CBL-b inhibitor

Abstract

A new compound having a CBL-B inhibitory activity, a pharmaceutical composition containing same, an intermediate for preparing same, and a method for treating cancer by means of using same.

Description

CBL-B inhibitors

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority to and the benefits of Chinese Patent Application No. 2023107008395, Chinese Patent Application No. 2023110661226, Chinese Patent Application No. 202311314264X, Chinese Patent Application No. 2024100391121, and Chinese Patent Application No. 2024107340614 filed with the National Intellectual Property Administration of China, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure belongs to the field of medicinal chemistry and relates to novel compounds having E3 ligase Casitas b-linege lymphoma B (CBL-B) inhibitory activity, pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and methods for treating CBL-B-mediated diseases using drugs containing the compounds of the present disclosure. Background Art

[0004] CBL-B is a RING E3 ligase and a member of the highly conserved CBL protein family, which in mammals consists of three CBL genes: CBL, CBL-B, and CBL-C. CBL proteins interact with target proteins through their protein-protein interaction domains, thereby regulating multiple signaling pathways, including tyrosine kinase (TK) signaling, in various cell types. The CBL protein structure consists of an amino-terminal tyrosine kinase binding domain (TKBD), a linker helix region (LHR), and a highly intriguing novel gene (RING) domain, followed by a carboxy-terminal region (SH3) containing SRC homology 2 (SH2) and SRC homology binding sites. The CBL TKBD consists of a four-helix bundle (4H), an EF hand, and a variant SH2 domain that binds substrates, such as activated TKs, in a phosphotyrosine-dependent manner. Ubiquitination of activated receptor TKs by CBL-B regulates the assembly of endocytic proteins at the membrane and in sorting endosomes, promoting lysosomal targeting, degradation, and signal termination. CBL-B is also important for reducing signaling from antigen and cytokine receptors by ubiquitinating receptor chains and associated cytosolic TKs, leading to inactivation and / or proteasomal degradation. CBL-B is expressed in the immune cell lineage and serves as a master regulator of immune cell activation and maintenance of peripheral tolerance. CBL-B inhibitors may enhance the activity of cancer vaccines. Furthermore, mutations in the RING domain of the CBL protein and the CBL-B linker sequence have been found in a variety of diseases and cancers, including luvenile myelocytic leukemia (IMMF), chronic myelocytic leukemia (CMMF) with Prader-Willi disease, myeloid membrane leukemia, and acute myeloid leukemia (AMF). Therefore, CBL-B inhibition represents an opportunity for therapeutics with both intrinsic and extra-tumoral toxicity.

[0005] Currently, there are many studies based on this mechanism of action, but no CBL-B inhibitor drugs have been found on the market. Therefore, there is an urgent need to develop effective CBL-B inhibitors for clinical patients.

[0006] Summary of the Invention

[0007] The present disclosure provides a compound of formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof,

[0008] in,

[0009] Ring A is selected from 6-10 membered aryl and 5-6 membered heteroaryl;

[0010] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0011] X1 is selected from -C(=CH2), CRa1 R a2 、N、NH、CR a3 ;

[0012] R a1 、R a2 、R a3 Each independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, nitro, substituted or unsubstituted C 2--4 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, -NRe1Re2, -CORe3, -SO2CH3;

[0013] Re1, Re2, and Re3 are each independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 alkyl;

[0014] X2 selected from CR b1 R b2 , CR b3 ;

[0015] R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0016] R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, -WC 3-6 Cycloalkyl;

[0017] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, cyano, nitro, substituted or unsubstituted C 3-6 Cycloalkyl, C1-4 Alkyl-C 1-4 Haloalkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 deuterated alkoxy; or R1 and X1 combine to form a substituted or unsubstituted 5-6 membered heterocyclic group;

[0018] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0019] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0020] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OC 1-4 Alkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy, NH=;

[0021] m is selected from 0, 1, 2, 3, 4, when there are multiple R2, adjacent R2 and the atoms connected thereto optionally form a substituted or unsubstituted C 3-6 Cycloalkyl;

[0022] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 3- 6-cycloalkylamino, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 Alkyl, -NH-C 1-4 Alkylene-C 1-4 Haloalkyl, -NH-C 1-4 Alkylene-CONH2, -OC 1-4 Alkylene -CN, -OC 3-6 Cycloalkylene -CN, -WC 3-6 Cycloalkyl, -W-(3-6 membered heterocyclic group), C 2-6 Alkenyl-CN, cyano, -CO-NH-C 1-4 Alkyl, the C 3-6Cycloalkyl, 3-6 heterocyclic groups can be optionally substituted with halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene-CN substitution;

[0023] W is selected from O, NH, S;

[0024] Z is selected from CR d1 R d2 , O, S, N, the R d1 、R d2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkyl-C 1-4 Halogenated alkyl, C 1-4 Alkyl-cyano, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, -OC 1-4 Haloalkyl, oxo, or R d1 、R d2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0025] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0026] The present disclosure provides a compound of formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof,

[0027] in,

[0028] Ring A is selected from 6-10 membered aryl and 5-6 membered heteroaryl;

[0029] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0030] X1 is selected from CRa1Ra2, N, NH, CR a3 ;

[0031] Ra1, Ra2, R a3 Each independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, -NRe1Re2, -CHO, -CONH2, -SO2CH3;

[0032] Re1 and Re2 are each independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl;

[0033] X2 selected from CR b1 R b2 , CR b3 ;

[0034] R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 Together with the carbon atoms linked together to form C 3-6 Cycloalkyl;

[0035] R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0036] R1 is selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-4 alkyl;

[0037] L1 is selected from C 1-4 Alkylene, -NH-C 1-4 alkylene;

[0038] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0039] R2 is selected from halogen, deuterium, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 deuterated alkyl;

[0040] m is selected from 0, 1, 2, 3, 4;

[0041] Y1 and Y2 are each independently selected from CH, N, CR c , the Rc Selected from cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 3-6 Cycloalkylamino, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 Alkyl, -OC 1-4 Alkylene -CN, -WC 3-6 Cycloalkyl, -W-(3-6 membered heterocyclic group), the cycloalkyl and heterocyclic groups may be optionally substituted with halogen, cyano, C 1-4 Alkyl substitution;

[0042] W is selected from O, NH, S;

[0043] Z is selected from O, S, CR d1 R d2 , the R d1 、R d2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkyl-cyano, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy, oxo, or R d1 、R d2 Together with the carbon atoms to which they are linked, they form a 3-6 membered heterocyclic group;

[0044] R3 is selected from halogen, C 1-4 alkyl.

[0045] The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

[0046] in,

[0047] Ring A is selected from 6-10 membered aryl and 5-6 membered heteroaryl;

[0048] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0049] X1 is selected from -C(=CH2), CR a1 R a2 、N、NH、CR a3 ;

[0050] Ra1 、R a2 、R a3 Each independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, nitro, substituted or unsubstituted C 2--4 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, -NRe1Re2, -CORe3, -SO2CH3;

[0051] Re1, Re2, and Re3 are each independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 alkyl;

[0052] X2 selected from CR b1 R b2 , CR b3 ;

[0053] R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0054] R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, -WC 3-6 Cycloalkyl;

[0055] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, cyano, nitro, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkyl-C 1-4 Haloalkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4deuterated alkoxy; or R1 and X1 combine to form a substituted or unsubstituted 5-6 membered heterocyclic group;

[0056] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0057] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0058] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OC 1-4 Alkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy, NH=;

[0059] m is selected from 0, 1, 2, 3, 4, when there are multiple R2, adjacent R2 and the atoms connected thereto optionally form a substituted or unsubstituted C 3-6 Cycloalkyl;

[0060] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 3- 6-cycloalkylamino, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 Alkyl, -NH-C 1-4 Alkylene-C 1-4 Haloalkyl, -NH-C 1-4 Alkylene-CONH2, -OC 1-4 Alkylene -CN, -OC 3-6 Cycloalkylene -CN, -WC 3-6 Cycloalkyl, -W-(3-6 membered heterocyclic group), C 2-6 Alkenyl-CN, cyano, -CO-NH-C 1-4 Alkyl, the C 3-6 Cycloalkyl, 3-6 heterocyclic groups can be optionally substituted with halogen, cyano, C 1-4 Alkyl, C 1-4 Alkylene-CN substitution;

[0061] W is selected from O, NH, S;

[0062] Z is selected from CR d1 R d2 , O, S, N, the R d1 、R d2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkyl-C 1-4 Halogenated alkyl, C 1-4 Alkyl-cyano, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, -OC 1-4 Haloalkyl, oxo, or R d1 、R d2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0063] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0064] The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

[0065] in,

[0066] Ring A is selected from 6-10 membered aryl and 5-6 membered heteroaryl;

[0067] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0068] X1 is selected from CRa1Ra2, N, NH, CR a3 ;

[0069] R a1 、R a2 、R a3 Each independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Alkylene-OC 1-4Alkyl, -NRe1Re2, -CHO, -CONH2, -SO2CH3;

[0070] Re1 and Re2 are each independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl;

[0071] X2 selected from CR b1 R b2 , CR b3 ;

[0072] R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 Together with the carbon atoms linked together to form C 3-6 Cycloalkyl;

[0073] R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0074] R1 is selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-4 alkyl;

[0075] L1 is selected from C 1-4 Alkylene, -NH-C 1-4 alkylene;

[0076] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0077] R2 is selected from halogen, deuterium, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 deuterated alkyl;

[0078] m is selected from 0, 1, 2, 3, 4;

[0079] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4Alkylamino, C 3-6 Cycloalkylamino, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 Alkyl, -OC 1-4 Alkylene -CN, -WC 3-6 Cycloalkyl, -W-(3-6 membered heterocyclic group), the cycloalkyl and heterocyclic groups may be optionally substituted with halogen, cyano, C 1-4 Alkyl substitution;

[0080] W is selected from O, NH, S;

[0081] Z is selected from O, S, CR d1 R d2 , the R d1 、R d2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkyl-cyano, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy, oxo, or R d1 、R d2 Together with the carbon atoms to which they are linked, they form a 3-6 membered heterocyclic group;

[0082] R3 is selected from halogen, C 1-4 alkyl.

[0083] The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

[0084] in,

[0085] Ring A is selected from aryl, 5-6 membered heteroaryl;

[0086] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0087] X1 is selected from -C(=CH2), CR a1 R a2 、N、NH、CR a3 ;

[0088] R a1 、R a2 Each independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4Halogenated alkyl, C 1-4 Alkylamino, nitro, substituted or unsubstituted C 2--4 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, -NRe1Re2, -CONH2, -SO2CH3, -CHO;

[0089] Re1, Re2, and Re3 are each independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 alkyl;

[0090] R a3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, cyano;

[0091] X2 selected from CR b1 R b2 , CR b3 ;

[0092] R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0093] R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0094] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, cyano, nitro, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkyl-C 1-4 Haloalkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 deuterated alkoxy;

[0095] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0096] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0097] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OC 1-4 Alkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy,

[0098] m is selected from 0, 1, 2, 3, 4;

[0099] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 3- 6-cycloalkylamino, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 Alkyl, -NH-C 1-4 Alkylene-C 1-4 Haloalkyl, -NH-C 1-4 Alkylene-CONH2, -OC 1-4 Alkylene-CN, WC 3-6 Cycloalkyl, W-(3-6 membered heterocyclic group), C 2-6 Alkenyl-CN, cyano, C 1-4 Alkyl-NHCO-, the C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups can be substituted with halogen, C 1-4 Alkyl, cyano, C 1-4 Alkylene-CN substitution;

[0100] W is selected from O, N, and S;

[0101] Z is selected from CR d1 R d2 , O, S, N, the R d1 、Rd2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkyl-C 1-4 Halogenated alkyl, C 1-4 Alkyl-cyano, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy, alkenyl, OC 1-4 Haloalkyl, or R d1 、R d2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl, 3-6 membered heterocyclic group; R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0102] The present disclosure provides a compound of formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof,

[0103] in,

[0104] Ring A is selected from aryl, 5-6 membered heteroaryl;

[0105] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0106] X1 is selected from -C(=CH2), CR a1 R a2 、N、NH、CR a3 ;

[0107] R a1 、R a2 Each independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, nitro, substituted or unsubstituted C 2--4 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, -NRe1Re2, -CONH2, -SO2CH3;

[0108] Re1 and Re2 are each independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl;

[0109] R a3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, cyano;

[0110] X2 selected from CR b1 R b2 , CR b3 ;

[0111] R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0112] R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0113] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, cyano, nitro, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkyl-C 1-4 Haloalkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 deuterated alkoxy;

[0114] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0115] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0116] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C1-4 Alkoxy, C 1-4 Alkyl-OC 1-4 Alkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy,

[0117] m is selected from 0, 1, 2, 3, 4;

[0118] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 3- 6-cycloalkylamino, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 Alkyl, -NH-C 1-4 Alkylene-C 1-4 Haloalkyl, -NH-C 1-4 Alkylene-CONH2, -OC 1-4 Alkylene-CN, WC 3-6 Cycloalkyl, W-(3-6 membered heterocyclic group), the cycloalkyl and heterocyclic group can be arbitrarily replaced by halogen, C 1-4 Alkyl substitution;

[0119] W is selected from O, N, and S;

[0120] Z is selected from CR d1 R d2 , O, S, N, the R d1 、R d2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkyl-C 1-4 Halogenated alkyl, C 1-4 Alkyl-cyano, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy, alkenyl, OC 1-4 Haloalkyl, or R d1 、R d2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl, 3-6 membered heterocyclic group; R3 is selected from hydrogen, halogen, C 1-4Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0121] The present disclosure provides a compound of formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof,

[0122] in,

[0123] Ring A is selected from aryl, 5-6 membered heteroaryl;

[0124] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0125] X1 is selected from -C(=CH2), CRa1Ra2, N, NH, CR a3 ;

[0126] Ra1 and Ra2 are each independently selected from C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, -NRe1Re2, -CONH2, -SO2CH3;

[0127] Re1 and Re2 are each independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl;

[0128] R a3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, cyano;

[0129] X2 selected from CR b1 R b2 , CR b3 ;

[0130] R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0131] R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0132] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, cyano, nitro, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkyl-C 1-4 Haloalkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 deuterated alkoxy;

[0133] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0134] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0135] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OC 1-4 Alkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy,

[0136] m is selected from 0, 1, 2, 3, 4;

[0137] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from -NH2, -NH-C 1-4 Alkyl, -NH-C 1-4 Alkylene-C 1-4 Haloalkyl, -NH-C 1-4 Alkylene-CONH2, -OC 1-4 Alkylene-CN, WC 3-6 Cycloalkyl, W-3-6 membered heterocyclic group, said cycloalkyl, heterocyclic group can be arbitrarily replaced by halogen, C 1-4 Alkyl substitution;

[0138] W is selected from O, N, and S;

[0139] Z is selected from CR d1 R d2, O, S, N, the R d1 、R d2 Each is independent of OC 1-4 alkyl halide;

[0140] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0141] The present disclosure provides a compound of formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof,

[0142] in,

[0143] Ring A is selected from aryl, 5-6 membered heteroaryl;

[0144] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0145] X1 is selected from -C(=CH2), CRa1Ra2, N, NH, CR a3 ;

[0146] Ra1 and Ra2 are each independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, nitro, substituted or unsubstituted C 2--4 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkyl;

[0147] R a3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, cyano;

[0148] X2 selected from CR b1 R b2 , CR b3 ;

[0149] R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0150] R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0151] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, cyano, nitro, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkyl-C 1-4 Haloalkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 deuterated alkoxy;

[0152] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0153] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0154] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OC 1-4 Alkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy,

[0155] m is selected from 0, 1, 2, 3, 4;

[0156] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C3-6 cycloalkylamino, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, WC 3-6 Cycloalkyl;

[0157] W is selected from O, N, and S;

[0158] Z is selected from CR d1R d2 , O, S, N, the R d1 、R d2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkyl-C 1-4 Halogenated alkyl, C 1-4 Alkyl-cyano, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy, alkenyl, or R d1 、R d2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0159] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0160] The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

[0161] in,

[0162] Ring A is selected from aryl, 5-6 membered heteroaryl;

[0163] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0164] X1 is selected from -C(=CH2), CR a1 R a2 、N、NH、CR a3 ;

[0165] R a1 、R a2 Each independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, nitro, substituted or unsubstituted C 2--4 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Alkylene-OC 1-4Alkyl, -NRe1Re2, -CORe3, -SO2CH3;

[0166] Re1, Re2, and Re3 are each independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 alkyl;

[0167] R a3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, cyano;

[0168] X2 selected from CR b1 R b2 , CR b3 ;

[0169] R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0170] R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0171] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, cyano, nitro, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkyl-C 1-4 Haloalkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 deuterated alkoxy;

[0172] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0173] Ring B is selected from C 3-6Cycloalkyl, 5-10 membered heterocyclic group;

[0174] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OC 1-4 Alkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy,

[0175] m is selected from 0, 1, 2, 3, 4;

[0176] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 3- 6-cycloalkylamino, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 Alkyl, -NH-C 1-4 Alkylene-C 1-4 Haloalkyl, -NH-C 1-4 Alkylene-CONH2, -OC 1-4 Alkylene-CN, WC 3-6 Cycloalkyl, W-(3-6 membered heterocyclic group), C 2-6 Alkenyl-CN, cyano, -CO-NH-C 1-4 Alkyl, the C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups can be substituted with halogen, C 1-4 Alkyl, cyano, C 1-4 Alkylene-CN substitution;

[0177] W is selected from O, N, and S;

[0178] Z is selected from CR d1 R d2 , O, S, N, the R d1 、R d2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkyl-C 1-4 Halogenated alkyl, C 1-4 Alkyl-cyano, C 1-4 Alkyl-C1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy, alkenyl, OC 1-4 Haloalkyl, or R d1 、R d2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl, 3-6 membered heterocyclic group; R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0179] The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

[0180] Ring A is selected from aryl, 5-6 membered heteroaryl;

[0181] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0182] X1 is selected from -C(=CH2), CR a1 R a2 、N、NH、CR a3 ;

[0183] R a1 、R a2 Each independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, nitro, substituted or unsubstituted C 2--4 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkyl;

[0184] R a3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, cyano;

[0185] X2 selected from CR b1 R b2 , CR b3 ;

[0186] R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and Rb2 , or R a2 and R b1 , or R a2 and R b2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0187] R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0188] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, cyano, nitro, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkyl-C 1-4 Haloalkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 deuterated alkoxy;

[0189] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0190] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0191] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OC 1-4 Alkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy,

[0192] m is selected from 0, 1, 2, 3, 4;

[0193] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 3- 6-cycloalkylamino, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, WC3-6 Cycloalkyl;

[0194] W is selected from O, N, and S;

[0195] Z is selected from CR d1 R d2 , O, S, N, the R d1 、R d2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkyl-C 1-4 Halogenated alkyl, C 1-4 Alkyl-cyano, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy, alkenyl, or R d1 、R d2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0196] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0197] The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

[0198] in,

[0199] Ring A is selected from aryl, 5-6 membered heteroaryl;

[0200] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0201] X1 selected from CR a3 , the R a3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, cyano;

[0202] X2 selected from CR b3 , the R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0203] R1 is selected from deuterium, C 1-4 Deuterated alkyl, C 1-4 deuterated alkoxy;

[0204] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0205] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0206] R2 is selected from

[0207] m is selected from 0, 1, 2, 3, 4;

[0208] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, WC 3-6 Cycloalkyl;

[0209] W is selected from O, N, and S;

[0210] Z is selected from -C(R d1 )(R d2 ), O, S, N, the R d1 、R d2 Each is independent of C 1-4 Halogenated alkyl, C 1-4 Alkyl-C 1-4 Halogenated alkyl, C 1-4 Alkyl-cyano, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy, alkenyl, or R d1 、R d2 Together with the carbon atoms to which they are linked, they form a substituted or unsubstituted 3-6 membered heterocyclic group;

[0211] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0212] The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

[0213] in,

[0214] Ring A is selected from aryl, 5-6 membered heteroaryl;

[0215] The bond “--” between X1 and X2 represents a single bond or a double bond;

[0216] X1 is selected from N, NH;

[0217] X2 selected from CR b1 R b2 , the R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0218] R1 is selected from deuterium, C 1-4 Deuterated alkyl, C 1-4 deuterated alkoxy;

[0219] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0220] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0221] R2 is selected from deuterium, C 1-4 Deuterated alkyl, C 1-4 deuterated alkoxy;

[0222] m is selected from 0, 1, 2, 3, 4;

[0223] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 3- 6-cycloalkylamino;

[0224] Z is selected from -C(R d1 )(R d2), O, S, N, the R d1 、R d2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, or R d1 、R d2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0225] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0226] The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

[0227] in,

[0228] Ring A is selected from aryl, 5-6 membered heteroaryl;

[0229] X1 is selected from -C(=CH2), CRa1Ra2, wherein Ra1 and Ra2 are independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1- 4-alkylamino, nitro, substituted or unsubstituted C 2--4 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkyl;

[0230] X2 selected from CR b1 R b2 , the R b1 、R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0231] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, cyano, nitro, substituted or unsubstituted C 3-6Cycloalkyl, C 1-4 Alkyl-C 1-4 alkyl halide;

[0232] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0233] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0234] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OC 1-4 alkyl;

[0235] m is selected from 0, 1, 2, 3, 4;

[0236] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 3- 6-cycloalkylamino;

[0237] Z is selected from CR d1 R d2 , O, S, N, the R d1 、R d2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, or R d1 、R d2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0238] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0239] The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

[0240] in,

[0241] Ring A is selected from aryl, 5-6 membered heteroaryl;

[0242] X1 is selected from -C(=CH2), CRa1Ra2, wherein Ra1 and Ra2 are independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1- 4-alkylamino, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkyl;

[0243] X2 selected from CR b1 R b2 , said Rb1, Rb2 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0244] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, cyano, nitro, substituted or unsubstituted C 3-6 Cycloalkyl;

[0245] L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 cycloalkylene;

[0246] Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group;

[0247] R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OC 1-4 alkyl;

[0248] m is selected from 0, 1, 2, 3, 4;

[0249] Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from hydrogen, halogen, C 1-4Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 3- 6-cycloalkylamino;

[0250] Z is selected from CR d1 R d2 , O, S, N, the R d1 、R d2 Each independently is hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, or R d1 、R d2 Form substituted or unsubstituted C with the common linked carbon atom 3-6 Cycloalkyl;

[0251] R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0252] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that ring A is selected from phenyl,

[0253] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that ring A is selected from

[0254] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that ring A is selected from

[0255] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that Ra1 and Ra2 are each independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -CHF2, -NH-CH3, -CH=CH2, -C(CH3)=CH 2、

[0256] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that Ra1 and Ra2 are each independently selected from -CH2CH3, -CH(CH3)2, -OCF3, -OCH3, -N(CH3)2, -CH2OCH3, -CONH2, -SO2CH3.

