) δ8.35(s,1H),8.13(s,1H),7.96(d,J=5.9Hz,1H),6.71-6.20(m,3H),5.24-4.73(m ,3H),3.58-3.26(m,4H),2.97-2.73(m,2H),2.42-2.21(m,2H),2.20-1.84(m,3H),1.04-0.76(m,4H).

[0755] MS m / z (ESI): 427.2 [M+H] +

[0756] Example 93: 1-(2,2-difluoroethyl)-6-((3aR,5r,6aS)-2-(2-morpholinopyridin-4-yl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0757] Referring to the synthesis method of Example 63, 4-bromo-1-methyl-1H-pyrazole in the step was replaced with 4-(4-bromopyridin-2-yl)morpholine, and compound 93 was prepared by the same method.

[0758] 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),8.14(s,1H),7.75(d,J=7.3Hz,1H),6.64-6.22(m,2H ),5.92(d,J=1.8Hz,1H),5.21-4.89(m,3H),3.86-3.56(m,8H),3.53-3.44(m,4H),2.93(br s,2H),2.39-2.22(m,2H),2.12-1.94(m,2H).

[0759] MS m / z(ESI): 472.1 [M+H] +

[0760] Example 94: 1-(2,2-difluoroethyl)-6-((3aR,5s,6aS)-2-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)octahydrocyclopentan[c]pyrrolo-5-yl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0761] Compound 48-5 (80.0 mg), 4-(bromomethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (40.0 mg), and potassium carbonate (150 mg) were added to N,N-dimethylformamide (2.00 mL). The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: YMC TAR-C18, 30 * 150 mm, 5 μm; mobile phase: [water (containing 7 mmol / L ammonium bicarbonate) - acetonitrile]; acetonitrile gradient: 50-80%) to obtain compound 94 (23.0 mg).

[0762] 1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.15(s,1H),7.91(s,1H),6.57-6.30(m,1H),5.16-4.97(m,2H), 4.90-4.75(m,1H),3.89(s,3H),3.53(s,2H),2.74-2.55(m,4H),2.32-2.24(m,4H),1.67-1.66(m,2H).

[0763] MS m / z(ESI): 472.1 [M+H] +

[0764] Biological testing methods

[0765] Experimental Example 1: Determination of the GCase activity of the disclosed compound on the lysosomal lysosomes of the HEK-293T cell line

[0766] 1) Materials and reagents:

[0767] 2) Instruments:

[0768] 3) Experimental methods:

[0769] Day 1: Laying out the boards

[0770] 2500 HEK-293T cells were seeded into each well of a 96-well plate, and 100 μL of DMEM medium (containing 10% FBS) was added to each well. The plates were then incubated at 37°C and 5% CO2 for 48 hours.

[0771] Day 3: Administer additional medication

[0772] Different concentrations of the disclosed compound were prepared (a 10 mM stock solution of the compound was prepared using DMSO, and then diluted to 1 μM, 5 μM, and 10 μM using DMEM medium solution, respectively). After discarding the old medium in the 96-well plate, 200 μL / well of medium containing 1 μM, 5 μM, and 10 μM of the compound was added to the 96-well plate, and the plate was incubated at 37°C with 5% CO2 for 72 hours.

[0773] Day 6: Enzyme activity test

[0774] a) Preparation of PFB-FDGlu mixed medium: Take 22 mL of phenol red-free DMEM medium, add 22 μL PFB-FDGlu (50 μg / mL) and mix thoroughly;

[0775] b) Preparation of mixed culture medium of PFB-FDGlu and Bafilomycin A1: Transfer 11 mL of the above-prepared mixed culture medium of PFB-FDGlu to a new 15 mL tube, add 2.2 μL of Bafilomycin A1 and mix thoroughly.

[0776] c) Discard the culture medium, wash the cells once with 100 μL / well of phenol red-free DMEM medium, and add 100 μL / well of mixed medium containing only PFB-FDGlu and mixed medium containing PFB-FDGlu and Bafilomycin A1 respectively.

[0777] d) Incubate the reaction in a 37°C incubator for 1 hour;

[0778] e) After incubation, read the kinetic curve using a microplate reader, 15 min / reading, for a total of 2 hours (excitation wavelength 485 nm / emission wavelength 525 nm). Calculate AC. 50 (This refers to the drug concentration at which the GCase enzyme activation activity is 150%).