[0257] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, and its hydrate are characterized in that Ra1 and Ra2 are each independently selected from -CHO and -CONHCH3.

[0258] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that Ra1 and Ra2 are each independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -CHF2,

[0259] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, and its hydrate are characterized in that R1 is selected from -Br, -F, -Cl, -CF3, and cyclopropyl.

[0260] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, and its hydrate are characterized in that R1 is selected from -CH3, -C2H5, -CH2-CF3, and -CHF2.

[0261] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate are characterized in that R1 is selected from H, -Br, -F, -Cl, -CH3, -CF3, and cyclopropyl.

[0262] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, and its hydrate are characterized in that Rb1 and Rb2 are each independently selected from -CH3.

[0263] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate are characterized in that Rb1 and Rb2 are each independently selected from H.

[0264] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that Rb3 is independently selected from

[0265] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0266] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0267] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0268] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0269] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0270] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that L1 is selected from -CH2-, -CH(CH3)-, -CD2-, -NH-CH2-,

[0271] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that L1 is selected from

[0272] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that L1 is selected from -NH-CH2-,

[0273] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, and its hydrate are characterized in that L1 is selected from -CH2-.

[0274] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that ring B is selected from

[0275] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that ring B is selected from

[0276] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that ring B is selected from

[0277] In some embodiments of the present disclosure, the above-mentioned compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, and its hydrate are characterized in that R2 is selected from -F, -CH3, -CH2CH3, -CH(CH3)2, and -(CH2)2OCH3.

[0278] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, and its hydrate are characterized in that R2 is selected from deuterium.

[0279] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R2 forms together with the carbon atom of ring B in Indicates the site of attachment to the rest of ring B.

[0280] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0281] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0282] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0283] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R c Selected from -CF3, cyclopropyl, methylamino, cyclopropylamino.

[0284] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R c Selected from -OC2H5, -OCF3, In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R cSelected from -NH2, -NH-C2H5, -NH-CH2-CHF2, -NH-CH2-CONH2, -OCH2-CN,

[0285] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R c Selected from -OCH2F, CN,

[0286] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R d1 、R d2 Selected from -F, -CH3, cyano, -OCH3.

[0287] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R d1 、R d2 Selected from -CHF2, -CH2-CHF2, -CH2-CN, -CH2-OCH3, -OCD3, -OCHF2, -CH=CH2.

[0288] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R d1 、R d2 Selected from -CH2F, -CHF2, -CF3, -CH2-CHF2, -CH2-CN, -CH2-OCH3, -OCD3, -OCH3, -OCHF2, -OCF3, -CH=CH2.

[0289] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R d1 、R d2 Formed with carbon atoms linked together

[0290] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that Rd1 、R d2 Formed with carbon atoms linked together

[0291] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R d1 、R d2 Selected from OCF3, C2H5, CH2CH2F.

[0292] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0293] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0294] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0295] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized by the structural unit Selected from

[0296] In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, and its hydrate are characterized in that R3 is selected from -CH3 and -CD3.

[0297] The present disclosure also provides the following compounds, their pharmaceutically acceptable salts, their stereoisomers, their isotope-labeled substances, their solvates, and their hydrates:

[0298] wherein X1, X2, Y2, R1, R2, R3, L1, ring B, Z, and m are the same as defined above.

[0299] The present disclosure also provides the following compounds, their pharmaceutically acceptable salts, their stereoisomers, their isotope-labeled substances, their solvates, and their hydrates:

[0300] Among them, X1, X2, Y2, R1, R2, R3, L1, Ring B, Z, m, R d1 、R d2 Same as above definition.

[0301] The present disclosure also provides the following compounds, their pharmaceutically acceptable salts, their stereoisomers, their isotope-labeled substances, their solvates, and their hydrates:

[0302] Among them, X1, X2, Y2, R1, R2, R3, L1, Ring B, m, R d1 、R d2 Same as above definition.

[0303] The present disclosure also provides the following compounds, their pharmaceutically acceptable salts, their stereoisomers, their isotope-labeled substances, their solvates, and their hydrates:

[0304] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound, isomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0305] In certain embodiments of the present invention, in the pharmaceutical composition, the content of the compound, stereoisomer or pharmaceutically acceptable salt thereof is selected from 0.1 mg to 1000 mg.

[0306] In certain embodiments of the present invention, in the pharmaceutical composition, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0307] The present disclosure also provides use of the above-mentioned compound, isomer or pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a drug for treating CBL-B target-mediated related diseases.

[0308] The present disclosure also provides use of the aforementioned compound, isomer, or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a drug for treating CBL-B-mediated related diseases, such as CBL-B-mediated related diseases including cancer.

[0309] The present disclosure also provides use of the aforementioned compound, isomer or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in treating CBL-B-mediated related diseases, such as the CBL-B-mediated related diseases including cancer.

[0310] The present disclosure also provides the above-mentioned compound, isomer or pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition for use in treating CBL-B-mediated related diseases, for example, the CBL-B-mediated related diseases include cancer.

[0311] The present disclosure also provides a method for treating CBL-B-mediated diseases, comprising administering a therapeutically effective amount of the aforementioned compound, isomer, or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition to a subject in need thereof, for example, the CBL-B-mediated diseases include cancer.

[0312] In the present disclosure, the CBL-B mediated related disease is CBL-B mediated cancer.

[0313] In the present disclosure, CBL-B-mediated cancers include genitourinary tract cancers (e.g., bladder cancer, kidney cancer, renal cell carcinoma, penile cancer, prostate cancer, testicular cancer, Von Hippel-Lindau disease, etc.), uterine cancer, cervical cancer, ovarian cancer, breast cancer, gastrointestinal cancer (e.g., esophageal cancer, oropharyngeal cancer, gastric cancer, small intestine cancer or large intestine cancer, colon cancer or rectal cancer), bone tumors, myeloma, skin cancer (e.g., melanoma), head and neck cancer, liver cancer, gallbladder cancer, bile duct cancer, heart cancer, lung cancer, pancreatic cancer, salivary gland cancer, adrenal cancer, thyroid cancer, brain tumors (e.g., glioma), ganglion cancer, central nervous system (CNS) tumors, peripheral nervous system (PNS) tumors, hematopoietic system tumors (i.e., blood malignancies), and immune system tumors (e.g., spleen tumors or thymoma).

[0314] Technical Effects

[0315] The disclosed compounds have significant CBL-B enzyme inhibitory activity and can be used to treat related cancers.

[0316] Description and Definition

[0317] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as ambiguous or unclear unless specifically defined, but should be understood according to its ordinary meaning.

[0318] The compounds disclosed herein exist as geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, and racemic mixtures and other mixtures thereof, all of which are within the scope of the disclosure.

[0319] The term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0320] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and are selected from among molecules that are not mirror images of each other.

[0321] The term "cis-trans isomers" refers to configurations in which a molecule cannot rotate freely about a double bond or a single bond of a ring-forming carbon atom.

[0322] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of a stereocenter. For example The methyl group and the amino group are located on the same side of the cyclopentane. Stereoisomers of the disclosed compounds can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. For example, one enantiomer of a compound disclosed herein can be prepared by asymmetric catalysis or chiral auxiliary derivatization. Alternatively, a compound with a single stereo configuration can be obtained from a mixture by chiral resolution techniques. Alternatively, the compound can be prepared directly using chiral starting materials. The separation of optically pure compounds disclosed herein is typically accomplished using preparative chromatography, employing chiral chromatographic columns to achieve the purpose of separating chiral compounds.

[0323] The absolute stereo configuration of a compound can be confirmed by conventional techniques in the art, such as single crystal X-ray diffraction. Alternatively, the absolute configuration of a compound can be confirmed based on the chiral structure of the starting materials and the reaction mechanism of asymmetric synthesis. Compounds labeled "absolute configuration not determined" herein are typically isolated from racemates by chiral preparative SFC separation to separate individual isomers, which are then characterized and tested.

[0324] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0325] The term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds prepared with relatively nontoxic acids or bases. These salts can be prepared during compound synthesis, isolation, and purification, or by reacting the purified free form of the compound with a suitable acid or base. When the compound contains relatively acidic functional groups, base addition salts are obtained by reaction with alkali metal or alkaline earth metal hydroxides or organic amines. These salts include cations based on alkali and alkaline earth metals, as well as nontoxic ammonium, quaternary ammonium, and amine cations, and also encompass salts of amino acids. When the compound contains relatively basic functional groups, acid addition salts are obtained by reaction with organic or inorganic acids.

[0326] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of those skilled in the art based on a wide range of factors. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semisolid dosage forms. In addition to the active agent, such carriers include a variety of different ingredients and additives, and the inclusion of such additional ingredients in a formulation for various reasons (e.g., to stabilize the active agent, binders, etc.) is well known to those skilled in the art.

[0327] The term "excipient" generally refers to a diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0328] Unless otherwise stated, structural units The link with other groups is

[0329] Unless otherwise specified, "substituted or unsubstituted" means that the compound may be substituted or unsubstituted. Here, substituted means substituted by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl. The "substituted or unsubstituted C 3-6Examples of "cycloalkyl" include, but are not limited to

[0330] The term "aryl" refers to a monocyclic or bicyclic group having a conjugated π electron system. The term "6-10 membered aryl" refers to a monocyclic or bicyclic group having a conjugated π electron system composed of 6-10 ring carbon atoms. Examples of "aryl" include, but are not limited to, phenyl and naphthyl.

[0331] The term "5-6 membered heteroaryl" refers to a monocyclic group having a conjugated π electron system consisting of 5-6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1 , 2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl), pyridyl, pyrimidinyl, etc.

[0332] The term "halogen" denotes a fluorine, chlorine, bromine or iodine atom.

[0333] The term "C 1-4 "Alkyl" is used to represent C 1-4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, and the like.

[0334] The term "C 1-4 "Haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. Examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.

[0335] The term "C 1-4 "Deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a deuterium atom, examples of which include but are not limited to monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, 2,2,2-trideuterioethyl, and the like.

[0336] The term "C 1-4 "Alkoxy" refers to a C 1-4 Alkyl. 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy.

[0337] The term "C 1-4 "Alkylene" is used to represent C 1-4 Straight-chain or branched saturated alkylene group. 1-4 Examples of alkylene include, but are not limited to, -CH2-, -(CH2)2-, -(CH2)3, -(CH2)4-, -CH(CH3)-, and -C(CH3)2-.

[0338] The term "C 1-4 Deuterated alkylene is used to represent C 1-4 The hydrogen atoms in the straight or branched saturated alkylene groups are replaced by D atoms. 1-4 Examples of deuterated alkylene groups include, but are not limited to, -CD2-, -CH(CD3)-.

[0339] The term "C 3-6 "Cycloalkyl" refers to a 3-6 membered monocyclic alkyl group. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0340] The term "C 3-6 "Cycloalkylene" is used to represent C 3-6 Examples of cyclic alkylene groups include, but are not limited to,

[0341] The term "5-10 membered heterocyclyl" refers to a substituted or unsubstituted 5-10 membered saturated or unsaturated non-aromatic ring group containing 1-3 heteroatoms selected from N, O or S. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The "heterocyclic group" described in the present disclosure refers to a non-aromatic cyclic group derived from removing a hydrogen atom and containing at least one heteroatom as a ring atom; including saturated or partially saturated monocyclic heterocyclic groups and bicyclic heterocyclic groups; wherein the bicyclic heterocyclic group may be a fused ring heterocyclic group, a 3-4 membered cycloalkyl and a 3-4 membered heterocyclic group, or a 3-4 membered cycloalkyl and a 5-6 membered heterocyclic group. The heterocyclic group is not related to the connection position (i.e., it can be connected through a carbon atom or a heteroatom). Examples of "heterocyclic groups" include but are not limited to

[0342] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0343] The solvents used in the present disclosure are commercially available.

[0344] The structures of the compounds disclosed herein are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS), or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are performed using a Bruker Neo 400M or Bruker Ascend 400 NMR instrument, with the measurement solvent selected from deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and heavy water (D2O), and the internal standard selected from tetramethylsilane (TMS).

[0345] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260-6125B single quadrupole mass spectrometer (with electrospray ionization as the ion source).

[0346] Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters UPLC H-class SQD mass spectrometer (with electrospray ionization as the ion source).

[0347] HPLC analysis was performed using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0348] Preparative HPLC was performed using a Waters 2555-2489 (10 μm, ODS 250 cm×5 cm) or a GILSON Trilution LC.

[0349] Chiral HPLC was performed using Waters Acquity UPC2; the column was selected from Daicel chi ring Clpak AD-H (5 μm, 4.6*250 mm).

[0350] Supercritical fluid chromatography (SFC) was performed using a Waters SFC 80Q.

[0351] The starting materials in the examples of the present disclosure are known and commercially available, or can be synthesized using or according to methods known in the art.

[0352] Unless otherwise specified, all reactions disclosed herein are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is selected from a dry solvent, and the reaction temperature unit is selected from °C. DETAILED DESCRIPTION

[0353] Hereinafter, the present disclosure will be explained in detail through the following examples in order to better understand various aspects of the present application and its advantages. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present application.

[0354] Example 1

[0355] 5-Bromo-2-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-(((S)-3-methylpiperidin-1-yl)methyl)isoquinolin-1(2H)-one

[0356] Reaction route:

[0357] Steps:

[0358] Step A: Dissolve methyl 7-isoquinolinecarboxylate (1.0 g, 5.34 mmol) in concentrated sulfuric acid (9.0 mL) at 0°C. Then, add N-bromosuccinimide (1.43 g, 8.01 mmol) sequentially to the solution. The reaction system is then stirred at room temperature for 16 hours.

[0359] After LCMS monitoring indicated the disappearance of the starting material, 2M aqueous sodium hydroxide solution was added dropwise to the reaction mixture until the pH reached 9. The mixture was extracted with ethyl acetate (25 mL x 3 times), and the organic phases were combined and washed with saturated brine (25 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.11 g of methyl 5-bromo-7-isoquinolinecarboxylate.

[0360] MS (ESI) M / Z: 266.1 [M+H] + .

[0361] Step B: Methyl 5-bromo-7-isoquinolinecarboxylate (1.11 g, 4.19 mmol) was dissolved in dry dichloromethane (28 mL) at 0°C under nitrogen. m-Chloroperbenzoic acid (1.09 g, 6.29 mmol) was then added to the solution. The reaction was stirred at room temperature for 16 hours.

[0362] After LCMS monitoring showed the disappearance of the starting material, dichloromethane (20 mL) was added to the reaction mixture for dilution. The mixture was washed with saturated sodium thiosulfate (40 mL x 3) and then with saturated brine (40 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue, 1.12 g of crude 5-bromo-7-(methoxycarbonyl)isoquinoline 2-oxide, was used directly in the next step without further purification.

[0363] MS (ESI) M / Z: 282.1 [M+H] + .

[0364] Step C: Dissolve 5-bromo-7-(methoxycarbonyl)isoquinoline 2-oxide (1.12 g, 3.99 mmol) in acetic anhydride (18 mL) at room temperature under nitrogen. Heat the solution to 160°C, stir for 2 hours, and then concentrate under reduced pressure. Add 2M aqueous sodium hydroxide solution (54 mL) to the residue, heat to 120°C, and continue stirring for 2 hours.

[0365] After LCMS monitoring indicated the disappearance of the starting material, 2M dilute hydrochloric acid was added dropwise to the reaction mixture until the pH reached 3. The mixture was extracted with ethyl acetate (25 mL x 3), and the organic phases were combined and washed with saturated brine (25 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 550 mg residue, 5-bromo-1-oxo-1,2-dihydroxyquinoline-7-carboxylic acid, was used directly in the next step without further purification.

[0366] MS (ESI) M / Z: 268.1 [M+H] + .

[0367] Step D: Dissolve 5-bromo-1-oxo-1,2-dihydroxyquinoline-7-carboxylic acid (550 mg, 2.06 mmol) in dry tetrahydrofuran (5 mL) at 0°C. Then, slowly add 1 M borane solution in tetrahydrofuran (10 mL, 10.03 mmol) dropwise to the solution. The reaction mixture is stirred at room temperature for 16 hours.

[0368] After LCMS monitoring showed the disappearance of the starting material, methanol was slowly added dropwise to the reaction solution to quench the reaction, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 280 mg of 5-bromo-7-(hydroxymethyl)isoquinolin-1(2H)-one.

[0369] MS (ESI) M / Z: 254.1 [M+H] + .

[0370] Step E: Dissolve 5-bromo-7-(hydroxymethyl)isoquinolin-1(2H)-one (280 mg, 1.11 mmol) in toluene (5.5 mL) at 0°C. Then, slowly add thionyl chloride (5.5 mL) dropwise to the solution. The reaction system is then stirred at 70°C for 2 hours.

[0371] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain 150 mg of the compound 5-bromo-7-(chloromethyl)isoquinolin-1(2H)-one.

[0372] MS (ESI) M / Z: 272.1 [M+H] + .

[0373] Step F: Dissolve (S)-3-methylpiperidine hydrochloride (113 mg, 0.83 mmol) in acetonitrile (5.5 mL) at room temperature. Add potassium iodide (92 mg, 0.55 mmol) and potassium carbonate (153 mg, 1.11 mmol) sequentially to the solution and stir for 0.5 hour. Then, add 5-bromo-7-(chloromethyl)isoquinolin-1(2H)-one (150 mg, 0.55 mmol) and continue stirring for 16 hours.

[0374] After LCMS monitoring showed the disappearance of the starting material, water (25 mL) was added to the reaction mixture to quench the mixture. The mixture was extracted with ethyl acetate (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (25 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 105 mg of compound (S)-5-bromo-7-((3-methylpiperidin-1-yl)methyl)isoquinolin-1(2H)-one.

[0375] MS (ESI) M / Z: 335.2 [M+H] + .

[0376] Step G: (S)-5-bromo-7-((3-methylpiperidin-1-yl)methyl)isoquinolin-1(2H)-one (95 mg, 0.28 mmol), 3-((1S,3S)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (111 mg, 0.36 mmol), L-trans-1,2-cyclohexanediamine (23 mg, 0.20 mmol), cuprous iodide (38 mg, 0.20 mmol), and cesium carbonate (183 mg, 0.56 mmol) were dissolved in 1,4-dioxane (2.8 mL) at room temperature under nitrogen. The solution was then heated to 110°C and stirred for 6 hours.

[0377] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (25 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the crude product. The crude product was purified by preparative HPLC under the following conditions: preparative column: YMC-Actus Triart C18 20.0 mm x 150 mm; mobile phase: water (containing 0.1% ammonium bicarbonate) and acetonitrile. This yielded 11.58 mg of the title compound, 5-bromo-2-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-(((S)-3-methylpiperidin-1-yl)methyl)isoquinolin-1(2H)-one (Compound 1).

[0378] MS (ESI) M / Z: 560.3 [M+H] + .

[0379] 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),8.18(s,1H),7.99(d,J=1.2Hz,1H),7.61(d,J=7.6Hz ,1H),7.57-7.48(m,2H),7.40-7.32(m,2H),6.78(d,J=7.6Hz,1H),3.56(s,2H),3.23(s,3H ),2.94-2.79(m,2H),2.77-2.66(m,2H),2.60-2.52(m,3H),1.95-1.85(m,1H),1.69-1.54( m,4H),1.53-1.40(m,1H),1.07(d,J=5.2Hz,3H),0.90-0.84(m,1H),0.81(d,J=5.6Hz,3H).

[0380] The following target compound was prepared by referring to the synthesis method of Example 1 above:

[0381] Example 8

[0382] 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0383] Reaction route:

[0384] Steps:

[0385] Step A: Dissolve ethyl 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1 g, 4.45 mmol) in N,N-dimethylformamide (20 mL) at room temperature. Add potassium carbonate (0.68 g, 4.9 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.63 g, 9.8 mmol) sequentially to the solution. The reaction mixture is then stirred at 80°C for 2 hours.

[0386] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 0.69 g of the compound, ethyl 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate.

[0387] MS (ESI) M / Z: 355.1 [M+H] + .

[0388] Step B: Ethyl 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.67 g, 1.94 mmol) was dissolved in dry tetrahydrofuran (10 mL) at 0°C under nitrogen. Lithium aluminum tetrahydride solution (0.92 mL, 2.3 mmol, 2.5 M) was then added to the solution. The reaction system was then stirred at 0°C for 0.5 hours.

[0389] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of ammonium chloride solution (20 mL). The mixture was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.41 g of the compound (7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol.

[0390] MS (ESI) M / Z: 313.2 [M+H] + .

[0391] Step C: Dissolve (7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (0.41 g, 1.31 mmol) in acetonitrile (5 mL) at 0°C under nitrogen. Add thionyl chloride (0.62 g, 5.24 mmol) dropwise to the reaction mixture. Continue stirring for 2 hours.

[0392] After LCMS monitoring showed the disappearance of the starting material, sodium bicarbonate solution (10 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (25 mL x 3 times), and the organic phases were combined and washed with saturated brine (25 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 0.27 g of the compound 7-chloro-2-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

[0393] MS (ESI) M / Z: 331.1 [M+H] + .

[0394] Step D: Dissolve 7-chloro-2-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (0.27 g, 0.81 mmol) and (3S)-3-piperidine (0.16 g, 1.62 mmol) in acetonitrile (5 mL) at room temperature under nitrogen. Then, add potassium carbonate (0.45 g, 3.24 mmol) and potassium iodide (0.013 g, 0.081 mmol). Heat the reaction mixture to 80°C and continue stirring for 2 hours.

[0395] After LCMS monitoring indicated conversion of the starting material to the product, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 0.23 g of the compound (S)-7-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

[0396] MS (ESI) M / Z: 394.3 [M+H] + .

[0397] Step E: (S)-7-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (220 mg, 0.56 mmol), trisdibenzylideneacetone dipalladium (409 mg, 0.45 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (266 mg, 0.56 mmol), and potassium hydroxide (376 mg, 6.7 mmol) were dissolved in 1,4-dioxane (5 mL) and water (5 mL) at room temperature under nitrogen. The solution was then heated to 100°C and stirred for 12 hours.

[0398] After LCMS monitoring showed the disappearance of the starting material, the mixture was diluted with water (20 mL) and extracted with dichloromethane (25 mL x 3). The organic phases were combined and washed with saturated brine (25 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 0.13 g of compound (S)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0399] MS (ESI) M / Z: 376.3 [M+H] + .

[0400] Step F: (S)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (110 mg, 0.29 mmol), 3-((1S,3S)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (120 mg, 0.38 mmol), cuprous iodide (11 mg, 0.058 mmol), N,N,N',N'-tetramethylethylenediamine (6.7 mg, 0.058 mmol), and potassium carbonate (120 mg, 0.87 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature under nitrogen. The solution was then heated to 150°C in a microwave oven and stirred for 12 hours.

[0401] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (25 mL). The mixture was extracted with dichloromethane (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (25 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 40 mg of the compound 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0402] MS (ESI) M / Z: 601.4 [M+H] + .

[0403] Step G: Compound 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (40 mg, 0.067 mmol) was dissolved in tetrabutylammonium fluoride in tetrahydrofuran (1.34 mL, 1.34 mmol, 1 M) at room temperature under nitrogen. The reaction mixture was heated to 80°C and stirred for 36 hours.

[0404] After LCMS monitoring indicated conversion of the starting material to product, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC. Purification conditions were as follows: preparative column: SNAP Ultra C18 30g 25μm; mobile phase: 0.1% formic acid in water and acetonitrile. This yielded 7 mg of the title compound, 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0405] MS (ESI) M / Z: 471.2 [M+H] + .

[0406] 1 H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.28(s,1H),7.55–7.43(m,1H),7.43–7.36(m,1H), 7.36–7.25(m,2H),7.16–7.08(m,1H),6.55(d,J=7.1Hz,1H),6.21(d,J=1.9Hz,1H),3.66–3 .49(m,2H),3.25(s,3H),2.96–2.81(m,2H),2.82–2.71(m,2H),2.58–2.52(m,3H),1.96–1. 80(m,1H),1.68–1.52(m,4H),1.52–1.36(m,1H),1.07(d,J=5.1Hz,3H),0.86–0.70(m,4H).

[0407] The following target compound was prepared by referring to the synthesis method of Example 8:

[0408] Example 42

[0409] 4-Chloro-6-(3-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0410] Reaction route:

[0411] Steps:

[0412] Step A: (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (100.0 mg, 0.24 mmol) was dissolved in dimethyl sulfoxide (6 mL) at room temperature under nitrogen. 3-((1R,3R)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (73.2 mg, 0.24 mmol), sodium bicarbonate (28.0 mg, 0.48 mmol), and copper acetate (144.0 mg, 0.72 mmol) were then added to the solution. The reaction was stirred at 80°C for 2 hours.

[0413] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (40 mL). The mixture was extracted with ethyl acetate (10 mL x 3 times), and the organic phases were combined and washed with saturated brine (25 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative HPLC to yield 109 mg of 4-chloro-6-(3-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0414] MS (ESI) M / Z: 635.2 [M+H] + .

[0415] Step B: 4-chloro-6-(3-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (109 mg, 0.17 mmol) was dissolved in dichloromethane (1.7 mL) at 0°C. Trifluoroacetic acid (0.85 mL) was then added dropwise to the solution. The reaction was stirred at room temperature for 2 hours.

[0416] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction solution to adjust to pH = 8, and the mixture was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 28 mg of 4-chloro-6-(3-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0417] MS (ESI) M / Z: 505.2 [M+H] + .

[0418] 1 H NMR (400MHz, DMSO-d6) δ12.37(s,1H),8.37(s,1H),7.47(t,J=8.2Hz,1H),7.42(s ,1H),7.33-7.27(m,2H),7.15(d,J=7.6Hz,1H),6.26(s,1H),3.59(s,2H),3.29(s ,3H),3.15-3.07(m,2H),2.86-2.69(m,2H),2.37-2.22(m,3H),1.95-1.82(m,1H) ,1.68-1.52(m,4H),1.51-1.38(m,1H),1.09(d,J=6.0Hz,3H),0.86-0.73(m,4H).

[0419] Example 43

[0420] 4-Chloro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0421] Reaction route:

[0422] Steps:

[0423] Step A: Dissolve 2-(3-bromophenyl)acetic acid (10.0 g, 46.7 mmol) in anhydrous tetrahydrofuran (100.0 mL) at 0°C. Add 2.0 M isopropylmagnesium chloride in tetrahydrofuran (52.0 mL) dropwise to the solution and stir for 1 hour. Add 2-(chloromethyl)oxirane (7.3 mL, 93.4 mmol) and continue stirring for 1.5 hours. Add 2.0 M isopropylmagnesium chloride in tetrahydrofuran (52.0 mL), warm to room temperature, and stir for 12 hours.

[0424] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into ice water (100 mL) to quench the reaction. Concentrated hydrochloric acid was then added dropwise to the mixture to adjust the pH to 4. The mixture was extracted with ethyl acetate (100 mL x 2), and the organic phases were combined and washed with saturated brine (50 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 5.4 g of crude (1S,3S)-1-(3-bromophenyl)-3-hydroxycyclobutane-1-carboxylic acid.

[0425] MS (ESI) M / Z: 271.0 [M+H] + .

[0426] Step B: Dissolve (1S,3S)-1-(3-bromophenyl)-3-hydroxycyclobutane-1-carboxylic acid (2.0 g, 7.10 mmol) and N-methylhydrazine methylsulfamide (900.0 mg, 8.5 mmol) in N,N-dimethylformamide (24.0 mL) at 0°C. Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.9 g, 7.8 mmol) and N,N-diisopropylethylamine (2.75 g, 21.3 mmol) were then added to the solution. The reaction was stirred at room temperature for 1 hour.

[0427] After LCMS monitoring showed the disappearance of the starting material, water (100 mL) was added to the reaction solution to quench it. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (100 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3.1 g of crude 2-((1S,3S)-1-(3-bromophenyl)-3-hydroxycyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide.

[0428] MS (ESI) M / Z: 358.0 [M+H] + .

[0429] Step C: Dissolve 2-((1S,3S)-1-(3-bromophenyl)-3-hydroxycyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide (2.5 g, 7.1 mmol) in tetrahydrofuran (80.0 mL) at room temperature. Add 2M sodium hydroxide solution (40.0 mL) dropwise to the solution. Stir the reaction at 80°C for 12 hours.

[0430] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into ice water (30 mL) to quench the reaction. Concentrated hydrochloric acid was then added dropwise to the mixture to adjust the pH to 3. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.7 g of crude product (1S,3S)-3-(3-bromophenyl)-3-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)cyclobutan-1-ol.

[0431] MS (ESI) M / Z: 340.0 [M+H] + .

[0432] Step D: Dissolve (1S,3S)-3-(3-bromophenyl)-3-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)cyclobutan-1-ol (2.7 g, 7.1 mmol) in dichloromethane (100 mL) at room temperature. Acetic acid (8.0 mL) and hydrogen peroxide (1.2 g) were then added dropwise to the solution. The reaction was stirred for 1 hour.

[0433] After LCMS monitoring indicated the disappearance of the starting material, 1 M sodium hydroxide solution was added dropwise to the reaction solution to adjust the pH to 10. The mixture was extracted with dichloromethane (50 mL × 3 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 550 mg of (1S,3S)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol.

[0434] MS (ESI) M / Z: 308.0 [M+H] + .

[0435] Step E: Dissolve (1S,3S)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol (92 mg, 0.3 mmol) in N,N-dimethylformamide (1.5 mL) at 0°C under nitrogen. Slowly add sodium hydride (21.6 mg, 0.5 mmol) to the solution and stir for 20 minutes. Then, add iodomethane (64 mg, 0.45 mmol) dropwise, warm to room temperature, and continue stirring for 1 hour.

[0436] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added dropwise to ice water (20 mL) to quench the mixture. The mixture was extracted with ethyl acetate (5 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 98 mg of 3-((1S,3S)-1-(3-bromophenyl)-3-methoxycyclobutyl)-4-methyl-4H-1,2,4-triazole.

[0437] MS (ESI) M / Z: 322.0 [M+H] + .

[0438] Step F: 3-((1S,3S)-1-(3-bromophenyl)-3-methoxycyclobutyl)-4-methyl-4H-1,2,4-triazole (50 mg, 0.15 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) at room temperature under nitrogen. (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (65 mg, 0.15 mmol), cuprous iodide (28 mg, 0.15 mmol), N,N'-dimethylethylenediamine (16 mg, 0.18 mmol), and potassium carbonate (41.4 mg, 0.3 mmol) were then added to the solution. The reaction system was then stirred at 150°C for 3 hours.

[0439] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (5 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 55 mg of 4-chloro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0440] MS (ESI) M / Z: 651.2 [M+H] +.

[0441] Step G: 4-chloro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (55 mg, 0.08 mmol) was dissolved in dichloromethane (0.8 mL) at room temperature. Trifluoroacetic acid (0.8 mL) was then added dropwise to the solution. The reaction was stirred for 2 hours.

[0442] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated sodium chloride solution (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to yield 12 mg of 4-chloro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0443] MS (ESI) M / Z: 521.3 [M+H] + .

[0444] 1H NMR (400MHz, DMSO-d6) δ12.38(s,1H),8.31(s,1H),7.50(t,J=7.8Hz,1H),7.47 -7.40(m,2H),7.38-7.33(m,1H),7.30(d,J=8.0,1H),6.27(s,1H),4.12-4.02(m ,1H),3.60(s,2H),3.27(s,3H),3.16(s,3H),3.14-3.05(m,2H),2.86-2.70(m,4 H),1.99-1.79(m,1H),1.73-1.53(m,4H),1.51-1.37(m,1H),0.90-0.73(m,4H).

[0445] Example 44

[0446] 4-Chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0447] Reaction route:

[0448] Steps:

[0449] Step A: (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (62 mg, 0.15 mmol), 3-((1S,3R)-1-(3-bromo-5-(trifluoromethoxy)phenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (60 mg, 0.15 mmol), N,N'-dimethylethylenediamine (16 mg, 0.18 mmol), cuprous iodide (29 mg, 0.15 mmol), and potassium carbonate (42 mg, 0.30 mmol) were dissolved in dimethyl sulfoxide (1.0 mL) at room temperature under nitrogen. The reaction system was then stirred at 150°C for 3 hours.

[0450] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 80 mg of 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0451] MS (ESI) M / Z: 719.3 [M+H] + .

[0452] Step B: Compound 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (70 mg, 0.10 mmol) was dissolved in dichloromethane (1 mL) at room temperature. Trifluoroacetic acid (2 mL) was then added dropwise to the solution and stirring was continued for 1 hour. After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia (7 mL) was added dropwise to the reaction solution and stirring was continued for 2 hours.

[0453] After LCMS monitoring showed the disappearance of the intermediate, water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (8 mL x 2). The organic phases were combined and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography to yield 5.8 mg of 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0454] MS (ESI) M / Z: 589.2 [M+H] + .

[0455] 1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.39(s,1H),7.49(s,1H),7.45(s,1H) ,7.39(t,J=1.6Hz,1H),7.06(s,1H),6.27(s,1H),3.59(s,2H),3.31(s,3H),3 .16-3.07(m,2H),2.81-2.70(m,2H),2.39-2.25(m,3H),1.94-1.84(m,1H),1. 67-1.53(m,4H),1.52-1.38(m,1H),1.09(d,J=6.0Hz,3H),0.88-0.75(m,4H).

[0456] Example 45

[0457] 4-Chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0458] Reaction route:

[0459] Steps:

[0460] Step A: (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (33 mg, 0.08 mmol), 3-((1R,3R)-1-(3-bromo-5-(trifluoromethyl)phenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (30 mg, 0.08 mmol), N,N'-dimethylethylenediamine (9 mg, 0.10 mmol), cuprous iodide (16 mg, 0.08 mmol), and potassium carbonate (23 mg, 0.16 mmol) were dissolved in dimethyl sulfoxide (0.5 mL) at room temperature under nitrogen. The reaction system was then stirred at 150°C for 3 hours.

[0461] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (5 mL). The mixture was extracted with dichloromethane (6 mL x 2). The organic phases were combined and washed with saturated brine (8 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 36 mg of 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0462] MS (ESI) M / Z: 703.3 [M+H] + .

[0463] Step B: Compound 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (36 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL) at room temperature. Trifluoroacetic acid (1 mL) was then added dropwise to the solution and stirring was continued for 1 hour. After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia (5 mL) was added dropwise to the reaction solution and stirring was continued for 2 hours.

[0464] After LCMS monitoring showed the disappearance of the intermediate, the reaction mixture was quenched with water (8 mL). The mixture was extracted with dichloromethane (8 mL x 2), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography to yield 12.6 mg of 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0465] MS (ESI) M / Z: 573.2 [M+H] + .

[0466] 1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.39(s,1H),7.77(s,1H),7.71(s,1 H),7.55(s,1H),7.37(s,1H),6.27(s,1H),3.59(s,2H),3.32(s,3H),3.20- 3.11(m,2H),2.81-2.71(m,2H),2.40-2.27(m,3H),1.94-1.83(m,1H),1.68 -1.53(m,4H),1.50-1.39(m,1H),1.09(d,J=5.6Hz,3H),0.88-0.72(m,4H).

[0467] Example 46

[0468] 2-((1S,3R)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile

[0469] Reaction route:

[0470] Steps:

[0471] Step A: 2-((1R,3R)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (70 mg, 0.21 mmol) and (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (86 mg, 0.21 mmol) were dissolved in dimethyl sulfoxide (1.1 mL) at room temperature under nitrogen. N,N'-dimethylethylenediamine (18 mg, 0.21 mmol), cuprous iodide (40 mg, 0.21 mmol), and potassium carbonate (58 mg, 0.42 mmol) were then added to the solution. The reaction was stirred at 150°C for 3 hours.

[0472] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 50 mg of 2-((1S,3R)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

[0473] MS (ESI) M / Z: 330.7 [M / 2+H] + .

[0474] Step B: Under nitrogen protection at room temperature, compound 2-((1S,3R)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (50 mg, 0.08 mmol) was dissolved in dichloromethane (0.8 mL). Subsequently, trifluoroacetic acid (0.8 mL) was added dropwise to the above solution and stirring was continued for 2 hours. The temperature was then lowered to 0°C, and aqueous ammonia (5.0 mL) was slowly added dropwise. The temperature was raised to room temperature and stirring was continued for 2 hours.

[0475] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (20 mL). The mixture was extracted with dichloromethane (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (25 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 17.7 mg of 2-((1S,3R)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

[0476] MS (ESI) M / Z: 530.3 [M+H] + .

[0477] 1H NMR (400MHz, DMSO-d6) δ12.38(s,1H),8.41(s,1H),7.49(t,J=8.2Hz,1H), 7.42(s,1H),7.36-7.30(m,2H),7.20-7.14(m,1H),6.26(s,1H),3.59(s,2H ),3.31(s,3H),3.18-3.09(m,2H),2.81-2.69(m,4H),2.61-2.51(m,2H),2 .49-2.41(m,1H),1.94-1.81(m,1H),1.67-1.37(m,5H),0.87-0.72(m,4H).

[0478] Example 47

[0479] (S)-3'-(4-chloro-2-((3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide

[0480] Reaction route:

[0481] Steps:

[0482] Step A: Dissolve 5-fluoro-2-iodobenzoic acid (1.50 g, 5.64 mmol) in N,N-dimethylformamide (28 mL) at room temperature. Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.57 g, 6.77 mmol) and N,N-diisopropylethylamine (2.18 g, 16.92 mmol) were added sequentially to the solution and stirred for 30 minutes. Dimethylamine (50% wt) (609 mg, 8.46 mmol) was then added dropwise and stirring continued for 1 hour.

[0483] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (50 mL). The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.5 g of 5-fluoro-2-iodo-N,N-dimethylbenzamide.

[0484] MS (ESI) M / Z: 294.0 [M+H] + .

[0485] Step B: 5-Fluoro-2-iodo-N,N-dimethylbenzamide (500 mg, 1.71 mmol), 2-(3-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (530 mg, 1.87 mmol), sodium carbonate (450 mg, 4.26 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (110 mg, 0.17 mmol) were dissolved in 1,4-dioxane (6 mL) and water (0.6 mL) under nitrogen at room temperature. The reaction was stirred at 90°C for 16 hours.

[0486] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 400 mg of 3'-bromo-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide.

[0487] MS (ESI) M / Z: 322.0 [M+H] + .

[0488] Step C: 3'-Bromo-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide (400 mg, 1.25 mmol), (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.49 mmol), potassium carbonate (206 mg, 1.49 mmol), and cuprous iodide (236 mg, 1.24 mmol) were dissolved in dimethyl sulfoxide (3.0 mL) at room temperature under nitrogen. The reaction system was then stirred at 150°C for 3 hours.

[0489] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (8 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 200 mg of (S)-3'-(4-chloro-2-((3-methylpiperidin-1-yl)methyl)-7-oxo-1-(2-(trimethylsilyl)ethoxy)methyl-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide.

[0490] MS (ESI) M / Z: 651.2 [M+H] + .

[0491] Step D: Compound (S)-3'-(4-chloro-2-((3-methylpiperidin-1-yl)methyl)-7-oxo-1-(2-(trimethylsilyl)ethoxy)methyl-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide (200 mg, 0.31 mmol) was dissolved in dichloromethane (1.5 mL) at room temperature. Trifluoroacetic acid (1.5 mL) was then added dropwise to the solution. The reaction was stirred for 2 hours.

[0492] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated sodium chloride solution (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to yield 89.47 mg of (S)-3'-(4-chloro-2-((3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide.

[0493] MS (ESI) M / Z: 521.3 [M+H] + .

[0494] 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),7.64-7.54(m,2H),7.53-7.47(m,1H),7.46-7.35(m,4H),7.26(dd,J=9.2,2.8Hz,1H),6.28 (s,1H),3.60(s,2H),2.86-2.72(m,5H),2.52(s,3H),1.97-1.82(m,1H),1.69-1.53(m,4H),1.52-1.39(m,1H),0.88-0.73(m,4H).

[0495] Example 48

[0496] 4-Chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl-2,2,6,6-d4)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0497] 4-Chloro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((((R)-3-methylpiperidin-1-yl-2,2,6,6-d4)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0498] Reaction route:

[0499] Steps:

[0500] Step A: Dissolve 3-methylpiperidine-2,6-dione (2.0 g, 15.74 mmol) in N,N-dimethylformamide (52 mL) at room temperature. Add potassium carbonate (4.35 g, 31.48 mmol) and benzyl bromide (3.77 g, 22.04 mmol) sequentially to the solution. Stir the reaction at 45°C for 16 hours.

[0501] After LCMS monitoring showed the disappearance of the starting material, water (150 mL) was added to the reaction mixture to quench the mixture. The mixture was extracted with ethyl acetate (30 mL x 3 times), and the organic phases were combined and washed with saturated brine (30 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.55 g of 1-benzyl-3-methylpiperidine-2,6-dione.

[0502] MS (ESI) M / Z: 218.3 [M+H] + .

[0503] Step B: Dissolve 1-benzyl-3-methylpiperidine-2,6-dione (500 mg, 2.30 mmol) in dry tetrahydrofuran (11.5 mL) at -78°C under nitrogen. Then, add lithium aluminum hydride (193 mg, 4.60 mmol) to the solution. The reaction mixture is stirred at room temperature for 3 hours.

[0504] After LCMS monitoring indicated the disappearance of the starting material, the reaction solution was poured into a mixture of ice water (30 mL) and ethyl acetate (30 mL). The mixture was extracted with ethyl acetate (20 mL x 3 times), and the organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 185 mg of 1-benzyl-3-methylpiperidine-2,2,6,6-d4.