[0779] The results of testing the activation level of GCase enzyme in HEK-293T cells by the disclosed compounds are shown in Table 1.

[0780] Table 1. Results of the assay of GCase activity of the disclosed compounds in HEK293T cells.

[0781] Experimental Example 2: Inhibitory effect of the disclosed compound on the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes.

[0782] Unless otherwise specified, all reagents and consumables used in this experiment are commercially available products.

[0783] The inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzyme activities by the disclosed compounds was determined using the following experimental method.

[0784] The experimental steps are as follows:

[0785] 1. Preparation of 100mM Phosphate Buffered Sodium (PBS): Weigh 7.098g Na₂HPO₄ and dissolve it in 500mL of pure water by sonication to obtain solution A. Weigh 3.400g KH₂PO₄ and dissolve it in 250mL of pure water by sonication to obtain solution B. Slowly add solution B to solution A on a stirrer until the pH reaches 7.4 to prepare a 100mM PBS buffer.

[0786] 2. Preparation of NADPH solution: Prepare 10mM NADPH (reduced coenzyme II) solution using 100mM PBS buffer.

[0787] 3. Preparation of working solutions for the test compounds: Dilute 10 mM of the DMSO stock solution of the compounds disclosed herein with DMSO to obtain working solutions of the compounds (10000 μM, 3333.3 μM, 1111.1 μM, 370.37 μM, 123.46 μM, 41.15 μM, 13.7 μM, 0 μM).

[0788] 4. Preparation of positive inhibitor working solution: Dilute the positive inhibitor DMSO stock solution with DMSO (CYP 2C9: sulfamethoxazole 1000μM, CYP 2D6: quinidine / CYP 3A4: ketoconazole, 100μM; CYP 1A2: α-naphthylflavonoid, 50μM; CYP 2C19: Nocacolone, 6000 μM) yielded positive inhibitor working solutions (sulfamethoxazole, 1000 μM, 300 μM, 100 μM, 30 μM, 10 μM, 3 μM, 0 μM; quinidine / ketoconazole, 100 μM, 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0 μM; α-naphthylflavonoid, 50 μM, 15 μM, 5 μM, 1.5 μM, 0.5 μM, 0.15 μM, 0 μM; nocacolone, 6000 μM, 1800 μM, 600 μM, 180 μM, 60 μM, 18 μM, 0 μM).

[0789] 5. Preparation of substrate working solution: Prepare substrate working solution (8000 μM phenacetin, 1000 μM diclofenac, 8000 μM S-methoxytocin, 1000 μM dextromethorphan and 400 μM midazolam) with water, acetonitrile or acetonitrile / methanol.

[0790] 6. Take 1 μL of 20 mg / mL liver microsome solution (source: gentest), 1 μL of substrate working solution, and 177 μL of PBS buffer, add 1 μL of compound working solution (for the positive control group, add 1 μL of positive inhibitor working solution instead of the compound working solution), mix well, and pre-incubate in a 37°C water bath for 10 minutes. Add 10 mM NADPH solution and pre-incubate in a 37°C water bath for 10 minutes. After 10 minutes, add 20 μL of NADPH to each well to start the reaction. Incubate at 37°C for 15 minutes (CYP1A2), 15 minutes (CYP2C9), 60 minutes (CYP2C19), 15 minutes (CYP2D6), or 15 minutes (CYP3A4). All incubated samples should be in duplicate. After the corresponding incubation time, add 400 μL of ice-cold methanol containing the internal standard to all samples to terminate the reaction. Vortex to mix, and centrifuge at 4000 rpm and 4°C for 30 minutes. After centrifugation, transfer 100 μL of supernatant to the sample plate, add 200 μL of ultrapure water and mix well for LC-MS / MS analysis.

[0791] The IC50 values ​​of the disclosed compound against CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 were calculated using Excel XLfit 5.3.1.3. 50 The values ​​are shown in Table 2.

[0792] Table 2 shows the IC50 values ​​of the disclosed compounds against CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. 50 value "-" indicates that no detection was performed.