[0505] MS (ESI) M / Z: 194.4 [M+H] + .

[0506] Step C: Dissolve 1-benzyl-3-methylpiperidine-2,2,6,6-d4 (185 mg, 0.96 mmol) in methanol (5.5 mL) at room temperature. Add 10% wet palladium on carbon (37 mg) to the solution. Stir the reaction under a hydrogen atmosphere for 16 hours.

[0507] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, and a 4M hydrochloric acid solution in 1,4-dioxane (1.0 mL) was added dropwise to the filtrate, and the mixture was concentrated under reduced pressure to obtain 102 mg of 3-methylpiperidine-2,2,6,6-d4 hydrochloride.

[0508] MS (ESI) M / Z: 104.3 [M+H] + .

[0509] Step D: 4-chloro-2-(chloromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (205 mg, 0.57 mmol) was dissolved in acetonitrile (2.9 mL) at room temperature. Potassium carbonate (157 mg, 1.14 mmol), potassium iodide (95 mg, 0.57 mmol), and 3-methylpiperidine-2,2,6,6-d4 hydrochloride (102 mg, 0.74 mmol) were then added to the solution. The reaction was stirred at room temperature for 4 hours.

[0510] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (20 mL). The mixture was extracted with ethyl acetate (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 175 mg of 4-chloro-7-methoxy-2-((3-methylpiperidin-1-yl-2,2,6,6-d4)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

[0511] MS (ESI) M / Z: 428.4 [M+H] + .

[0512] Step E: 4-chloro-7-methoxy-2-((3-methylpiperidin-1-yl-2,2,6,6-d4)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (175 mg, 0.41 mmol) was dissolved in acetonitrile (2.1 mL) at room temperature. Sodium iodide (93 mg, 0.62 mmol) and trimethylsilyl chloride (68 mg, 0.62 mmol) were then added to the solution. The reaction was stirred at room temperature for 2 hours.

[0513] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 105 mg of 4-chloro-2-((3-methylpiperidin-1-yl-2,2,6,6-d4)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0514] MS (ESI) M / Z: 414.2 [M+H] + .

[0515] Step F: Under nitrogen protection, the compound 4-chloro-2-((3-methylpiperidin-1-yl-2,2,6,6-d4)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (105 mg, 0.25 mmol), 3-((1S,3S)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (85 mg, 0.28 mmol) and N,N'-dimethylethylenediamine (26 mg, 0.30 mmol) were dissolved in dimethyl sulfoxide (2.5 mL) at room temperature. Subsequently, cuprous iodide (48 mg, 0.25 mmol) and potassium carbonate (69 mg, 0.50 mmol) were added to the above solution. The reaction system was then stirred at 150 ° C for 3 hours.

[0516] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filtrate was diluted with water (25 mL). The mixture was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 125 mg of 4-chloro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl-2,2,6,6-d4)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0517] MS (ESI) M / Z: 639.4 [M+H] + .

[0518] Step G: 4-chloro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl-2,2,6,6-d4)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (125 mg, 0.20 mmol) was dissolved in dichloromethane (1.0 mL) at room temperature. Trifluoroacetic acid (1.0 mL) was then added dropwise to the solution. The reaction was stirred at room temperature for 3 hours.

[0519] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was adjusted to pH 8 by the addition of 30% aqueous ammonia, and diluted with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 3), and the combined organic phases were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 100 mg of the crude product. Chiral separation (column: Daicel AD-3, mobile phase: EtOH [1% NH3 (7M in MeOH)]) then afforded compound 48-P1 (retention time 2.316 min) and compound 48-P2 (retention time 2.803 min).

[0520] Compound 48-P1:

[0521] MS (ESI) M / Z: 509.2 [M+H] + .

[0522] 1H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.29(s,1H),7.50(t,J=7.8Hz,1H),7.46(t,J=1.8Hz,1H), 7.44(s,1H),7.36-7.29(m,2H),6.26(s,1H),3.59(s,2H),3.24(s,3H),2.94-2.82(m,2H),2.5 9-2.51(m,3H),1.66-1.50(m,3H),1.49-1.39(m,1H),1.07(d,J=5.2Hz,3H),0.85-0.73(m,4H).

[0523] Compound 48-P2:

[0524] MS (ESI) M / Z: 509.2 [M+H] + .

[0525] 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.29(s,1H),7.50(t,J=7.8Hz,1H),7.46(t,J=1.8Hz,1H),7.44(s,1H),7.37-7.29(m,2H),6.26(s,1H),3 .59(s,2H),3.24(s,3H),2.94-2.82(m,2H),2.59-2.51(m,3H),1.66-1. 52(m,3H),1.49-1.38(m,1H),1.07(d,J=5.2Hz,3H),0.87-0.73(m,4H).

[0526] Example 49

[0527] 4-Chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0528] Reaction route:

[0529] Steps:

[0530] Step A: Dissolve 4-methyl-4H-1,2,4-triazole (935 mg, 11.15 mmol) in ethylene glycol dimethyl ether (52 mL) at -45°C under nitrogen. Slowly add a 2.5 M solution of n-butyl lithium in n-hexane (4.5 mL, 11.15 mmol) dropwise to the solution and stir for 30 minutes. Then, add a solution of 3-bromo-5-(trifluoromethoxy)benzaldehyde (3 g, 11.15 mmol) in ethylene glycol dimethyl ether (3 mL) dropwise. The reaction system is then stirred at 0°C for 1 hour.

[0531] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding saturated aqueous ammonium chloride (10 mL) and then diluted with water (80 mL). The mixture was extracted with dichloromethane (40 mL x 2), and the organic phases were combined and washed with saturated brine (50 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.3 g of (3-bromo-5-(trifluoromethoxy)phenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methanol.

[0532] MS (ESI) M / Z: 351.9 [M+H] + .

[0533] Step B: Dissolve (3-bromo-5-(trifluoromethoxy)phenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methanol (1.3 g, 3.69 mmol) in tetrahydrofuran (40 mL) at 0°C under nitrogen. Add imidazole (1.25 g, 18.45 mmol), iodine (3.28 g, 12.91 mmol), and triphenylphosphine (3.38 g, 12.91 mmol). Stir the reaction at 80°C for 3 hours.

[0534] After LCMS monitoring showed the disappearance of the starting material, a 10% aqueous sodium thiosulfate solution was added dropwise to the reaction solution until the solution became colorless, followed by dilution with water (40 mL). The mixture was extracted with dichloromethane (50 mL x 2), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 600 mg of 3-(3-bromo-5-(trifluoromethoxy)benzyl)-4-methyl-4H-1,2,4-triazole.

[0535] MS (ESI) M / Z: 335.9 [M+H] + .

[0536] Step C: Dissolve 3-(3-bromo-5-(trifluoromethoxy)benzyl)-4-methyl-4H-1,2,4-triazole (600 mg, 1.78 mmol) and 1,3-dibromo-2-methylpropane (384 mg, 1.78 mmol) in tetrahydrofuran (18 mL) at 0°C under nitrogen. Then, slowly add a 1M solution of lithium bistrimethylsilylamide in tetrahydrofuran (3.6 mL, 3.56 mmol) dropwise to the solution. Stir the reaction for 1 hour.

[0537] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with saturated aqueous ammonium chloride (2 mL) and diluted with water (20 mL). The mixture was extracted with dichloromethane (15 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 280 mg of 3-(1-(3-bromo-5-(trifluoromethoxy)phenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole.

[0538] MS (ESI) M / Z: MS 390.2 [M+H] + .

[0539] The crude product was purified by preparative high performance liquid chromatography to obtain 130 mg of compound P1 (short retention time) and 60 mg of compound P2 (long retention time).

[0540] Compound P1

[0541] 1 H NMR(400MHz,CD3Cl)δ8.05(s,1H),7.43(t,J=1.6Hz,1H),7.30(s,1H),7.15(s, 1H),3.22(s,3H),2.84-2.74(m,2H),2.73-2.58(m,3H),1.15(d,J=6.0Hz,3H).

[0542] Compound P2

[0543] 1 H NMR(400MHz,CD3Cl)δ8.10(s,1H),7.27(s,2H),7.00(s,1H),3.26(s,3H),3. 20-3.10(m,2H),2.66-2.49(m,1H),2.30-2.19(m,2H),1.13(d,J=6.8Hz,3H).

[0544] Step D: (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (123 mg, 0.30 mmol), 3-((1S,3S)-1-(3-bromo-5-(trifluoromethoxy)phenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (120 mg, 0.30 mmol), N,N'-dimethylethylenediamine (32 mg, 0.36 mmol), cuprous iodide (57 mg, 0.30 mmol), and potassium carbonate (83 mg, 0.60 mmol) were dissolved in dimethyl sulfoxide (2.0 mL) at room temperature under nitrogen. The reaction system was then stirred at 150°C for 3 hours.

[0545] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 120 mg of 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0546] MS (ESI) M / Z: 719.3 [M+H] + .

[0547] Step E: 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (120 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL) at room temperature. Trifluoroacetic acid (2 mL) was then added dropwise to the solution and stirring was continued for 2 hours. After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia (7 mL) was added dropwise to the reaction solution and stirring was continued for 2 hours.

[0548] After LCMS monitoring showed the disappearance of the intermediate, the reaction mixture was quenched with water (20 mL). The mixture was extracted with dichloromethane (10 mL x 2), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography to yield 23.8 mg of 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0549] MS (ESI) M / Z: 589.2 [M+H] + .

[0550] 1 H NMR (400MHz, DMSO-d6) δ12.40(s,1H),8.31(s,1H),7.55(t,J=1.6Hz,1H),7. 52(s,1H),7.48(s,1H),7.23(s,1H),6.27(s,1H),3.59(s,2H),3.27(s,3H),2 .96-2.85(m,2H),2.82-2.70(m,2H),2.62-2.51(m,3H),1.95-1.83(m,1H),1. 67-1.53(m,4H),1.51-1.39(m,1H),1.07(d,J=5.6Hz,3H),0.88-0.73(m,4H).

[0551] Example 50

[0552] 2-((1R,3S)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile

[0553] Reaction route:

[0554] Steps:

[0555] Step A: Dissolve 2-(3-bromophenyl)acetonitrile (10.0 g, 51.02 mmol) in N,N-dimethylformamide (100 mL) at room temperature under nitrogen. Add sodium hydride (4.49 g, 112.24 mmol, 60%) portionwise to the solution and stir for 10 minutes. Then, add 1,3-dibromo-2,2-dimethoxypropane (14.70 g, 56.12 mmol) dropwise. Heat the temperature to 60°C and continue stirring for 16 hours.

[0556] After LCMS monitoring indicated the disappearance of the starting material, the reaction solution was poured into a saturated ammonium chloride solution (400 mL) to quench the mixture. The mixture was extracted with ethyl acetate (70 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 6.15 g of 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carbonitrile.

[0557] MS (ESI) M / Z: 318.0 [M+Na] + .

[0558] Step B: Dissolve 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carbonitrile (6.15 g, 20.85 mmol) in ethanol (27 mL) and water (25 mL) at 0°C. Slowly add sodium hydroxide (2.51 g, 62.55 mmol) to the solution. Stir the reaction at 85°C for 16 hours.

[0559] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into a mixture of ice water (30 mL) and ethyl acetate (30 mL) for quenching and adjusted to pH 2 with 2M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 6.30 g of crude 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carboxylic acid was obtained.

[0560] MS (ESI) M / Z: 315.1 [M+H] + .

[0561] Step C: Dissolve 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carboxylic acid (6.30 g, 20.06 mmol) in dichloromethane (67 mL) at 0°C under nitrogen. Add triethylamine (4.05 g, 40.12 mmol) and isobutyl chloroformate (4.12 g, 30.09 mmol) dropwise to the solution and stir for 10 minutes. Then, add hydrazine hydrate (2.57 g, 80.24 mmol) dropwise, warm to room temperature, and continue stirring for 3 hours.

[0562] After LCMS monitoring indicated the disappearance of the starting material, the reaction solution was poured into a mixture of ice water (40 mL) and dichloromethane (30 mL) to quench the mixture. The mixture was extracted with dichloromethane (30 mL x 3 times), and the organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 4.02 g of 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carboxylic acid hydrazide.

[0563] MS (ESI) M / Z: 297.2 [M-N2H3] + .

[0564] Step D: Dissolve 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carboxylic acid hydrazide (4.02 g, 12.25 mmol) in tetrahydrofuran (61 mL) at room temperature under nitrogen. Methyl isothiocyanate (2.68 g, 36.75 mmol) was then added to the solution, the temperature was raised to 65°C, and stirring was continued for 1 hour. The temperature was then lowered to 0°C, and 10 M potassium hydroxide aqueous solution (61.25 mmol, 6.1 mL) was added dropwise. The temperature was raised to 65°C, and stirring was continued for 3 hours.

[0565] After LCMS monitoring indicated the disappearance of the starting material, the reaction solution was poured into a mixture of ice water (30 mL) and ethyl acetate (30 mL) for quenching. The pH was adjusted to 2 with 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 3.81 g of 5-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol.

[0566] MS (ESI) M / Z: 384.1 [M+H] + .

[0567] Step E: Dissolve 5-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (3.81 g, 9.95 mmol) in dichloromethane (50 mL) and acetic acid (10 mL) at 0°C. Hydrogen peroxide (5.6 mL, 49.75 mmol, 30%) was added dropwise to the solution. The reaction was stirred at room temperature for 1 hour.

[0568] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into a mixture of ice water (30 mL) and dichloromethane (30 mL) to quench the mixture and adjust the pH to 2 with 1 M sodium hydroxide solution. The mixture was extracted with dichloromethane (30 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 2.91 g of 3-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole.

[0569] MS (ESI) M / Z: 352.2 [M+H] + .

[0570] Step F: Dissolve 3-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole (2.91 g, 8.29 mmol) in acetone (41 mL) at 0°C. Add 12 M concentrated hydrochloric acid (20 mL) dropwise to the solution. The reaction mixture is stirred at room temperature for 16 hours.

[0571] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into a mixture of ice water (20 mL) and ethyl acetate (30 mL) for quenching and adjusted to pH 8 with 2 M sodium hydroxide solution. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.11 g of 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutan-1-one.

[0572] MS (ESI) M / Z: 306.1 [M+H] + .

[0573] Step G: Dissolve 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutan-1-one (500 mg, 1.64 mmol) in tetrahydrofuran (10 mL) at 0°C under nitrogen. Add diethyl cyanomethylphosphonate (321 mg, 1.81 mmol) and potassium tert-butoxide (203 mg, 1.81 mmol) to the solution. Stir the reaction at room temperature for 2 hours.

[0574] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (20 mL). The mixture was extracted with ethyl acetate (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 480 mg of 2-(3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutenyl)acetonitrile.

[0575] MS (ESI) M / Z: 329.1 [M+H] + .

[0576] Step H: Dissolve 2-(3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutenyl)acetonitrile (480 mg, 1.46 mmol) in ethanol (4.6 mL) and isopropanol (4.6 mL) at 0°C. Then, slowly add sodium borohydride (162 mg, 4.38 mmol) to the solution. The reaction mixture is stirred at 60°C for 6 hours.

[0577] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into an ice-cold saturated ammonium chloride solution (30 mL) for quenching. The mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (15 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 400 mg of crude product. The resulting crude product was subjected to chiral separation to obtain 135 mg of compound Q1 (short retention time) and 90 mg of compound Q2 (long retention time).

[0578] Compound Q1

[0579] MS (ESI) M / Z: 331.2 [M+H] + .

[0580] 1H NMR (400MHz, DMSO-d6) δ8.33(s,1H),7.53-7.46(m,2H),7.39-7.32(m,2H),3.19(s,3H),2.92-2.80(m,2H),2.78-2.64(m,5H).

[0581] Compound Q2

[0582] MS (ESI) M / Z: 331.2 [M+H] + .

[0583] 1H NMR (400MHz, DMSO-d6) δ8.41(s,1H),7.49-7.44(m,2H),7.36(t,J=1.8Hz,1H),7.32(t,J=8.0Hz,1H),7.18 -7.12(m,1H),3.21(s,3H),3.13-3.04(m,2H),2.73(d,J=6.4Hz,2H),2.29-2.51(m,1H),2.48-2.39(m,2H).

[0584] Step I: Compound P1 (70 mg, 0.21 mmol) and (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (86 mg, 0.21 mmol) were dissolved in dimethyl sulfoxide (1.1 mL) at room temperature under nitrogen. N,N'-dimethylethylenediamine (18 mg, 0.21 mmol), cuprous iodide (40 mg, 0.21 mmol), and potassium carbonate (58 mg, 0.42 mmol) were then added to the solution. The reaction was stirred at 150°C for 3 hours.

[0585] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 45 mg of 2-((1R,3S)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

[0586] MS (ESI) M / Z: 660.1 [M+H] + .

[0587] Step J: Dissolve 2-((1R,3S)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (45 mg, 0.07 mmol) in dichloromethane (0.7 mL) at room temperature. Trifluoroacetic acid (0.7 mL) was then added dropwise to the solution and stirred for 2 hours. The temperature was then lowered to 0°C, and aqueous ammonia (5.0 mL) was slowly added dropwise. The mixture was allowed to warm to room temperature and stirred for another 2 hours.

[0588] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (20 mL). The mixture was extracted with dichloromethane (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (25 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 22.69 mg of 2-((1R,3S)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

[0589] MS (ESI) M / Z: 530.3 [M+H] + .

[0590] 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),8.32(s,1H),7.55-7.49(m,2H),7.47(s,1H),7.37(d,J=8.0Hz,1H),7.33(d,J=7.6Hz,1H),6.28(s,1H) ,3.62(s,2H),3.26(s,3H),3.00-2.87(m,2H),2.84-2.64(m,7H),2.01 -1.84(m,1H),1.68-1.53(m,4H),1.52-1.39(m,1H),0.89-0.74(m,4H).

[0591] Example 51

[0592] 4-Chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0593] Reaction route:

[0594] Steps:

[0595] Step A: Dissolve 2-bromo-6-chloro-4-methylpyridine (5 g, 24.3 mmol), cyclopropylboronic acid (4.5 g, 52.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1 g, 1.2 mmol), and potassium phosphate (15 g, 71.9 mmol) in toluene / water (60 mL / 6 mL) at room temperature under nitrogen. The reaction mixture was stirred at 95°C for 4 hours.

[0596] After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.4 g of 2-chloro-6-cyclopropyl-4-methylpyridine.

[0597] MS (ESI) M / Z: 168.0 [M+H] + .

[0598] Step B: Dissolve 2-chloro-6-cyclopropyl-4-methylpyridine (3.4 g, 20.4 mmol) in tetrahydrofuran (34 mL) at -70°C under nitrogen. Add a 2M solution of lithium diisopropylamide in tetrahydrofuran / n-heptane (25.5 mL, 51.0 mmol) dropwise to the solution and stir for 1 hour. Add dimethyl carbonate (2.7 g, 30.6 mmol), warm to 0°C, and continue stirring for 2 hours.

[0599] After LCMS monitoring showed the disappearance of the starting material, saturated aqueous ammonium chloride (30 mL) was added to the reaction mixture to quench it. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined and washed with saturated brine (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 3.2 g of methyl 2-(2-chloro-6-cyclopropylpyridin-4-yl)acetate.

[0600] MS (ESI) M / Z: 226.0 [M+H] + .

[0601] Step C: Methyl 2-(2-chloro-6-cyclopropylpyridin-4-yl)acetate (3.2 g, 14.1 mmol) and 1,3-dibromo-2-methylpropane (3.1 g, 14.3 mmol) were dissolved in tetrahydrofuran (70 mL) at 0°C under nitrogen. 60% wt sodium hydride (1.25 g, 31.0 mmol) was then slowly added to the solution. The reaction was stirred for 4 hours.

[0602] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched with saturated aqueous ammonium chloride (10 mL) and diluted with water (50 mL). The mixture was extracted with ethyl acetate (40 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 3 g of methyl 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carboxylate.

[0603] MS (ESI) M / Z: MS 280.0 [M+H] + .

[0604] Step D: Dissolve methyl 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carboxylate (3 g, 10.7 mmol) in methanol / tetrahydrofuran (40 mL / 10 mL) at room temperature. Add lithium hydroxide (770 mg, 32.1 mmol) in water (20 mL). Stir the reaction for 1 hour.

[0605] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure to remove the organic solvent and then adjusted to pH 5 with 2M dilute hydrochloric acid. The mixture was extracted with dichloromethane (40 mL x 2), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 2.2 g of crude 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid.

[0606] MS (ESI) M / Z: MS 266.0 [M+H] + .

[0607] Step E: Dissolve 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid (2.2 g, 8.27 mmol) in N,N-dimethylformamide (36 mL) at room temperature. Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.08 g, 10.75 mmol) and N,N-diisopropylethylamine (3.2 g, 24.81 mmol) to the solution and stir for 10 minutes. Then, add N-methylhydrazine methylsulfamide (1.04 g, 9.92 mmol) and continue stirring for 1 hour.

[0608] After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (50 mL × 2 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with petroleum ether / ethyl acetate (20 mL / 6 mL) to obtain 2.5 g of 2-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide.

[0609] MS(ESI)M / Z:MS 353.0[M+H] + .

[0610] Step F: Dissolve 2-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide (2.5 g, 7.08 mmol) in tetrahydrofuran (44 mL) at room temperature. Add sodium hydroxide (2.83 g, 70.8 mmol) in water (22 mL). Stir the reaction at 80°C for 4 hours.

[0611] After LCMS monitoring showed the disappearance of the starting material, 2 M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 5. The mixed solution was extracted with ethyl acetate (30 mL × 2 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.6 g of crude product 5-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol.

[0612] MS(ESI)M / Z:MS 335.0[M+H] + .

[0613] Step G: Dissolve 5-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (2.6 g, 7.78 mmol) in dichloromethane / acetic acid (40 mL / 6 mL) at 0°C. Then, slowly add 30% wt hydrogen peroxide (6 mL) dropwise to the solution and continue stirring for 30 minutes.

[0614] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into ice water (80 mL) to quench the mixture. The mixture was extracted with dichloromethane (30 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1 g of the mixture. 450 mg of the mixture was purified by preparative high-performance liquid chromatography to obtain 240 mg of compound X1 (short retention time) and 60 mg of compound X2 (long retention time).

[0615] Compound X1

[0616] 1 H NMR (400MHz, CD3Cl) δ8.05(s,1H),7.07(d,J=1.6Hz,1H),6.95(d,J=1.2Hz,1H),3.23(s,3H),2.85-2.75( m,2H),2.70-2.61(m,3H),1.96-1.88(m,1H),1.14(d,J=5.6Hz,3H),1.07-1.01(m,2H),1.00-0.95(m,2H).

[0617] Compound X2

[0618] 1 H NMR (400MHz, CD3Cl) δ8.12(s,1H),6.92(d,J=1.2Hz,1H),6.81(d,J=1.2Hz,1H),3.27(s,3H),3.19-3.06(m,2H),2. 62-2.51(m,1H),2.32-2.19(m,2H),1.95-1.86(m,1H),1.13(d,J=6.4Hz,3H),1.05-1.00(m,2H),0.99-0.93(m,2H).

[0619] Step H: At room temperature under nitrogen protection, compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (230 mg, 0.56 mmol), 2-chloro-6-cyclopropyl-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (compound X1, 170 mg, 0.56 mmol), N,N'-dimethylethylenediamine (59 mg, 0.67 mmol), cuprous iodide (106 mg, 0.56 mmol) and potassium carbonate (155 mg, 1.12 mmol) were dissolved in dimethyl sulfoxide (2.5 mL). The reaction system was then stirred at 150°C for 6 hours.

[0620] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 250 mg of 4-chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0621] MS (ESI) M / Z: 676.3 [M+H] + .

[0622] Step I: Dissolve 4-chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (250 mg, 0.37 mmol) in dichloromethane (2.5 mL) at room temperature. Trifluoroacetic acid (3.0 mL) was added dropwise to the solution, and stirring was continued for 2 hours. After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia (5.5 mL) was added dropwise to the reaction mixture until it became alkaline, and stirring was continued for 16 hours.

[0623] After LCMS monitoring showed the disappearance of the intermediate, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (15 mL x 2), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography to yield 90 mg of 4-chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0624] MS (ESI) M / Z: 546.2 [M+H] + .

[0625] 1 H NMR (400MHz, DMSO-d6) δ12.43(s,1H),8.34(s,1H),7.60(s,1H),7.47(d,J=1.2Hz,1H) ,7.32(d,J=1.6Hz,1H),6.25(s,1H),3.59(s,2H),3.28(s,3H),2.94-2.84(m,2H),2.8 2-2.70(m,2H),2.63-2.53(m,3H),2.24-2.15(m,1H),1.94-1.83(m,1H),1.66-1.53(m ,4H),1.50-1.39(m,1H),1.08(d,J=5.6Hz,3H),1.01-0.92(m,4H),0.85-0.72(m,4H).

[0626] Example 52

[0627] 4-Chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0628] Reaction route:

[0629] Steps:

[0630] Step A: (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (82 mg, 0.56 mmol), 2-chloro-6-cyclopropyl-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (60 mg, 0.20 mmol), N,N'-dimethylethylenediamine (21 mg, 0.24 mmol), cuprous iodide (38 mg, 0.20 mmol), and potassium carbonate (55 mg, 0.40 mmol) were dissolved in dimethyl sulfoxide (1 mL) at room temperature under nitrogen. The reaction system was then stirred at 150°C for 6 hours.

[0631] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 80 mg of 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0632] MS (ESI) M / Z: 676.3 [M+H] + .

[0633] Step B: 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (80 mg, 0.12 mmol) was dissolved in dichloromethane (2.2 mL) at room temperature. Trifluoroacetic acid (2.2 mL) was then added dropwise to the solution and stirring continued for 2 hours. After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia (5.0 mL) was added dropwise to the reaction solution until it became alkaline and stirring continued for 4 hours.

[0634] After LCMS monitoring showed the disappearance of the intermediate, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (15 mL x 2), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography to yield 7.9 mg of 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0635] MS (ESI) M / Z: 546.2 [M+H] + .

[0636] 1 H NMR (400MHz, DMSO-d6) δ12.43(s,1H),8.40(s,1H),7.59(s,1H),7.34(d,J=1.6Hz,1H) ,7.18(d,J=1.6Hz,1H),6.25(s,1H),3.59(s,2H),3.34(s,3H),3.17-3.08(m,2H),2.8 1-2.70(m,2H),2.41-2.24(m,3H),2.22-2.13(m,1H),1.95-1.83(m,1H),1.66-1.53(m ,4H),1.50-1.40(m,1H),1.10(d,J=6.0Hz,3H),0.99-0.90(m,4H),0.86-0.72(m,4H).

[0637] Example 53

[0638] 4-Chloro-6-(6-ethoxy-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

[0639] Reaction route:

[0640] Steps:

[0641] Step A: Compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (45 mg, 0.11 mmol), 2-chloro-6-ethoxy-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (40 mg, 0.12 mmol), N,N'-dimethylethylenediamine (10 mg, 0.11 mmol), cuprous iodide (21 mg, 0.11 mmol), and potassium carbonate (30 mg, 0.22 mmol) were dissolved in dimethyl sulfoxide (0.5 mL) at room temperature under nitrogen. The reaction system was then stirred at 150°C for 3 hours.

[0642] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 55 mg of 4-chloro-6-(6-ethoxy-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

[0643] MS (ESI) M / Z: 680.3 [M+H] + .

[0644] Step B: 4-chloro-6-(6-ethoxy-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (55 mg, 0.08 mmol) was dissolved in dichloromethane (0.8 mL) at 0°C. Trifluoroacetic acid (0.4 mL) was then added dropwise to the solution, and the reaction was stirred at room temperature for 2 hours. After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction mixture until alkaline, and stirring was continued for 1 hour.

[0645] After LCMS monitoring showed the disappearance of the intermediate, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 3), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 21.67 mg of 4-chloro-6-(6-ethoxy-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

[0646] MS (ESI) M / Z: 550.2 [M+H] + .

[0647] 1 H NMR (400MHz, DMSO-d6) δ12.44(s,1H),8.41(s,1H),7.68(s,1H),7.15(d,J=1.2Hz,1H), 6.62(d,J=1.2Hz,1H),6.26(s,1H),4.30(q,J=7.2Hz,2H),3.59(s,2H),3.31(s,3H),3.1 3-3.04(m,2H),2.81-2.70(m,2H),2.42-2.21(m,3H),1.94-1.83(m,1H),1.66-1.53(m, 4H),1.51-1.39(m,1H),1.32(t,J=7.0Hz,3H),1.10(d,J=6.0Hz,3H),0.86-0.74(m,4H).

[0648] Example 54

[0649] 4-Chloro-6-(3-ethoxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0650] Reaction route:

[0651] Steps:

[0652] Step A: Dissolve 3-bromo-5-hydroxybenzoic acid (5.0 g, 23.04 mmol) in N,N-dimethylformamide (52 mL) at room temperature. Add potassium carbonate (12.72 g, 92.16 mmol) and iodoethane (8.98 g, 57.60 mmol) sequentially to the solution. Stir the reaction at 50°C for 2 hours.

[0653] After LCMS monitoring showed the disappearance of the starting material, ethyl acetate (50 mL) was added to the reaction solution to dilute it and filter it. The filtrate was washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6.1 g of ethyl 3-bromo-5-ethoxybenzoate.

[0654] MS (ESI) M / Z: 273.0 [M+H] + .

[0655] Step B: Dissolve ethyl 3-bromo-5-ethoxybenzoate (6.1 g, 22.34 mmol) in tetrahydrofuran (70 mL) at -70°C under nitrogen. Add 2.5 M lithium aluminum hydride in tetrahydrofuran (9.0 mL, 22.34 mmol) dropwise to the solution. Stir the reaction at -50°C for 1 hour.

[0656] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into a mixture of ice water (150 mL) and ethyl acetate (60 mL) to quench the mixture. The mixture was extracted with ethyl acetate (30 mL x 2), and the organic phases were combined and washed with saturated brine (50 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5 g of (3-bromo-5-ethoxyphenyl)methanol.

[0657] MS (ESI) M / Z: 230.9 [M+H] + .

[0658] Step C: Dissolve (3-bromo-5-ethoxyphenyl)methanol (5 g, 21.64 mmol) in dichloromethane (100 mL) at room temperature. Add Dess-Martin periodinane (11 g, 25.97 mmol) in portions. Stir the reaction mixture for 1 hour.

[0659] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched by adding a mixture of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium thiosulfate solution (20 mL / 20 mL) and diluted with water (80 mL). The mixture was extracted with dichloromethane (30 mL × 2 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 4.3 g of 3-bromo-5-ethoxybenzaldehyde.

[0660] MS (ESI) M / Z: 228.9 [M+H] + .

[0661] Step D: Dissolve 4-methyl-4H-1,2,4-triazole (2.2 g, 26.29 mmol) in ethylene glycol dimethyl ether (100 mL) at -45°C under nitrogen. Slowly add a 2.5 M solution of n-butyl lithium in n-hexane (12 mL, 30.05 mmol) dropwise to the solution and stir for 30 minutes. Then, add a solution of 3-bromo-5-ethoxybenzaldehyde (4.3 g, 18.78 mmol) in ethylene glycol dimethyl ether (10 mL) dropwise. Warm the mixture to 0°C and continue stirring for 1 hour.

[0662] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (15 mL) and then diluted with water (80 mL). The mixture was then concentrated under reduced pressure to remove ethylene glycol dimethyl ether. The resulting mixture was extracted with dichloromethane (80 mL x 2), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 5.0 g of (3-bromo-5-ethoxyphenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methanol.

[0663] MS (ESI) M / Z: 312.0 [M+H] + .

[0664] Step E: Dissolve (3-bromo-5-ethoxyphenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methanol (2.0 g, 6.41 mmol) in tetrahydrofuran (60 mL) at 0°C under nitrogen. Then, add imidazole (2.18 g, 32.05 mmol), iodine (5.69 g, 22.43 mmol), and triphenylphosphine (5.87 g, 22.43 mmol) sequentially to the solution. The reaction mixture is stirred at 80°C for 3 hours.

[0665] After LCMS monitoring showed the disappearance of the starting material, a 10% aqueous sodium thiosulfate solution was added to the reaction solution until the solution became colorless, followed by dilution with water (60 mL). The mixture was extracted with dichloromethane (60 mL x 2), and the organic phases were combined and washed with saturated brine (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.9 g of 3-(3-bromo-5-ethoxybenzyl)-4-methyl-4H-1,2,4-triazole.

[0666] MS (ESI) M / Z: 296.0 [M+H] + .

[0667] Step F: Dissolve 3-(3-bromo-5-ethoxybenzyl)-4-methyl-4H-1,2,4-triazole (1.9 g, 6.42 mmol) and 1,3-dibromo-2-methylpropane (1.38 g, 6.42 mmol) in tetrahydrofuran (35 mL) at 0°C under nitrogen. Slowly add a 1M solution of lithium bistrimethylsilylamide in tetrahydrofuran (12.8 mL, 12.84 mmol) dropwise to the solution. Stir the reaction for 1 hour.

[0668] After LCMS monitoring showed the disappearance of the starting material, saturated aqueous ammonium chloride solution (8 mL) was added to the reaction solution to quench the mixture, and then diluted with water (40 mL). The mixed solution was extracted with dichloromethane (30 mL × 2 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 700 mg of an isomer mixture, which was purified by preparative high-performance liquid chromatography to obtain 190 mg of compound Y1 (short retention time) and 80 mg of compound Y2 (long retention time).

[0669] Compound Y1

[0670] 1 H NMR (400MHz, CD3Cl) δ8.11(s,1H),7.08(t,J=1.6Hz,1H),6.93(t,J=1.8Hz,1H),6.76(t,J=2.0Hz,1H),3.95(q, J=6.8Hz,2H),3.23(s,3H),2.84-2.73(m,2H),2.68-2.57(m,3H),1.38(t,J=7.0Hz,3H),1.13(d,J=5.6Hz,3H).

[0671] Compound Y2

[0672] 1H NMR (400MHz, CD3Cl) δ8.13(s,1H),6.92(t,J=1.6Hz,1H),6.89(t,J=2.0Hz,1H),6.61(t,J=1.8Hz,1H),3.94(q,J=6.8Hz, 2H),3.25(s,3H),3.13-3.04(m,2H),2.59-2.48(m,1H),2.29-2.19(m,2H),1.38(t,J=7.0Hz,3H),1.11(d,J=6.8Hz,3H).

[0673] Step G: (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (117 mg, 0.28 mmol), 3-((1S,3S)-1-(3-bromo-5-ethoxyphenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (100 mg, 0.28 mmol), N,N'-dimethylethylenediamine (30 mg, 0.34 mmol), cuprous iodide (54 mg, 0.28 mmol), and potassium carbonate (83 mg, 0.57 mmol) were dissolved in dimethyl sulfoxide (1.5 mL) under nitrogen at room temperature. The reaction system was then stirred at 150°C for 3 hours.

[0674] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 130 mg of 4-chloro-6-(3-ethoxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0675] MS (ESI) M / Z: 679.4 [M+H] + .

[0676] Step H: Dissolve 4-chloro-6-(3-ethoxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (130 mg, 0.19 mmol) in dichloromethane (1.5 mL) at room temperature. Trifluoroacetic acid (2 mL) was then added dropwise to the solution and stirred for 2 hours. The mixture was then cooled to 0°C and aqueous ammonia was slowly added dropwise to adjust the pH to 8. Stirring was continued for 2 hours.

[0677] After LCMS monitoring showed the disappearance of the intermediate, the reaction mixture was quenched with water (20 mL). The mixture was extracted with dichloromethane (10 mL x 2), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography to yield 58.7 mg of 4-chloro-6-(3-ethoxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0678] MS (ESI) M / Z: 549.3 [M+H] + .

[0679] 1 H NMR (400MHz, DMSO-d6) δ12.34(s,1H),8.29(s,1H),7.42(s,1H),6.99(t,J=1.6Hz,1H),6.92( t,J=2.0Hz,1H),6.80(t,J=2.0Hz,1H),6.25(s,1H),4.02(q,J=6.8Hz,2H),3.59(s,2H),3.25 (s,3H),2.92-2.82(m,2H),2.80-2.69(m,2H),2.59-2.51(m,3H),1.95-1.82(m,1H),1.72-1. 52(m,4H),1.51-1.41(m,1H),1.31(t,J=7.0Hz,3H),1.06(d,J=5.2Hz,3H),0.89-0.71(m,4H).

[0680] The following target compounds were prepared by referring to the synthetic methods of Examples 42-54 above:

[0681] Example 61

[0682] (S)-4-Chloro-6-(3-(3-(4-methyl-4H-1,2,4-triazol-3-yl)oxetan-3-yl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0683] Reaction route:

[0684] Steps:

[0685] Step A: Methyl 2-(3-bromophenyl)acetate (36 g, 157.2 mmol) was dissolved in N,N-dimethylformamide (270 mL) at room temperature under nitrogen. Paraformaldehyde (19.2 g, 628.8 mmol) and sodium methoxide (1.73 g, 31.44 mmol) were then added to the solution. The reaction was stirred at room temperature for 48 hours.

[0686] After LCMS monitoring showed the disappearance of the starting material, water (70 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 10 g of methyl 2-(3-bromophenyl)-3-hydroxy-2-(hydroxymethyl)propanoate.

[0687] MS (ESI) M / Z: 289.0 [M+H] + .

[0688] Step B: Dissolve methyl 2-(3-bromophenyl)-3-hydroxy-2-(hydroxymethyl)propanoate (10 g, 36.46 mmol) in tetrahydrofuran (182 mL) at room temperature under nitrogen. Cool the solution to -78°C and slowly add a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (29 mL, 72.92 mmol) dropwise. Stir the reaction at -78°C for 1 hour.

[0689] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was quenched with water (25 mL). The mixture was extracted with ethyl acetate (20 mL x 3 times), and the organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 3.4 g of 2-(3-bromophenyl)-2-(hydroxymethyl)propane-1,3-diol.

[0690] MS (ESI) M / Z: 283.0 [M+Na] + .

[0691] Step C: Dissolve 2-(3-bromophenyl)-2-(hydroxymethyl)propane-1,3-diol (3.4 g, 13.03 mmol) in dichloromethane (65 mL) at room temperature. Then, triethylamine (5.26 g, 52.12 mmol), 4-dimethylaminopyridine (795 mg, 6.52 mmol), and p-toluenesulfonyl chloride (2.24 g, 11.73 mmol) were added to the solution in sequence. The reaction was stirred for 24 hours.

[0692] After LCMS monitoring showed the disappearance of the starting material, ice water (25 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.15 g of 2-(3-bromophenyl)-3-hydroxy-2-(hydroxymethyl)propyl-4-methylbenzenesulfonate.

[0693] MS (ESI) M / Z: 437.0 [M+Na] + .

[0694] Step D: Dissolve 2-(3-bromophenyl)-3-hydroxy-2-(hydroxymethyl)propyl-4-methylbenzenesulfonate (1.15 g, 2.78 mmol) in tetrahydrofuran (28 mL) at room temperature under nitrogen. The solution was then cooled to 0°C and potassium ethoxide (467 mg, 5.56 mmol) was added. The reaction was stirred at room temperature for 18 hours.

[0695] After LCMS monitoring showed the disappearance of the starting material, water (25 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 330 mg of (3-(3-bromophenyl)oxetane-3-yl)methanol.

[0696] MS (ESI) M / Z: 265.0 [M+Na] + .

[0697] Step E: Dissolve (3-(3-bromophenyl)oxetan-3-yl)methanol (330 mg, 1.36 mmol) in acetonitrile (6.8 mL) at 0°C. Then, add 2,2,6,6-tetramethylpiperidine-N-oxide (21 mg, 0.14 mmol), 7.5% wt sodium hypochlorite solution (6.5 g, 5.44 mmol), and sodium chlorite (81 mg, 1.09 mmol) sequentially. The reaction mixture is stirred at room temperature for 18 hours.

[0698] After LCMS monitoring showed the disappearance of the starting material, water (25 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 270 mg of 3-(3-bromophenyl)oxetane-3-carboxylic acid.

[0699] MS (ESI) M / Z: 279.0 [M+Na] + .

[0700] Step F: 3-(3-bromophenyl)oxetane-3-carboxylic acid (265 mg, 1.04 mmol) was dissolved in N,N-dimethylformamide (5 mL) at room temperature. N-methylhydrazine methylsulfamide (130 mg, 1.24 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (435 mg, 1.14 mmol), and N,N-diisopropylethylamine (403 mg, 3.12 mmol) were then added to the solution. The reaction mixture was stirred for 0.5 h.

[0701] After LCMS monitoring showed the disappearance of the starting material, water (25 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 225 mg of 2-(3-(3-bromophenyl)oxetane-3-carbonyl)-N-methylhydrazine-1-methylsulfamide was obtained.

[0702] MS (ESI) M / Z: 344.1 [M+H] + .

[0703] Step G: Dissolve 2-(3-(3-bromophenyl)oxetane-3-carbonyl)-N-methylhydrazine-1-methylsulfamide (210 mg, 0.61 mmol) in tetrahydrofuran (3.1 mL) at room temperature. Then, add 2M sodium hydroxide (0.34 mL, 0.67 mmol) in water. Stir the reaction for 2 hours.

[0704] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with ice water (25 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 170 mg of 5-(3-(3-bromophenyl)oxetane-3-yl)-4-methyl-4H-1,2,4-triazole-3-thiol was obtained.

[0705] MS (ESI) M / Z: 326.1 [M+H] + .

[0706] Step H: Dissolve 5-(3-(3-bromophenyl)oxetane-3-yl)-4-methyl-4H-1,2,4-triazole-3-thiol (160 mg, 0.49 mmol) in dichloromethane (2.5 mL) at room temperature under nitrogen. The solution was then cooled to 0°C, and acetic acid (0.49 mL) and 30% aqueous hydrogen peroxide (278 mg, 2.45 mmol) were added dropwise. The reaction was then stirred for 0.5 hours.

[0707] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (25 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 50 mg of 3-(3-(3-bromophenyl)oxetan-3-yl)-4-methyl-4H-1,2,4-triazole.

[0708] MS (ESI) M / Z: 294.0 [M+H] + .

[0709] Step I: 3-(3-(3-bromophenyl)oxetane-3-yl)-4-methyl-4H-1,2,4-triazole (40 mg, 0.14 mmol), (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (46 mg, 0.12 mmol), N,N'-dimethylethylenediamine (12 mg, 0.14 mmol), cuprous iodide (22 mg, 0.12 mmol), and potassium carbonate (32 mg, 0.24 mmol) were dissolved in dimethyl sulfoxide (2 mL) at room temperature under nitrogen. The reaction system was then stirred at 140°C for 2 hours.