[0793] Experimental Example 3: Imaging determination of the high lysosomal GCase activity of the disclosed compound in the SH-SY5Y cell line.

[0794] 1) Materials and reagents:

[0795] 2) Instruments:

[0796] 3) Experimental methods:

[0797] Complete cell culture medium: DMEM / F-12, HEPES, containing 10% FBS and 1% penicillin-streptomycin;

[0798] High-content imaging detection medium: DMEM / F-12, HEPES, phenol red-free, FBS-free;

[0799] 20,000 SH-SY5Y cells were seeded per well in a 384-well plate, along with 40 μL of complete cell culture medium per well, and incubated overnight at 37°C with 5% carbon dioxide.

[0800] Dissolve the disclosed compound in DMSO to a concentration of 20 mM, and then dilute it 1:1 with DMSO to 10 mM. The 20 mM and 10 mM compound solutions were then diluted 1:400 with complete cell culture medium to obtain concentrations of 50 μM and 25 μM, respectively. Add 10 μL of culture medium containing 50 μM or 25 μM of the disclosed compound to the wells of a 384-well plate, resulting in final concentrations of the test compound of 10 μM or 5 μM, and a final DMSO concentration of 0.05%. Centrifuge at 500 rpm for 30 seconds and incubate at 37°C with 5% CO2 for 72 hours.

[0801] Prepare high-content imaging detection medium (DMEM / F-12, HEPES, phenol red-free, FBS-free), add 75 nM Lysotracker and 58 μM PFB-FDGlu to a final concentration; remove the original supernatant from the cell plate, add medium containing 40 μL Lysotracker and PFB-FDGlu, centrifuge at 500 rpm for 30 s, and incubate at 37°C and 5% CO2 for 45 minutes; remove the cell plate and perform continuous high-content imaging at 30-minute intervals for a total duration of 3 hours, acquiring images from brightfield, Alexa 488, and Alexa 647 channels, with 10 fields of view per well. Calculate the average fluorescence intensity of cells, lysosomes, and cell-lysosome colocalization. Using the untreated DMSO wells as a background, calculate the fluorescence intensity at the endpoint of each well. The drug concentration at which the fluorescence intensity of the analyte is twice the background fluorescence intensity is taken as the AC value. 100 Value (AC) 100 This refers to the drug concentration at which the GCase activation activity is 200%.

[0802] The disclosed compound exhibited high GCase activation levels in SH-SY5Y cells, as shown in Table 3. (Compound AC was also tested.) 100 Value range: A: AC 100 ≤5μM; B: 5μM <AC 100 ≤10μM; C: >10μM;

[0803] Table 3. Results of the assay of GCase activity of the disclosed compounds in SH-SY5Y cells.

[0804] Experimental Example 4: Determination of the potential inhibitory effect of the disclosed compound on the voltage-gated potassium ion channel hERG

[0805] This experiment used the Chinese hamster ovary (CHO) cell line (B'SYS GmbH) stably expressing the hERG potassium channel. hERG-CHO cells were clamped in a whole-cell voltage-clamp configuration using a SyncroPatch 384i / 384 (Nanion) automated patch-clamp system, and hERG currents were induced by appropriate voltages. The test compounds were then tested: cells were first perfused six times with extracellular fluid containing 0.1% DMSO. The measured stable hERG current was used as the baseline, and the baseline current value was the mean of five stable sampling points (tail current magnitude). 空白 After the hERG current stabilized, five concentration gradients of the test compound (0.37 μM, 1.11 μM, 3.33 μM, 10 μM, and 30 μM) were perfused around the cells. The cells were allowed to fully react with the compound for 10 minutes while the hERG current was recorded simultaneously. Once the current stabilized, five stable hERG current values ​​were read, and their average was taken as the final current value at the specific concentration (tail current magnitude). 化合物 Cisapride (Sigma (C4740)) was used as a positive control for simultaneous assays at six concentrations (0.001 μM, 0.004 μM, 0.012 μM, 0.037 μM, 0.111 μM, and 0.333 μM) to verify the stability of the test cells and the accuracy of the results. After testing the compounds, 450 nM of Dopiride (Beijing Yipulis Technology Development Co., Ltd., D525700) was added to all test cells to completely suppress their current, serving as a complete positive control for these cells (tail current size). 阳性对照 Finally, the tail current suppression rate is calculated using the following formula: {Tail current suppression rate (%) = [1 - (tail current magnitude)]} 化合物 - Tail current magnitude 阳性对照 ) / (tail current magnitude) 空白 - Tail current magnitude 阳性对照 The dose-response curve was fitted using Graphpad Prism 8.0 software, and the IC was calculated. 50 value.