[0710] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 34 mg of (S)-4-chloro-6-(3-(3-(4-methyl-4H-1,2,4-triazol-3-yl)oxetan-3-yl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0711] MS (ESI) M / Z: 623.3 [M+H] + .

[0712] Step J: Compound (S)-4-chloro-6-(3-(3-(4-methyl-4H-1,2,4-triazol-3-yl)oxetane-3-yl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (34 mg, 0.06 mmol) was dissolved in dichloromethane (1.0 mL) at room temperature. Trifluoroacetic acid (0.5 mL) was then added dropwise to the solution. The reaction was stirred at room temperature for 2 hours.

[0713] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction mixture to adjust the pH to 8, and stirring was continued for 30 minutes. Water (25 mL) was then added to the solution to quench the mixture. The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the crude product. The crude product was purified by preparative HPLC to yield 12 mg of (S)-4-chloro-6-(3-(3-(4-methyl-4H-1,2,4-triazol-3-yl)oxetane-3-yl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0714] MS (ESI) M / Z: 493.3 [M+H] + .

[0715] 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),8.47(s,1H),7.56(t,J=7.8Hz,1H),7. 47(s,1H),7.46-7.40(m,2H),7.30(d,J=8.0Hz,1H),6.26(s,1H),5.39(d,J=6 .4Hz,2H),5.13(d,J=6.4Hz,2H),3.59(s,2H),3.30(s,3H),2.81-2.70(m,2H) ,1.93-1.83(m,1H),1.67-1.52(m,4H),1.52-1.38(m,1H),0.85-0.73(m,4H).

[0716] Example 62

[0717] 4-Chloro-6-(3-(((1R,3S)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0718] Reaction route:

[0719] Steps:

[0720] Step A: Dissolve (1R,3R)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol (150 mg, 0.49 mmol) in N,N-dimethylformamide (2.5 mL) at 0°C under nitrogen. Add sodium hydride (30 mg, 0.74 mmol) and stir for 30 minutes. Add deuterated iodomethane (213 mg, 1.47 mmol) dropwise, warm to room temperature, and continue stirring for 10 minutes.

[0721] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of ice water (10 mL). The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 140 mg of 3-((1R,3R)-1-(3-bromophenyl)-3-(methoxy-d3)cyclobutyl)-4-methyl-4H-1,2,4-triazole.

[0722] MS (ESI) M / Z: 325.0 [M+H] + .

[0723] Step B: 3-((1R,3R)-1-(3-bromophenyl)-3-(methoxy-d3)cyclobutyl)-4-methyl-4H-1,2,4-triazole (140 mg, 0.43 mmol) was dissolved in dry dimethyl sulfoxide (4.6 mL) at room temperature under nitrogen. (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (90 mg, 0.22 mmol), cuprous iodide (82 mg, 0.43 mmol), N,N'-dimethylethylenediamine (46 mg, 0.52 mmol), and potassium carbonate (120 mg, 0.86 mmol) were then added to the solution. The reaction was stirred at 150°C for 3 hours.

[0724] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (20 mL). The mixture was extracted with ethyl acetate (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 200 mg of 4-chloro-6-(3-(((1R,3S)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0725] MS (ESI) M / Z: 654.2 [M+H] + .

[0726] Step C: At 0°C, under nitrogen protection, the compound 4-chloro-6-(3-(((1R,3S)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.31 mmol) was dissolved in dichloromethane (1.8 mL). Subsequently, trifluoroacetic acid (1.7 mL) was added dropwise to the above solution, and the mixture was warmed to room temperature and stirred for 2 hours. The temperature was then lowered to 0°C, and aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8. The mixture was warmed to room temperature and stirred for 1 hour.

[0727] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (15 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 40.27 mg of 4-chloro-6-(3-(((1R,3S)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0728] MS (ESI) M / Z: 524.3 [M+H] + .

[0729] 1H NMR (400MHz, DMSO-d6) δ11.59(s,1H),8.39(s,1H),7.48(t,J=7.8Hz,1H),7.43(s,1H ),7.36-7.28(m,2H),7.16(d,J=8.0Hz,1H),6.26(s,1H),3.90-3.80(m,1H),3.59(s, 2H),3.33-3.31(m,2H),3.29(s,3H),2.82-2.69(m,2H),2.56-2.53(m,1H),2.50-2.4 6(m,1H),1.94-1.83(m,1H),1.67-1.53(m,4H),1.52-1.37(m,1H),0.87-0.72(m,4H).

[0730] The following target compounds were prepared by referring to the synthetic methods of Examples 42-54 above:

[0731] Example 67

[0732] 4-Chloro-6-(3-((2,2-difluoroethyl)amino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

[0733] Reaction route:

[0734] Steps:

[0735] Step A: Dissolve 4-methyl-4H-1,2,4-triazole (3.8 g, 45.4 mmol) in ethylene glycol dimethyl ether (200 mL) at -50°C under nitrogen. Slowly add 2.5 M n-butyl lithium / n-hexane solution (18 mL, 30.3 mmol) dropwise to the solution and stir for 1 hour. Then, slowly add 3,5-dibromobenzaldehyde (8.0 g, 45.4 mmol) in ethylene glycol dimethyl ether (20 mL) dropwise, warm to 0°C, and continue stirring for 1 hour.

[0736] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was slurried with petroleum ether / ethyl acetate to obtain 5.2 g of (3,5-dibromophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methanol.

[0737] MS (ESI) M / Z: 347.9 [M+H] + .

[0738] Step B: Dissolve (3,5-dibromophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methanol (5.0 g, 14.4 mmol) in tetrahydrofuran (70 mL) at 0°C under nitrogen. Then, add imidazole (3.9 g, 57.6 mmol), iodine (11.0 g, 43.2 mmol), and triphenylphosphine (11.3 g, 43.2 mmol) sequentially to the solution. The reaction mixture is stirred at 80°C for 16 hours.

[0739] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was quenched with saturated aqueous sodium thiosulfate (20 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 3.0 g of 3-(3,5-dibromobenzyl)-4-methyl-4H-1,2,4-triazole.

[0740] MS (ESI) M / Z: 331.9 [M+H] + .

[0741] Step C: Dissolve 3-(3,5-dibromobenzyl)-4-methyl-4H-1,2,4-triazole (1.5 g, 4.5 mmol) and 1,3-dibromo-2-methylpropane (972 mg, 4.5 mmol) in tetrahydrofuran (15 mL) at 0°C under nitrogen. Slowly add a 1.0 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (9.0 mL, 9.0 mmol) dropwise to the solution. Stir the reaction for 2 hours.

[0742] After LCMS monitoring showed the disappearance of the starting material, saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to quench the reaction. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product, which was then purified by preparative high-performance liquid chromatography to obtain 340 mg of compound Z1 (short retention time) and 125 mg of compound Z2 (long retention time).

[0743] Compound Z1

[0744] 1 H NMR (400MHz, CDCl3) δ7.57(t,J=1.6Hz,1H),7.42(d,J=1.6Hz,2H),3.22(s,3H),2.86-2.73(m,2H),2.71-2.56(m,3H),1.14(d,J=5.6Hz,3H).

[0745] Compound Z2

[0746] 1 H NMR(400MHz, CDCl3)δ7.54(t,J=1.6Hz,1H),7.31-7.23(m,2H),3.26(s,3H),3 .23-3.08(m,2H),2.62-2.49(m,1H),2.28-2.18(m,2H),1.13(d,J=6.4Hz,3H).

[0747] Step D: (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (60 mg, 0.15 mmol), 3-((1S,3S)-1-(3,5-dibromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (90 mg, 0.22 mmol), N,N'-dimethylethylenediamine (13 mg, 0.15 mmol), cuprous iodide (28 mg, 0.15 mmol), and potassium carbonate (42 mg, 0.30 mmol) were dissolved in dimethyl sulfoxide (1.0 mL) at room temperature under nitrogen. The reaction system was then stirred at 130°C for 2 hours.

[0748] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 58 mg of 6-(3-bromo-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

[0749] MS (ESI) M / Z: 713.3 [M+H] + .

[0750] Step E: At room temperature, under nitrogen protection, compound 6-(3-bromo-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-7(6H)- Ketone (28 mg, 0.039 mmol), 2,2-difluoroethylamine (16 mg, 0.20 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium methanesulfonate (7 mg, 0.0078 mmol), and cesium carbonate (25 mg, 0.078 mmol) were dissolved in tetrahydrofuran (0.4 mL). The reaction system was then stirred at 100°C for 2 hours.

[0751] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 22 mg of 4-chloro-6-(3-((2,2-difluoroethyl)amino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

[0752] MS (ESI) M / Z: 714.4 [M+H] + .

[0753] Step F: At 0 ° C, the compound 4-chloro-6-(3-((2,2-difluoroethyl)amino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (22 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL). Subsequently, trifluoroacetic acid (0.2 mL) was added dropwise to the above solution, and the mixture was warmed to room temperature and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, ammonia water was added dropwise to the reaction solution until pH = 8 and stirring was continued for 1 hour.

[0754] After LCMS monitoring showed the disappearance of the intermediate, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 3), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 0.98 mg of 4-chloro-6-(3-((2,2-difluoroethyl)amino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

[0755] MS (ESI) M / Z: 584.3 [M+H] + .

[0756] 1 H NMR(400MHz,DMSO-d6)δ12.72(s,1H),9.70(s,1H),8.44(s,1H),7.46(s,1H),6.72(s,1H),6.66(d, J=2.0Hz,1H),6.60(s,1H),6.55(s,1H),6.10(tt,J1=4.0Hz,J2=56.0Hz,1H),4.38(s,2H),3.59-3. 54(m,2H),3.35-3.32(m,2H),3.29(s,3H),2.87-2.71(m,3H),2.60-2.51(m,2H),2.08-1.92(m,1H) ,1.91-1.75(m,2H),1.74-1.58(m,2H),1.53-1.38(m,1H),1.13-0.94(m,4H),0.89(d,J=6.4Hz,3H).

[0757] The following target compounds were prepared by referring to the synthetic methods of Examples 42-54 above:

[0758] Example 79

[0759] 4-Chloro-6-(3-((1s,3R)-3-(2,2-difluoroethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0760] 4-Chloro-6-(3-((1r,3S)-3-(2,2-difluoroethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0761] Reaction route:

[0762] Steps:

[0763] Step A: At 0°C under nitrogen, dissolve methyltriphenylphosphonium bromide (1.75 g, 4.91 mmol) in tetrahydrofuran (20 mL). Add potassium bis(trimethylsilyl)amide (4.91 mmol, 4.91 mL, 1 M) dropwise to the reaction mixture. Stirring is continued for 1 hour. Then, dissolve 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl-1-one (1 g, 3.27 mmol) in tetrahydrofuran (S1, 10 mL) and add the resulting mixture. Warm the reaction mixture to room temperature and continue stirring for 12 hours.

[0764] After LCMS monitoring indicated conversion of the starting material to the product, the reaction mixture was quenched by the addition of water (40 mL). The mixture was extracted with ethyl acetate (30 mL x 3 times), and the organic phases were combined and washed with aqueous sodium chloride (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 0.38 g of the compound 3-(1-(3-bromophenyl)-3-methylenebicyclobutyl)-4-methyl-4H-1,2,4-triazole.

[0765] MS (ESI) M / Z: 304.0 [M+H] + .

[0766] Step B: Dissolve 3-(1-(3-bromophenyl)-3-methylenebicyclobutyl)-4-methyl-4H-1,2,4-triazole (0.3 g, 0.99 mmol) in tetrahydrofuran (1 mL) at room temperature. Add iodobenzenediacetic acid (0.96 g, 2.97 mmol) and 2,2-difluoroacetic acid (0.57 g, 5.94 mmol). Heat the reaction mixture to 50°C and continue stirring under blue light (450 nm) for 4 hours. Then, add additional iodobenzenediacetic acid (0.96 g, 2.97 mmol) and continue the reaction for 2 hours.

[0767] After LCMS monitoring indicated conversion of the starting material to the product, the reaction mixture was quenched with sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3 times), and the organic phases were combined and washed with aqueous sodium chloride (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 0.12 g of the compound 3-(1-(3-bromophenyl)-3-(2,2-difluoroethyl)cyclobutyl)-4-methyl-4H-1,2,4-triazole.

[0768] MS (ESI) M / Z: 356.1 [M+H] + .

[0769] Step C: 4-chloro-2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (0.12 g, 0.29 mmol), 3-(1-(3-bromophenyl)-3-(2,2-difluoroethyl)cyclobutyl)-4-methyl-4H-1,2,4-triazole (0.10 g, 0.29 mmol), N,N,N',N'-tetramethylethylenediamine (0.034 g, 0.29 mmol), cuprous iodide (0.055 g, 0.29 mmol), and potassium carbonate (0.080 g, 0.58 mmol) were dissolved in dimethyl sulfoxide (1 mL) at room temperature under nitrogen. The reaction mixture was heated to 150°C and stirred for 6 hours.

[0770] After LCMS monitoring indicated conversion of the starting material to the product, the product was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.15 g of the compound 4-chloro-6-(3-(3-(2,2-difluoroethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one.

[0771] MS (ESI) M / Z: 685.3 [M+H] + .

[0772] Step D: Dissolve 4-chloro-6-(3-(3-(2,2-difluoroethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (0.12 g, 0.18 mmol) in dichloromethane (1 mL) at room temperature. Trifluoroacetic acid (1 mL) was then added dropwise to the solution and stirred for 2 hours. The temperature was then lowered to 0°C, and aqueous ammonia (10.0 mL) was slowly added dropwise to adjust the pH to 8. The mixture was allowed to warm to room temperature and stirred for another 2 hours.

[0773] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (20 mL). The mixture was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Daicel IG-3; mobile phase: CO2 / EtOH [1.0% NH3 (7M in MeOH)] = 55 / 45) to obtain 10 mg of compound 79-P1 (retention time: 2.346 min) and 8 mg of compound 79-P2 (retention time: 2.692 min).

[0774] Compound 79-P1

[0775] MS (ESI) M / Z: 555.3 [M+H] + .

[0776] 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.29(s,1H),7.54–7.48(m,2H),7.44(s,1H),7.40–7.30(m,2H),6.26(s,1H),6.18–5.87(m,1H),3. 59(s,2H),3.25(s,3H),2.93–2.88(m,2H),2.78–2.59(m,5H),2.06–1 .85(m,3H),1.64–1.57(m,4H),1.47–1.44(m,1H),0.82–0.81(m,4H).

[0777] Compound 79-P2

[0778] MS (ESI) M / Z: 555.3 [M+H]+ .

[0779] 1 H NMR(400MHz,DMSO-d6)δ12.36(s,1H),8.39(s,1H),7.48–7.41(m,1H),7. 41(s,1H),7.39–7.29(m,2H),7.14–7.12(m,1H),6.26(s,1H),6.20–5.86( m,1H),3.59(s,2H),3.29(s,3H),3.10(s,2H),2.76–2.75(m,2H),2.49–2 .44(m,3H),2.11–1.89(m,2H),1.99–1.98(m,1H),1.64–1.57(m,4H),1.47 -1.44(m,1H),0.82–0.81(m,4H).

[0780] Example 80

[0781] 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one

[0782] Reaction route:

[0783] Steps:

[0784] Step A: Dissolve N-Boc-aminopropyne (15 g, 96.66 mmol) and ethyl isocyanoacetate (9.84 g, 86.99 mmol) in 1,4-dioxane (200 mL) at room temperature under nitrogen. Add silver carbonate (2.67 g, 9.67 mmol). Heat the reaction mixture to 100°C and continue stirring for 12 hours.

[0785] After LCMS monitoring indicated conversion of the raw material to product, water (50 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (100 mL x 3 times), and the organic phases were combined and washed with aqueous sodium chloride (30 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 6.8 g of the compound, ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrrole-2-carboxylate.

[0786] MS (ESI) M / Z: 169.2 [M-99] + .

[0787] Step B: Dissolve ethyl 3-(((tert-Butyloxycarbonyl)amino)methyl)-1H-pyrrole-2-carboxylate (6.8 g, 25.34 mmol) in ethanol (60 mL) and water (30 mL) at room temperature. Add lithium hydroxide monohydrate (4.25 g, 101.36 mmol). Heat the reaction mixture to 60°C and continue stirring overnight.

[0788] After LCMS monitoring indicated conversion of the starting material to product, the reaction system was adjusted to weak acidity (pH = 4) with hydrochloric acid (2 M). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with aqueous sodium chloride solution (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product that was used directly in the next step.

[0789] MS (ESI) M / Z: 141.1 [M+H] + .

[0790] Step C: Under nitrogen, dissolve 3-(((tert-Butyloxycarbonyl)amino)methyl)-1H-pyrrole-2-carboxylic acid (5.2 g, 21.64 mmol) in dichloromethane (80 mL). The reaction mixture was then cooled to 0°C. Thionyl chloride (10.30 g, 86.56 mmol) was then added dropwise to the reaction mixture. The reaction mixture was slowly warmed to room temperature and stirred for 8 hours. The reaction mixture was then slowly added to a saturated sodium bicarbonate solution until the mixture became weakly alkaline.

[0791] After LCMS monitoring showed that the raw material was converted into the product, the precipitated solid was filtered and dried to obtain 2.4 g of the target product 1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one.

[0792] MS (ESI) M / Z: 123.2 [M+H] + .

[0793] Step D: Under nitrogen, dissolve 1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one (1 g, 8.19 mmol) in tetrahydrofuran (50 mL). Cool the reaction to -78°C and add N-iodosuccinimide (1.84 g, 8.19 mmol) dissolved in tetrahydrofuran (4 mL). Slowly warm the reaction to room temperature and continue stirring overnight.

[0794] After LCMS monitoring showed that the raw material was converted into the product, the product was directly dried by spin drying. The resulting residue was purified by silica gel column chromatography to obtain 0.75 g of the compound 2-iodo-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one.

[0795] MS (ESI) M / Z: 248.6 [M+H] + .

[0796] Step E: 2-iodo-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one (0.7 g, 2.82 mmol), potassium (S)-trifluoro((3-methylpiperidin-1-yl)methyl)borate (0.93 g, 4.23 mmol), XPhos G3 (0.48 g, 0.56 mmol), potassium carbonate (0.78 g, 5.64 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.27 g, 0.56 mmol) were dissolved in 1,4-dioxane (15 mL) and water (1.5 mL) under nitrogen at room temperature. The reaction system was then heated to 100°C and stirred overnight.

[0797] After LCMS monitoring indicated conversion of the starting material to the product, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (20 mL x 3 times), and the organic phases were combined and washed with aqueous sodium chloride (10 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 200 mg of the compound 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one.

[0798] MS (ESI) M / Z: 234.2 [M+H] + .

[0799] Step F: 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one (0.2 g, 0.86 mmol), 4-methyl-3-[(1s,3S)-1-(3-bromophenyl)-3-methylcyclobutyl]-4H-1,2,4-triazole (0.34 g, 1.12 mmol), palladium acetate (0.039 g, 0.17 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.18 g, 0.31 mmol), and cesium carbonate (0.56 g, 1.72 mmol) were dissolved in 1,4-dioxane (5 mL) at room temperature under nitrogen. The reaction mixture was heated to 120°C and stirred for 2 hours.

[0800] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (15 mL). The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with aqueous sodium chloride (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to yield 0.006 g of the compound 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one.

[0801] MS (ESI) M / Z: 460.2 [M+H] + .

[0802] 1 H NMR(400MHz,DMSO-d6)δ11.77(s,1H),8.28(s,2H),7.86–7.85(m,1H),7.61–7.58( m,1H),7.35-7.31(m,1H),6.95–6.93(m,1H),6.04(s,1H),4.68(s,2H),3.48–3.27( m,2H),3.20(s,3H),2.83–2.81(m,2H),2.77–2.72(m,2H),2.53(s,3H),1.88–1.83( m,1H),1.63–1.52(m,4H),1.49–1.41(m,1H),1.09–1.07(m,3H),0.84–0.77(m,4H).

[0803] The following target compounds were prepared by referring to the synthetic methods of Examples 42-54 above:

[0804] Example 83

[0805] 4-(Difluoromethyl)-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0806] 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carbaldehyde

[0807] Reaction route:

[0808] Steps:

[0809] Step A: Ethyl 4-bromo-7-methoxy-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (2 g, 4.66 mmol) was dissolved in 1,4-dioxane (23 mL) and water (4 mL) at room temperature under nitrogen. Potassium vinyl trifluoroborate (1.25 g, 9.32 mmol), potassium carbonate (1.29 g, 9.32 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (287 mg, 0.70 mmol), and palladium acetate (157 mg, 0.70 mmol) were then added to the solution. The reaction mixture was stirred at 90°C for 4 hours.

[0810] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.6 g of ethyl 7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate.

[0811] MS (ESI) M / Z: 377.2 [M+H] + .

[0812] Step B: Dissolve ethyl 7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1.55 g, 4.11 mmol) in tert-butanol (21 mL) and water (21 mL) at room temperature. Then, add 4-methylmorphine-N-oxide (625 mg, 5.35 mmol) and potassium osmate dihydrate (151 mg, 0.41 mmol) to the solution and stir for 0.5 hour. Then, add sodium periodate (1.76 g, 8.22 mmol) and continue stirring for 1 hour.

[0813] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 1.2 g of ethyl 4-formyl-7-methoxy-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate.

[0814] MS (ESI) M / Z: 379.3 [M+H] + .

[0815] Step C: Ethyl 4-formyl-7-methoxy-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1.1 g, 2.91 mmol) was dissolved in dichloromethane (9.7 mL) at room temperature under nitrogen. Diethylaminosulfur trifluoride (2.34 g, 14.55 mmol) was then added dropwise to the solution. The reaction was stirred at room temperature for 18 hours.

[0816] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with ice water (25 mL). The mixture was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 450 mg of ethyl 4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate.

[0817] MS (ESI) M / Z: 401.2 [M+H] + .

[0818] Step D: At room temperature, under nitrogen, ethyl 4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (450 mg, 1.12 mmol) was dissolved in tetrahydrofuran (11 mL). The temperature was then lowered to -78°C, and a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (0.45 mL, 1.12 mmol) was added dropwise. The reaction system was then stirred at -78°C for 1 hour.

[0819] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (25 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 390 mg of (4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol.

[0820] MS (ESI) M / Z: 359.2 [M+H] + .

[0821] Step E: Dissolve (4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (390 mg, 1.09 mmol) in dichloromethane (1.1 mL) at room temperature. Then, add thionyl chloride (0.14 mL) dropwise to the solution. The reaction is stirred at room temperature for 2 hours.

[0822] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure to obtain 390 mg of a crude product of 2-(chloromethyl)-4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

[0823] MS (ESI) M / Z: 377.2 [M+H] + .

[0824] Step F: Dissolve (S)-3-methylpiperidine hydrochloride (210 mg, 1.55 mmol) in acetonitrile (5 mL) at room temperature. Add potassium iodide (256 mg, 1.55 mmol) and potassium carbonate (426 mg, 3.09 mmol) sequentially to the solution and stir for 0.5 hour. Add 2-(chloromethyl)-4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (388 mg, 1.03 mmol) and continue stirring for 16 hours.

[0825] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 200 mg of (S)-4-(difluoromethyl)-7-methoxy-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-pyrrolo[2,3-c]pyridine.

[0826] MS (ESI) M / Z: 440.2 [M+H] + .

[0827] Step G: Compound (S)-4-(difluoromethyl)-7-methoxy-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.45 mmol) was dissolved in acetonitrile (2.3 mL) under nitrogen at room temperature. Sodium iodide (102 mg, 0.68 mmol) and trimethylsilyl chloride (74 mg, 0.68 mmol) were then added to the solution. The reaction was stirred at room temperature for 2 hours.

[0828] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with ice water (25 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 110 mg of (S)-4-(difluoromethyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0829] MS (ESI) M / Z: 426.2 [M+H] + .

[0830] Step H: Compound (S)-4-(difluoromethyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (110 mg, 0.22 mmol), 4-methyl-3-((1s,3s)-3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-12,4-triazole (272 mg, 0.77 mmol), sodium bicarbonate (26 mg, 0.44 mmol), and copper acetate (131 mg, 0.66 mmol) were dissolved in dimethyl sulfoxide (3 mL) at room temperature. The oxygen was replaced by vacuum three times, and the reaction system was stirred at 90°C for 3 hours.

[0831] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 40 mg of 4-(difluoromethyl)-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0832] MS (ESI) M / Z: 651.3 [M+H] + .

[0833] Step 1: 4-(difluoromethyl)-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (35 mg, 0.05 mmol) was dissolved in dichloromethane (0.27 mL) at room temperature. Trifluoroacetic acid (0.27 mL) was then added dropwise to the solution. The reaction was stirred at room temperature for 2 hours.

[0834] After LCMS monitoring showed the disappearance of the starting material, water (25 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography to give 4.5 mg of 4-(difluoromethyl)-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Compound 83-P1) and 3.3 mg of 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carbaldehyde (Compound 83-P2).

[0835] Compound 83-P1

[0836] MS (ESI) M / Z: 521.2 [M+H] + .

[0837] 1 H NMR(400MHz,DMSO-d6)δ12.27(s,1H),8.29(s,1H),7.62(s,1H),7.56-7.45(m,2 H),7.38-7.30(m,2H),6.94(t,J=54.8Hz,1H),6.33(s,1H),3.61(s,2H),3.25(s, 3H),2.92-2.85(m,2H),2.83-2.72(m,2H),2.61-2.53(m,3H),1.99-1.83(m,1H) ,1.69-1.54(m,4H),1.52-1.40(m,1H),1.07(d,J=5.2Hz,3H),0.86-0.74(m,4H).

[0838] Compound 83-P2

[0839] MS (ESI) M / Z: 499.3 [M+H] + .

[0840] 1H NMR (400MHz, DMSO-d6) δ12.32(s,1H),9.75(s,1H),8.30(s,1H),8.22(s,1H),7.60-7.52(m,2H),7.43-7.37( m,2H),6.78(s,1H),3.61(s,2H),3.26(s,3H),2.95-2.84(m,2H),2.83-2.72(m,2H),2.62-2.54(m,3H),1.97 -1.83(m,1H),1.68-1.53(m,4H),1.52-1.39(m,1H),1.08(d,J=5.6Hz,3H),0.87-0.75(m,4H).

[0841] Example 84

[0842] 4-Chloro-2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-(((S)-3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one

[0843] Reaction route:

[0844] Steps:

[0845] Step A: Dissolve 7-bromo-5-(trifluoromethyl)isoquinolin-1(2H)-one (500 mg, 1.72 mmol) in N,N-dimethylformamide (5 mL) at room temperature under nitrogen. Add N-chlorosuccinimide (298 mg, 2.24 mmol) to the solution. Stir the reaction at 20°C for 16 hours.

[0846] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was directly purified using a C18 reverse phase column to obtain 224 mg of 7-bromo-4-chloro-5-(trifluoromethyl)isoquinolin-1(2H)-one.

[0847] MS (ESI) M / Z: 325.1 [M+H] + .

[0848] Step B: 7-Bromo-4-chloro-5-(trifluoromethyl)isoquinolin-1(2H)-one (224 mg, 0.72 mmol) was dissolved in N,N-dimethylformamide (3.6 mL) at room temperature under nitrogen. Oxalic acid (92 mg, 1.08 mmol), acetic anhydride (110 mg, 1.08 mmol), N,N-diisopropylethylamine, palladium acetate (16 mg, 0.07 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (84 mg, 0.14 mmol) were then added to the solution. The reaction mixture was stirred at 100°C for 2 hours.

[0849] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3 times), and the organic phases were combined and washed with saturated brine (30 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 110 mg of 4-chloro-1-oxo-5-(trifluoromethyl)-1,2-dihydroisoquinoline-7-carboxylic acid.

[0850] MS (ESI) M / Z: 292.0 [M+H] + .

[0851] Step C: Dissolve 4-chloro-1-oxo-5-(trifluoromethyl)-1,2-dihydroisoquinoline-7-carboxylic acid (100 mg, 0.39 mmol) in tetrahydrofuran (2 mL) at room temperature under nitrogen. Add 1 M borane solution in tetrahydrofuran (2.4 mL, 2.34 mmol). Stir the reaction at 50°C for 1 hour.

[0852] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (25 mL). The mixture was extracted with ethyl acetate (20 mL x 3 times), and the organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 75 mg of 4-chloro-7-(hydroxymethyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one.

[0853] MS (ESI) M / Z: 278.1 [M+H] + .

[0854] Step D: Dissolve 4-chloro-7-(hydroxymethyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one (75 mg, 0.31 mmol) in dichloromethane (1.6 mL) at 0°C. Then, slowly add thionyl chloride (0.22 mL) dropwise to the solution. The reaction mixture is stirred at 50°C for 2 hours.

[0855] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure to obtain 80 mg of 4-chloro-7-(chloromethyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one.

[0856] MS(ESI)M / Z:N / A[M+H] + .

[0857] Step E: Dissolve (S)-3-methylpiperidine hydrochloride (55 mg, 0.40 mmol) in acetonitrile (1.6 mL) at room temperature. Add potassium iodide (67 mg, 0.40 mmol) and potassium carbonate (127 mg, 0.92 mmol) sequentially to the solution and stir for 0.5 hour. Then, add 4-chloro-7-(chloromethyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one (80 mg, 0.31 mmol) and continue stirring for 16 hours.

[0858] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (25 mL). The mixture was extracted with ethyl acetate (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (25 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 40 mg of (S)-4-chloro-7-((3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one.

[0859] MS (ESI) M / Z: 359.1 [M+H] + .

[0860] Step F: (S)-4-chloro-7-((3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one (40 mg, 0.12 mmol), 4-methyl-3-((1s,3s)-3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-1,2,4-triazole (40 mg, 0.12 mmol), copper acetate (100 mg, 0.551 mmol), and pyridine (87 mg, 1.11 mmol) were dissolved in dimethyl sulfoxide (0.8 mL) at room temperature under nitrogen. The reaction system was then stirred at 80°C for 2 hours.

[0861] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (25 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative HPLC to yield 7.11 mg of 4-chloro-2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-(((S)-3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one.

[0862] MS (ESI) M / Z: 584.5 [M+H] + .

[0863] 1 H NMR(400MHz,DMSO-d6)δ8.63–8.56(m,1H),8.30(s,1H),8.28–8.23(m,1H),7.97(s,1H) ),7.64–7.58(m,1H),7.57–7.48(m,1H),7.46–7.39(m,1H),7.37–7.30(m,1H),3.67(s, 2H),3.23(s,3H),2.92–2.83(m,2H),2.75–2.67(m,2H),2.57–2.51(m,3H),2.01–1.89( m,1H),1.71–1.55(m,4H),1.54–1.39(m,1H),1.07(d,J=5.1Hz,3H),0.92–0.77(m,4H).

[0864] Example 85

[0865] 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1s,3S)-3-ethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-3H,4H,5H-imidazo[4,5-c]pyridin-4-one

[0866] Reaction route:

[0867] Steps:

[0868] Step A: Dissolve 2-chloropyridine-3,4-diamine (1.43 g, 9.96 mmol) in 1,4-dioxane (20 mL) at room temperature. Add 1,1,1-trimethoxy-2-chloroethane (3.08 g, 19.92 mmol) and toluene-4-sulfonic acid (0.86 g, 4.98 mmol). Stir the reaction at 120°C for 3 hours.

[0869] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was diluted with dichloromethane and methanol (10:1) (70 mL × 100 mL). The mixture was then washed with water (10 mL × 3 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 0.8 g of 4-chloro-2-(chloromethyl)-3H-imidazo[4,5-c]pyridine.

[0870] MS (ESI) M / Z: 202.1 [M+H] +.

[0871] Step B: Dissolve 4-chloro-2-(chloromethyl)-3H-imidazo[4,5-c]pyridine (500 mg, 2.47 mmol) in acetonitrile (7 mL) at room temperature. Then, add (S)-3-methylpiperidine hydrochloride (0.34 g, 2.47 mmol), potassium carbonate (1.02 g, 7.41 mmol), and potassium iodide (0.082 g, 0.49 mmol) sequentially to the solution. The reaction mixture is stirred for 16 hours.

[0872] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (2 mL). The mixture was extracted with a 10:1 ratio of dichloromethane and methanol (4 mL x 3 times). The organic phases were combined and washed with saturated brine (2 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC to yield 400 mg of (3S)-1-[(4-chloro-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-methylpiperidine.

[0873] MS (ESI) M / Z: 265.2 [M+H] + .

[0874] Step C: Dissolve (3S)-1-[(4-chloro-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-methylpiperidine (350 mg, 1.32 mmol) in N,N-dimethylformamide (5 mL) at 0°C. Then, potassium carbonate (0.55 g, 3.96 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.33 g, 1.98 mmol) were added dropwise to the solution. The reaction was stirred at 25°C for 2 hours.

[0875] After LCMS monitoring showed the disappearance of the starting material, ice water (2 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with a 10:1 ratio of dichloromethane and methanol (5 mL × 2 times). The organic phases were combined and washed with saturated brine (2 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 300 mg of (3S)-1-[(4-chloro-3-[(2-(trimethylsilyl)ethoxy)methyl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-methylpiperidine.

[0876] MS (ESI) M / Z: 395.2 [M+H] + .

[0877] Step D: Compound (3S)-1-[(4-chloro-3-[(2-(trimethylsilyl)ethoxy)methyl]-3Himidazo[4,5-c]pyridin-2-yl)methyl]-3-methylpiperidine (270 mg, 0.68 mmol) was dissolved in a mixed solution of 1,4-dioxane (3 mL) and water (3 mL) at room temperature under nitrogen. Subsequently, potassium hydroxide (0.38 g, 6.80 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.12 g, 0.14 mmol), and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (0.097 g, 0.20 mmol) were added to the above solution in sequence. The reaction system was then stirred at 80°C for 2 hours.

[0878] After LCMS monitoring showed the disappearance of the starting material, water (2 mL) and a mixture of dichloromethane and methanol (10:1) (4 mL) were added to the reaction mixture. The mixture was extracted with dichloromethane and methanol (10:1) (4 mL x 3 times), and the organic phases were combined and washed with saturated brine (2 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 180 mg of 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-3-[(2-(trimethylsilyl)ethoxy)methyl]-3H-imidazo[4,5-c]pyridin-4-ol.

[0879] MS (ESI) M / Z: 377.3 [M+H] + .

[0880] Step E: 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-3-[(2-(trimethylsilyl)ethoxy)methyl]-3H-imidazo[4,5-c]pyridin-4-ol (60 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (0.6 mL) at room temperature under nitrogen. 4-Methyl-3-[(1S,3S)-1-(3-bromophenyl)-3-methylcyclobutyl]-4H-1,2,4-triazole (0.049 g, 0.16 mmol), potassium carbonate (0.066 g, 0.48 mmol), cuprous iodide (0.030 g, 0.16 mmol), and N,N'-dimethylethylenediamine (0.017 g, 0.19 mmol) were then added to the solution. The reaction mixture was stirred at 150°C for 3 hours.

[0881] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (2 mL). The mixture was extracted with a 10:1 ratio of dichloromethane and methanol (5 mL x 3 times). The organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 18 mg of 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-3-[(2-(trimethylsilyl)ethoxy)methyl]-3H,4H,5H-imidazo[4,5-c]pyridin-4-one.

[0882] MS (ESI) M / Z: 602.3 [M+H] +.

[0883] Step F: 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-3-[(2-(trimethylsilyl)ethoxy)methyl]-3H,4H,5H-imidazo[4,5-c]pyridin-4-one (16 mg, 0.027 mmol) was dissolved in dichloromethane (0.6 mL) at room temperature. Trifluoroacetic acid (2.49 g, 21.81 mmol) was then added dropwise to the solution. The reaction was stirred for 2 hours.

[0884] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated aqueous sodium chloride (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to yield 3 mg of 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1S,3S)-3-ethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-3H,4H,5H-imidazo[4,5-c]pyridin-4-one.

[0885] MS (ESI) M / Z: 472.3 [M+H] +.

[0886] 1 H NMR(400MHz,DMSO-d6)δ12.63(s,1H),8.29(s,1H),7.55–7.46(m,1H),7. 43–7.33(m,3H),7.33–7.27(m,1H),6.59(s,1H),3.71–3.57(m,2H),3.24( s,3H),2.93–2.82(m,2H),2.81–2.72(m,2H),2.58–2.52(m,3H),2.02–1.9 2(m,1H),1.72–1.40(m,5H),1.07(d,J=4.8Hz,3H),0.82(d,J=6.1Hz,4H).

[0887] Example 86

[0888] 4-Chloro-6-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((R)-1-((1-methylcyclobutyl)amino)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0889] 4-Chloro-6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((S)-1-((1-methylcyclobutyl)amino)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0890] Reaction route:

[0891] Steps:

[0892] Step A: Dissolve ethyl 4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (2.41 g, 6.16 mmol) in tetrahydrofuran (40 mL) at -78°C under nitrogen. Add 2M lithium aluminum hydride in tetrahydrofuran (1.23 mL, 2.46 mmol) dropwise to the solution. Stir the reaction at zero temperature for 0.5 hours.

[0893] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of saturated ammonium chloride (40 mL). The mixture was extracted with ethyl acetate (15 mL x 2). The organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.7 g of (4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol.

[0894] MS (ESI) M / Z: 347.1 [M+H] + .

[0895] Step B: Dissolve (4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (1.7 g, 4.89 mmol) in dichloromethane (30 mL) at room temperature under nitrogen. Dess-Martin periodinane (4.15 g, 9.78 mmol) was then added dropwise to the solution. The reaction was stirred for 3 hours.

[0896] After LCMS monitoring indicated the disappearance of the starting material, ethyl acetate (200 mL) was added to the reaction solution, and the mixture was washed sequentially with saturated sodium thiosulfate solution (20 mL), aqueous sodium carbonate solution (20 mL), and brine (20 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.8 g of 4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde.

[0897] MS (ESI) M / Z: 344.6 [M+H] + .

[0898] Step C: Dissolve 4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde (1.7 g, 4.92 mmol) in tetrahydrofuran (30 mL) at 0°C. Methylmagnesium bromide solution (7.87 mL, 7.87 mmol, 1 M) was then added dropwise to the solution. The reaction was stirred at 25°C for 2 hours.

[0899] After LCMS monitoring showed the disappearance of the starting material, ice water (50 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined and washed with saturated brine (50 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.9 g of 1-(4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)ethan-1-ol.

[0900] MS (ESI) M / Z: 360.6 [M+H] + .

[0901] Step D: Dissolve 1-(4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)ethan-1-ol (0.3 g, 0.83 mmol) in dichloromethane at room temperature. Then, add thionyl chloride (0.15 g, 1.24 mmol). The reaction mixture is stirred at 25°C for 1 hour.

[0902] After LCMS monitoring showed the disappearance of the starting material, dichloromethane (10 mL) was added to the reaction solution for dilution, and the mixture was washed with water (10 mL x 3). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This yielded 500 mg of crude 4,7-dichloro-2-(1-chloroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

[0903] MS(ESI)M / Z:N / A[M+H] + .

[0904] Step E: Dissolve crude 4,7-dichloro-2-(1-chloroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (400 mg, 1.05 mmol) in acetonitrile (8 mL) at room temperature. 1-Methylcyclobutane-1-amine hydrochloride (320 mg, 2.63 mmol), potassium iodide (79 mg, 0.53 mmol), and potassium carbonate (580 mg, 4.2 mmol) were added to the solution in that order. The reaction was stirred for 16 hours. Additional 1-Methylcyclobutane-1-amine hydrochloride (320 mg, 2.63 mmol), potassium iodide (79 mg, 0.53 mmol), and potassium carbonate (580 mg, 4.2 mmol) were added to the reaction mixture.

[0905] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (8 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 240 mg of N-(1-(4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)ethyl)-1-methylcyclobutane-1-amine.

[0906] MS (ESI) M / Z: 428.2 [M+H] + .

[0907] Step F: At room temperature, under nitrogen, dissolve N-(1-(4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)ethyl)-1-methylcyclobutane-1-amine (200 mg, 0.47 mmol) in a mixture of 1,4-dioxane (2 mL) and water (2 mL). Tris(dibenzylideneacetone)dipalladium (0.086 g, 0.094 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.045 g, 0.094 mmol), and potassium hydroxide (0.13 g, 2.35 mmol) were added sequentially to the solution. The reaction system was then stirred at 80°C for 2 hours.

[0908] After LCMS monitoring showed the disappearance of the starting material, a mixture of water (4 mL) and ethyl acetate (4 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (4 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 3.5 g of 4-chloro-2-(1-((1-methylcyclobutyl)amino)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0909] MS (ESI) M / Z: 410.2 [M+H] + .

[0910] Step G: 4-chloro-2-(1-((1-methylcyclobutyl)amino)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (98 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature under nitrogen. 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (74 mg, 0.24 mmol), cuprous iodide (46 mg, 0.24 mmol), N,N'-dimethylethylenediamine (21 mg, 0.24 mmol), and potassium carbonate (100 mg, 0.72 mmol) were then added to the solution. The reaction was stirred at 150°C for 3 hours.

[0911] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (2 mL). The mixture was extracted with a 10:1 ratio of dichloromethane and methanol (5 mL x 3 times). The organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 40 mg of 4-chloro-6-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(1-((1-methylcyclobutyl)amino)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0912] MS (ESI) M / Z: 635.3 [M+H] + .

[0913] Step H: 4-chloro-6-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(1-((1-methylcyclobutyl)amino)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one) (40 mg, 0.054 mmol) was dissolved in dichloromethane (0.8 mL) at room temperature. Trifluoroacetic acid (0.8 mL) was then added dropwise to the solution. The reaction was stirred for 2 hours.

[0914] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated sodium chloride solution (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to yield 30 mg of 4-chloro-6-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(1-((1-methylcyclobutyl)amino)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0915] The product was separated by chiral separation (chromatographic column: Daicel IC-3; mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 50 / 50, flow rate: 3 mL / min) to give 4.61 mg of compound 86-P1 (retention time: 3.614 min) and 5.42 mg of compound 86-P2 (retention time: 4.014 min).

[0916] Compound 86-P1:

[0917] MS (ESI) M / Z: 505.3 [M+H] + .

[0918] 1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.28(s,1H),7.52–7.45(m,2H),7.4 1(s,1H),7.36–7.28(m,2H),6.30(s,1H),4.07–3.99(m,1H),3.24(s,3H),2 .92–2.84(m,2H),2.58–2.51(m,4H),1.84–1.77(m,1H),1.74–1.61(m,2H) ,1.59–1.45(m,2H),1.40–1.27(m,4H),1.17(s,3H),1.07(d,J=4.9Hz,3H).

[0919] Compound 86-P2:

[0920] MS (ESI) M / Z: 505.3 [M+H] + .