[0806] The inhibition of hERG by the disclosed compounds is shown in Table 4 below. The test data indicate that the hERG inhibitory activity of the disclosed compounds is poor, and the potential safety risks in the future are relatively small.

[0807] Table 4. Inhibitory activity of the disclosed compounds in the voltage-gated potassium channel hERG.

Claims

1. A compound represented by Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein is selected from a single or double bond; Q is selected from N or C; G is selected from N, CH or C(O); Ring B is selected from the following groups: a)C6-C 14 Spirocycloalkylene, C6-C 14 fused cycloalkylene, C5-C 12 Bridged cycloalkyl groups, 6-14 membered spirocycloalkyl groups, 6-14 membered fused heterocyclic groups, or 5-12 membered bridged heterocyclic groups; or, b) W is selected from the group consisting of a bond, -CR a R b -, -CR a R b O-, C(O), O, or S; R a , R b is independently selected from H, halogen, Ci-C6alkyl, Ci-C6haloalkyl or Ci-C4alkoxy; Ring A is selected from C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl; Each R 1 Independently selected from CN, NH2, OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or 4-10 heterocyclic group, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or 4-10 heterocyclic group is optionally substituted with NH2, OH, halogen or C1-C6 alkyl; R 2 is selected from H, C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halogen, C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl; R 3 is selected from H, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-6 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl optionally substituted with NH2, OH, halogen, or C1-C6alkyl; Each R 4 It is independently selected from deuterium, OH, halogen, =O, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; R 5 selected from H, deuterium, NH2, CN, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-7 membered heterocyclyl; p, q are independently selected from 0, 1 or 2.

2. The compound of formula (I) as claimed in claim 1, or its stereoisomers or pharmaceutically acceptable salts thereof, wherein, wherein, For a single bond, Q is N and G is C(O); or is a double bond, Q is C, and G is N.

3. The compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, The compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (I-2) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , p, q, W are as defined in claim 1; or wherein: Ring B is selected from C6-C 14 Spirocycloalkylene, 6-14 membered spiroheterocyclic alkylene, or 6-14 membered fused heterocyclic alkylene; W is selected from the group consisting of a bond, -CR a R b -, -CR a R b O-, C(O) or O; R a , R b is independently selected from H or C1-C6 alkyl; Ring A is selected from C3-C 12 Cycloalkyl, 4-12 membered heterocyclic, 5-10 membered heteroaryl or phenyl; Each R 1 Independently selected from CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or 4-10 membered heterocyclic group, wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with OH or halogen; R 2 selected from C1-C6alkyl or 4-10 membered heterocyclyl, said C1-C6alkyl optionally substituted with halogen; R 3 selected from H, C1-C6 alkyl or C1-C6 alkoxy; R 4 selected from =0 or C1-C6alkyl; R 5 is selected from H or C1-C6 alkyl.

4. The compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein, Ring B is selected from the following groups: a) 6-14 membered spiro- heterocyclylenyl, 6-14 membered fused- heterocyclylenyl or 5-12 membered bridged- heterocyclylenyl; or, b) or Ring B is selected from the following groups: a) 6-14 membered spiro- heterocyclylenyl or 6-14 membered fused- heterocyclylenyl; or b) or Ring B is selected from 6-14 membered spiro- heterocyclylenyl or 6-14 membered fused- heterocyclylenyl; or Ring B is selected from 6-14 membered spiro- heterocyclylenyl, 6-14 membered fused- heterocyclylenyl or 5-12 membered bridged- heterocyclylenyl; or Ring B is selected from 3 / 6 bicyclic spiro- heterocyclylenyl, 4 / 4 bicyclic spiro- heterocyclylenyl, 4 / 5 bicyclic spiro- heterocyclylenyl, 4 / 6 bicyclic spiro- heterocyclylenyl, 5 / 5 bicyclic spiro- heterocyclylenyl or 5 / 6 bicyclic spiro- heterocyclylenyl; or Ring B is selected from 4 / 4 bicyclic spiro- heterocyclylenyl, 4 / 5 bicyclic spiro- heterocyclylenyl, 5 / 6 bicyclic spiro- heterocyclylenyl, 4 / 6 bicyclic spiro- heterocyclylenyl, 5 / 6 bicyclic fused- heterocyclylenyl or 5 / 5 bicyclic fused- heterocyclylenyl; or Ring B is selected from 4 / 4 bicyclic spiro- heterocyclylenyl, 4 / 5 bicyclic spiro- heterocyclylenyl, 5 / 6 bicyclic spiro- heterocyclylenyl or 4 / 6 bicyclic spiro- heterocyclylenyl; Alternatively, ring B is selected from Alternatively, ring B is selected from: Alternatively, ring B is selected from:

5. The compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein, W is selected from the group consisting of a bond, -CR a R b -, -CR a R b O- or C(O); or W is selected from a bond, -CR a R b -, -CR a R b O-, C(O) or O; or W is selected from a bond, -CR a R b - or -CR a R b O-; or W is selected from a bond or -CR a R b O-; or W is selected from -CR a R b - or -CR a R b O-; or W is selected from a bond, -CH2-, -CH2O- or C(O); or W is selected from a bond, -CH2- or -CH2O-; or W is selected from a bond or -CH2O-.

6. The compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein, Ring A is selected from C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl; or, ring A is selected from C3-C 12 cycloalkyl, 5-10 membered heteroaryl, or phenyl; or, ring A is selected from C3-C 12 cycloalkyl or 5-10 membered heteroaryl; Alternatively, ring A is selected from C3-C6 cycloalkyl, 4-9 membered heterocyclic, 5-6 membered heteroaryl, or phenyl; or ring A is selected from C3-C6 cycloalkyl, 4-9 membered heterocyclic, 5-6 membered heteroaryl, or phenyl. 12 Cycloalkyl or 4-12 membered heterocyclic groups; or, ring A is selected from C5-C 10 bridged cycloalkyl, C5-C 10 spirocycloalkyl or 4-9 membered heterocyclyl; or, ring A is selected from C5-C 10 bridged cycloalkyl; or Ring A is selected from 5-7 membered heterocyclyl; or Ring A is 5-6 membered heteroaryl; Alternatively, ring A is selected from Alternatively, ring A is selected from Alternatively, ring A is selected from 7. The compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein, R 1 independently selected from CN, NH2, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C3-C6cycloalkyl or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halogen, C1-C6alkyl; or R 1 independently selected from CN, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6alkyl or C1-C6alkoxy optionally substituted with OH or halogen; or R is H, or R 1 independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy optionally substituted with halogen; Or, R 1 Selected from C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the C1-C6 alkoxy group is optionally substituted with a halogen; or R 1 is selected from halogen, Ci-C6-alkyl or Ci-C6-haloalkyl.

8. The compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein, R 2 H, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halogen, or C1-C6 alkyl; or R is selected from C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halo, or C1-C6alkyl; 2 or R is selected from C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-10 membered heterocyclyl optionally substituted with NH2, OH, halo, or C1-C6alkyl; or R is selected from C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl optionally substituted with NH2, OH, halo, or C1-C6alkyl; 2 or R is selected from C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl optionally substituted with NH2, OH, halo, or C1-C6alkyl; or R 2 is selected from C1-C6alkyl or 4-10 membered heterocyclyl, said C1-C6alkyl being optionally substituted with halogen; or R 2 Ci-C6alkyl substituted by halogen; Or, R 2 Selected from CH2CHF2 or oxocyclic butyl; or R 2 is CH2CHF2.

9. The compound of Formula (I) as claimed in any one of claims 1-8, wherein, R 3 selected from H, C1-C6 alkyl or C1-C6 alkoxy; Or, R 3 It is H.

10. The compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein, R 4 selected from deuterium, OH, halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, or C3- C6cycloalkyl; Or, R 4 Selected from deuterium, OH, halogen, =O, C1-C6 alkyl or C1-C6 haloalkyl; or R 4 is selected from =0 or C1-C6alkyl; or R 4 is =0.

11. The compound of Formula (I) as claimed in any one of claims 1-10, wherein, R 5 selected from H, deuterium, halogen or C3-C6cycloalkyl; or R 5 is selected from H, halogen, Ci-C6alkyl or C3-C6cycloalkyl; or R 5 is selected from H or Ci-C6alkyl; or R 5 is selected from H or CH3.

12. The compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein, p is selected from 0 or 1; and / or q is selected from 0 or 1.

13. The compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein, The compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (II-2) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: X1is selected from O, S or CR 6 R 7 ; X2is selected from CR 8 or N; X3is selected from C, CR 9 or N; R 6 , R 7 , R 8 , R 9 is independently selected from H, deuterium, NH2, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C6cycloalkyl; s, m, n are independently selected from 0, 1 or 2; q' is selected from 0 or 1; q" is selected from 0 or 1; Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , p, W are defined as in any one of claims 1-12.

14. The compound of Formula (I) according to any one of claims 1-12, or a stereoisomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of Formula (V-2), or a stereoisomer or a pharmaceutically acceptable salt thereof: ###00033### (V-2) Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , p, q, W are defined as in any one of claims 1-12.

15. The compound of Formula (I) according to any one of claims 1-12, or a stereoisomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of Formula (VI-2), or a stereoisomer or a pharmaceutically acceptable salt thereof: ###00034### (VI-2) Z1is selected from CR 10 or N; Z2is selected from CR 10 or N; R 10 selected from H, deuterium, NH2, OH, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C6cycloalkyl; t, f are independently selected from 0, 1 or 2; q' is selected from 0 or 1; q" is selected from 0 or 1; Rings A, R 1 R 2 R 3 R 4 R 5 p, W are as defined in any one of claims 1 to 12.

16. The compound of Formula (I) according to any one of claims 1-2, or a stereoisomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of Formula (I-1), or a stereoisomer or a pharmaceutically acceptable salt thereof: ###00010### (I-1) Ring A is selected from C3-C 12 cycloalkyl or 4-12 membered heterocyclyl; when W is selected from a bond or -CR a R b - when W is selected from a bond or -CR Ring B, R 1 , R 2 , R 3 , R 4 , R 5 , p, q, W are defined as in any of claims 1-2.

17. The compound of Formula (I) according to any one of claims 1-2, or a stereoisomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of Formula (I-1), or a stereoisomer or a pharmaceutically acceptable salt thereof: ###00006### (I-1) Ring A is selected from C3-C6 cycloalkyl, 4-9 membered heterocyclyl or 5-6 membered heteroaryl; R 1 , R 2 , R 3 , R 4 , R 5 , p, q, W are defined as in any one of claims 1-2.

18. The compound of Formula (I) according to any one of claims 1-3, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein, The compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following compounds or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

19. The compound of Formula (I) according to claim 1 or 2, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, The compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following compounds or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

20. A pharmaceutical composition comprising a compound of Formula (I) as claimed in any one of claims 1-19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

21. Use of a compound of Formula (I) as claimed in any one of claims 1-19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 20, for the manufacture of a medicament for the prevention or treatment of a GCase-mediated disease.

22. A method of preventing or treating a GCase-mediated disease in a subject, comprising administering to a subject, preferably a mammal, more preferably a human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I) as described in any one of claims 1-19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 20.

23. The use as described in claim 21 or the method as described in claim 22, wherein: the GCase-mediated disease is a disease that benefits from allosteric modulation of GCase; or the GCase-mediated disease is a disease that benefits from activation of GCase; or the GCase-mediated disease is selected from a neurodegenerative disease; preferably, the neurodegenerative disease is Alzheimer’s disease or Parkinson’s disease.

24. The use as described in claim 21 or the method as described in claim 22, wherein: the GCase-mediated disease is a disease that benefits from allosteric modulation of GCase; or the GCase-mediated disease is a disease that benefits from activation of GCase; or the GCase-mediated disease is selected from a neurodegenerative disease; preferably, the neurodegenerative disease is Alzheimer’s disease or Parkinson’s disease.

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