[0921] 1 H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.28(s,1H),7.53–7.44(m,2H),7.40(s, 1H),7.35–7.28(m,2H),6.29(s,1H),4.10–3.96(m,1H),3.24(s,3H),2.94–2.81 (m,2H),2.55–2.51(m,3H),2.37–2.31(m,1H),1.85–1.76(m,1H),1.72–1.61(m ,2H),1.58–1.46(m,2H),1.38–1.27(m,4H),1.17(s,3H),1.07(d,J=5.1Hz,3H).

[0922] Example 87

[0923] 4-Chloro-6-(3-(((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((S)-1-((S)-3-methylpiperidin-1-yl)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0924] 4-Chloro-6-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((R)-1-((S)-3-methylpiperidin-1-yl)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0925] Reaction route:

[0926] Steps:

[0927] Step A: Dissolve crude 4,7-dichloro-2-(1-chloroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (400 mg, 1.05 mmol) in acetonitrile (8 mL) at room temperature. Then, add (S)-3-methylpiperidine hydrochloride (283 mg, 2.11 mmol), potassium iodide (79 mg, 0.53 mmol), and potassium carbonate (434 mg, 3.15 mmol) sequentially to the solution. The reaction mixture is stirred for 16 hours.

[0928] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (8 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC to yield 240 mg of 4,7-dichloro-2-(1-((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

[0929] MS (ESI) M / Z: 442.2 [M+H] + .

[0930] Step B: 4,7-dichloro-2-(1-((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.47 mmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (2 mL) at room temperature under nitrogen. Tris(dibenzylideneacetone)dipalladium (0.086 g, 0.094 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.045 g, 0.094 mmol), and potassium hydroxide (0.13 g, 2.35 mmol) were then added to the solution. The reaction system was stirred at 80°C for 2 hours.

[0931] After LCMS monitoring showed the disappearance of the starting material, a mixture of water (4 mL) and ethyl acetate (4 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (4 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 102 mg of 4-chloro-2-(1-(((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7-ol.

[0932] MS (ESI) M / Z: 424.2 [M+H] + .

[0933] Step C: 4-chloro-2-(1-(((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7-ol (102 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature under nitrogen. 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (74 mg, 0.24 mmol), cuprous iodide (46 mg, 0.24 mmol), N,N'-dimethylethylenediamine (21 mg, 0.24 mmol), and potassium carbonate (100 mg, 0.72 mmol) were added to the solution in sequence. The reaction system was then stirred at 150°C for 3 hours.

[0934] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (2 mL). The mixture was extracted with a 10:1 ratio of dichloromethane and methanol (5 mL x 3 times). The organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 45 mg of 4-chloro-6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(1-((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0935] MS (ESI) M / Z: 649.3 [M+H] + .

[0936] Step D: 4-chloro-6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(1-((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (45 mg, 0.054 mmol) was dissolved in dichloromethane (0.8 mL) at room temperature. Trifluoroacetic acid (0.8 mL) was then added dropwise to the solution. The reaction was stirred for 2 hours.

[0937] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8. The mixture was extracted with ethyl acetate (30 mL x 3 times), and the organic phases were combined and washed with saturated aqueous sodium chloride solution (30 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to yield 32 mg of the racemic compound.

[0938] The obtained product was subjected to chiral separation (chromatographic column: Daicel AD-3; mobile phase: CO2 / IPA [1% NH3 (7M in MeOH)] = 60 / 40) to give 7.42 mg of compound 87-P1 (retention time: 0.742 min) and 5.33 mg of compound 87-P2 (retention time: 0.927 min).

[0939] Compound 87-P1

[0940] MS (ESI) M / Z: 519.2 [M+H] + .

[0941] 1 H NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.28(s,1H),7.53–7.45(m,2H),7.43(s,1H),7. 35–7.28(m,2H),6.23(s,1H),3.89–3.81(m,1H),3.24(s,3H),2.93–2.79(m,3H),2.78– 2.71(m,1H),2.58–2.52(m,3H),1.82–1.74(m,1H),1.64–1.51(m,4H),1.42–1.36(m,3 H),1.27–1.20(m,1H),1.07(d,J=5.0Hz,3H),0.79(d,J=5.2Hz,3H),0.76–0.66(m,1H).

[0942] Compound 87-P2

[0943] MS (ESI) M / Z: 519.2 [M+H] + .

[0944] 1 H NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.28(s,1H),7.53–7.46(m,2H),7.43(s,1H) ),7.36–7.29(m,2H),6.23(s,1H),3.87–3.81(m,1H),3.24(s,3H),2.89–2.75(m,4 H),2.56–2.53(m,3H),1.88–1.80(m,1H),1.64–1.51(m,3H),1.51–1.43(m,2H),1 .42–1.36(m,3H),1.07(d,J=4.8Hz,3H),0.81(d,J=6.1Hz,3H),0.77–0.69(m,1H).

[0945] Example 91

[0946] 2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one

[0947] Reaction route:

[0948] Steps:

[0949] Step A: Dissolve 2-bromo-3-(trifluoromethyl)benzoic acid (2.0 g, 7.43 mmol) in N,N-dimethylformamide (20 mL) at room temperature under nitrogen. Then, add N-(4-methoxybenzyl)cyclopropylamine (1.58 g, 8.92 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.39 g, 8.92 mmol), and N,N-diisopropylethylamine (2.88 g, 22.29 mmol) to the solution. Stir at room temperature for 16 hours.

[0950] After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (70 mL × 3 times). The organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 2.2 g of 2-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-3-(trifluoromethyl)benzamide.

[0951] MS (ESI) M / Z: 428.0 [M+H] + .

[0952] Step B: 2-Bromo-N-cyclopropyl-N-(4-methoxybenzyl)-3-(trifluoromethyl)benzamide (2.2 g, 5.14 mmol) was dissolved in 1,3,5-trimethylbenzene (40 mL) at room temperature under nitrogen. Tris(dibenzylideneacetone)dipalladium (0.47 g, 0.51 mmol), pivalic acid (0.79 g, 7.71 mmol), and cesium carbonate (5.02 g, 15.42 mmol) were then added to the solution. The reaction mixture was stirred at 118°C for 16 hours.

[0953] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was directly concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 7.5 g of 2-(4-methoxybenzyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

[0954] MS (ESI) M / Z: 348.4 [M+H] + .

[0955] Step C: At room temperature, under nitrogen protection, dissolve the compound 2-(4-methoxybenzyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one (6.30 g, 20.06 mmol) in trifluoroacetic acid (20 mL), raise the temperature to 60°C, and continue stirring for 16 hours.

[0956] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was partially evaporated to remove the solvent and poured into water (40 mL) for quenching. The mixture was adjusted to pH 9 with saturated aqueous sodium carbonate solution and extracted with a 10:1 ratio of dichloromethane and methanol (30 mL x 3 times). The organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1 g of 7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

[0957] MS (ESI) M / Z: 227.6 [M+H] + .

[0958] Step D: Dissolve 7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one (1 g, 4.44 mmol) in concentrated sulfuric acid (10 mL) at room temperature under nitrogen. Then, add N-bromosuccinimide (1.03 g, 5.81 mmol) to the solution and stir at room temperature for 16 hours.

[0959] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into vigorously stirred ice water (30 mL) to quench the mixture and adjusted to pH 9 with saturated aqueous sodium carbonate. This gave a white suspension, which was filtered and dissolved in methanol. The resulting solid was purified using a C18 reverse-phase column to yield 0.81 g of 5-bromo-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

[0960] Step E: 5-Bromo-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one (400 mg, 1.31 mmol) was dissolved in N,N-dimethylformamide (10 mL) at room temperature under nitrogen. Oxalic acid (0.18 mL, 1.97 mmol), acetic anhydride (0.18 mL, 1.97 mmol, 30%), N,N-diisopropylethylamine (0.65 mL, 3.93 mmol), palladium acetate (29 mg, 0.13 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (150 mg, 0.26 mmol) were then added to the solution. The reaction mixture was stirred at 100°C for 5 hours.

[0961] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was directly purified using a C18 reverse phase column to obtain 0.2 g of 3-oxo-7-(trifluoromethyl)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c]isoquinoline-5-carboxylic acid.

[0962] MS (ESI) M / Z: 272.1 [M+H] + .

[0963] Step F: Dissolve 3-oxo-7-(trifluoromethyl)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c]isoquinoline-5-carboxylic acid (0.2 g, 0.74 mmol) in tetrahydrofuran (5 mL) at 0°C. Borane solution in tetrahydrofuran (2.96 mL, 2.96 mmol) was then added dropwise to the solution. The reaction was stirred at 60°C for 16 hours.

[0964] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to 0°C, and methanol (1 mL) and 1 M hydrochloric acid (3 mL) were added dropwise. The resulting mixed solution was stirred for 0.5 hours and then directly dried by spin-drying. The resulting residue was purified by silica gel column chromatography to obtain 0.15 g of 5-(hydroxymethyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

[0965] MS (ESI) M / Z: 258.1 [M+H] + .

[0966] Step G: At 0°C under nitrogen, 5-(hydroxymethyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one (150 mg, 0.58 mmol) was dissolved in dichloromethane (3 mL). Supplementary information follows: thionyl chloride (690 mg, 5.8 mmol) was added to the solution. The resulting reaction solution was directly dried, and the crude product was directly dissolved in acetonitrile (4 mL). Potassium iodide (22 mg, 0.15 mmol), sodium carbonate (230 mg, 2.19 mmol), and (S)-3-methylpiperidine hydrochloride (150 mg, 1.09 mmol) were added to the solution in sequence. The reaction system was then stirred at room temperature for 5 hours.

[0967] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (4 mL). The mixture was extracted with a 10:1 ratio of dichloromethane and methanol (15 mL x 3 times). The organic phases were combined and washed with saturated brine (5 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 100 mg of 5-(((S)-3-methylpiperidin-1-yl)methyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

[0968] MS (ESI) M / Z: 339.2 [M+H] + .

[0969] Step H: 5-(((S)-3-methylpiperidin-1-yl)methyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one (50 mg, 0.15 mmol) was dissolved in 1,4-dioxane (2 mL) at room temperature under nitrogen. Cesium carbonate (150 mg, 0.45 mmol), 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (46 mg, 0.15 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (17 mg, 0.03 mmol), and tris(dibenzylideneacetone)dipalladium (14 mg, 0.015 mmol) were then added to the solution. The reaction mixture was stirred at 120°C for 6 hours.

[0970] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched by adding water (2 mL). The mixture was extracted with a 10:1 ratio of dichloromethane and methanol (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (5 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to yield 6 mg of 2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

[0971] MS (ESI) M / Z: 564.6 [M+H] + .

[0972] 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),8.15(s,1H),7.87–7.82(m,1H),7.59–7.53(m,1H),7.52–7.42( m,2H),7.30–7.23(m,1H),3.62–3.55(m,1H),3.57–3.51(m,2H),3.23(s,3H),2.90–2.79(m,2H),2.73 –2.65(m,2H),2.61–2.52(m,4H),1.95–1.84(m,1H),1.69–1.54(m,5H),1.5 1–1.40(m,1H),1.08(d,J=5.3Hz,3H),0.91–0.78(m,4H),0.80–0.73(m,1H).

[0973] Example 92

[0974] 4-Chloro-6-(6-((3,3-difluorocyclobutyl)amino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0975] Reaction route:

[0976] Steps:

[0977] Step A: Dissolve 2,6-dichloro-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (90 mg, 0.30 mmol) in dimethyl sulfoxide (1.6 mL) at room temperature under nitrogen. Then, add 3,3-difluorocyclobutane-1-amine (325 mg, 3.04 mmol). The reaction mixture is stirred at 138°C for 18 hours.

[0978] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with ice water (20 mL). The mixture was extracted with dichloromethane (20 mL x 3 times), and the organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 90 mg of 6-chloro-N-(3,3-difluorocyclobutyl)-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine.

[0979] MS (ESI) M / Z: 368.2 [M+H] + .

[0980] Step B: At room temperature, under nitrogen protection, compound 6-chloro-N-(3,3-difluorocyclobutyl)-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine (90 mg, 0.25 mmol), (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (72 mg, 0.18 mmol), N,N'-dimethylethylenediamine (16 mg, 0.18 mmol), cuprous iodide (34 mg, 0.18 mmol) and potassium carbonate (50 mg, 0.36 mmol) were dissolved in N-methylpyrrolidone (0.9 mL). The reaction system was then stirred at 180°C for 8 hours.

[0981] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 20 mg of 4-chloro-6-(6-((3,3-difluorocyclobutyl)amino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0982] MS (ESI) M / Z: 741.2 [M+H] + .

[0983] Step C: 4-chloro-6-(6-((3,3-difluorocyclobutyl)amino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (20 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL) at room temperature. Trifluoroacetic acid (0.5 mL) was then added to the solution and stirred for 2 hours.

[0984] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8, and then stirring was continued for 30 minutes. Subsequently, water (15 mL) was added to the above solution to quench the mixture, and the mixture was extracted with ethyl acetate (15 mL × 3 times). The organic phases were combined and washed with saturated brine (25 mL × 2 times). Then, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The resulting crude product was purified by preparative high performance liquid chromatography to give 7 mg of 4-chloro-6-(6-((3,3-difluorocyclobutyl)amino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[0985] MS (ESI) M / Z: 611.3 [M+H] + .

[0986] 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),8.34(s,1H),7.63(s,1H),7.38(d,J=6.0Hz,1H),6.97(s,1H),6. 34(s,1H),6.25(s,1H),4.15-4.02(m,1H),3.59(s,2H),3.28(s,3H),3.02-2.88(m,2H),2.87-2.67(m, 4H),2.63-2.51(m,5H),1.96-1.82(m,1H),1.68-1.52(m,4H),1.51-1.37(m,1H),1.07(d,J=5.6Hz,3H),0.88-0.73(m,4H).

[0987] Example 93

[0988] 4-Chloro-6-(3-(ethylamino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

[0989] Reaction route:

[0990] Steps:

[0991] Step A: At room temperature, under nitrogen protection, compound 6-(3-bromo-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (40 mg, 0.056 mmol), tert-aminocarbamic acid Butyl ester (33 mg, 0.280 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5 mg, 0.011 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (10 mg, 0.011 mmol), and cesium carbonate (36 mg, 0.112 mmol) were dissolved in 1,4-dioxane (0.4 mL). The reaction was then stirred at 110°C for 2 hours.

[0992] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 25 mg of tert-butyl (3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamate.

[0993] MS (ESI) M / Z: 750.4 [M+H] + .

[0994] Step B: Tert-butyl (3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamate (25 mg, 0.033 mmol) was dissolved in N,N-dimethylformamide (0.5 mL) at 0°C under nitrogen. 60% wt sodium hydride (1.5 mg, 0.036 mmol) and iodoethane (6 mg, 0.040 mmol) were then added to the solution. The reaction was stirred at room temperature for 2 hours.

[0995] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 12 mg of tert-butyl (3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)(ethyl)carbamate.

[0996] MS (ESI) M / Z: 778.4 [M+H] + .

[0997] Step C: Dissolve tert-butyl (3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)(ethyl)carbamate (12 mg, 0.018 mmol) in dichloromethane (0.5 mL) at 0°C. Trifluoroacetic acid (0.2 mL) was then added to the solution, and the mixture was stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added to the reaction mixture until alkaline, and stirring was continued for 1 hour.

[0998] After LCMS monitoring showed the disappearance of the intermediate, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 3), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 0.72 mg of 4-chloro-6-(3-(ethylamino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

[0999] MS (ESI) M / Z: 548.2 [M+H] + .

[1000] 1 H NMR (400MHz, DMSO-d6) δ12.71(s,1H),9.70(s,1H),8.50(s,1H),7.46(s,1H),6.66(d,J= 2.0Hz,1H),6.56(s,1H),6.50(s,1H),6.43(s,1H),4.38(s,2H),3.44-3.39(m,1H),3.37 -3.27(m,4H),3.01(q,J=7.0Hz,2H),2.86-2.73(m,3H),2.62-2.51(m,4H),1.91-1.75(m ,2H),1.74-1.60(m,2H),1.13(t,J=7.2Hz,3H),1.09-0.99(m,4H),0.89(d,J=6.8Hz,3H).

[1001] Example 95

[1002] (S)-4-Chloro-6-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1003] Reaction route:

[1004] Steps:

[1005] Step A: Dissolve 2-(3-bromophenyl)acetonitrile (5 g, 25.6 mmol) in tetrahydrofuran (64 mL) at -78°C under nitrogen. Add 2.7 M methyllithium (9.5 mL) dropwise to the solution and stir for 1 hour. Then, add 2-(chloromethyl)oxirane (2.37 g, 25.6 mmol) dropwise and continue stirring for 1 hour. Then, add 3 M methylmagnesium bromide in tetrahydrofuran (28 mL) dropwise, warm to room temperature, and stir for 2 hours.

[1006] After LCMS monitoring showed the disappearance of the starting material, ice water (40 mL) was added to the reaction solution to quench the reaction. Subsequently, the pH was adjusted to 6 with 1M dilute hydrochloric acid, and the mixture was extracted with dichloromethane (30 mL × 2 times). The organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 6.0 g of 1-(3-bromophenyl)-3-hydroxycyclobutane-1-carbonitrile.

[1007] Step B: Dissolve 1-(3-bromophenyl)-3-hydroxycyclobutane-1-carbonitrile (5.7 g, 22.7 mmol) in ethyl acetate (174 mL) at room temperature under nitrogen. Add 2-iodoacylbenzoic acid (19 g, 68.1 mmol) to the solution. Stir the reaction at 80°C for 5 hours.

[1008] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.6 g of 1-(3-bromophenyl)-3-oxocyclobutane-1-carbonitrile.

[1009] MS (ESI) M / Z: 267.3 [M+18] + .

[1010] Step C: Dissolve 1-(3-bromophenyl)-3-oxocyclobutane-1-carbonitrile (3.6 g, 14.5 mmol) in dichloromethane (73 mL) at room temperature under nitrogen. Add diethylaminosulfur trifluoride (11.7 g, 72.3 mmol) dropwise to the solution. Stir the reaction at room temperature for 16 hours.

[1011] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (20 mL). The mixture was extracted with dichloromethane (8 mL x 2). The organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.3 g of 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonitrile.

[1012] Step D: Dissolve 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonitrile (1.3 g, 5 mmol) in ethanol (6.3 mL) and water (6.3 mL) at room temperature. Add sodium hydroxide (602 mg, 15 mmol) to the solution. Stir the reaction at 80°C for 16 hours.

[1013] After LCMS monitoring showed the disappearance of the starting material, the pH was adjusted to 3 with 1M dilute hydrochloric acid, and the mixture was extracted with dichloromethane (8 mL × 2 times). The organic phases were combined and washed with saturated brine (10 mL × 2 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 421 mg of 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carboxylic acid.

[1014] Step E: Dissolve 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carboxylic acid (421 mg, 1.5 mmol) in N,N-dimethylformamide (7.3 mL) at room temperature. Then, add N-methylhydrazine methylsulfamide (183 mg, 1.7 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (606 mg, 1.6 mmol), and N,N-diisopropylethylamine (561 mg, 4.4 mmol) to the solution. The reaction mixture is stirred at room temperature for 10 minutes.

[1015] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (20 mL). The mixture was extracted with dichloromethane (8 mL × 2 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 417 mg of 2-(1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide was obtained.

[1016] MS (ESI) M / Z: 378.2 [M+H] + .

[1017] Step F: Dissolve 2-(1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide (400 mg, 1.1 mmol) in tetrahydrofuran (3.5 mL) and water (1.8 mL) at room temperature. Then, add sodium hydroxide (127 mg, 3.2 mmol). The reaction mixture is stirred at 90°C for 16 hours.

[1018] After LCMS monitoring showed the disappearance of the starting material, the mixture was adjusted to pH 4 with 1M dilute hydrochloric acid. The mixture was extracted with dichloromethane (8 mL x 2), and the organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 320 mg of 5-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol was obtained.

[1019] MS (ESI) M / Z: 360.1 [M+H] + .

[1020] Step G: 5-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (320 mg, 0.9 mmol) was dissolved in dichloromethane (3 mL) at 0°C. Acetic acid (1.5 mL) and 30% wt aqueous hydrogen peroxide (0.5 mL, 15 mmol) were then added to the solution. The reaction was stirred at room temperature for 1 hour.

[1021] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was extracted with dichloromethane (8 mL x 2). The organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 129 mg of 3-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole.

[1022] MS (ESI) M / Z: 328.2 [M+H] + .

[1023] Step H: 3-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole (129 mg, 0.4 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) at room temperature under nitrogen. (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (125 mg, 0.3 mmol), N,N'-dimethylethylenediamine (33 mg, 0.4 mmol), cuprous iodide (59 mg, 0.3 mmol), and potassium carbonate (85 mg, 0.6 mmol) were then added to the solution. The reaction mixture was stirred at 150°C for 6 hours.

[1024] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (15 mL). The mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 137 mg of (S)-4-chloro-6-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1025] MS (ESI) M / Z: 657.3 [M+H] + .

[1026] Step I: Dissolve (S)-4-chloro-6-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (137 mg, 0.2 mmol) in dichloromethane (1 mL) at room temperature. Trifluoroacetic acid (0.5 mL) was added dropwise to the solution and stirred for 2 hours. The temperature was then lowered to 0°C, and aqueous ammonia (2.0 mL) was slowly added dropwise to adjust the pH to 8. The mixture was allowed to warm to room temperature and stirred for another 2 hours.

[1027] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (15 mL). The mixture was extracted with dichloromethane (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 43.95 mg of (S)-4-chloro-6-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1028] MS (ESI) M / Z: 527.2 [M+H] + .

[1029] 1H NMR (400MHz, DMSO-d6) δ12.37(s,1H),8.40(s,1H),7.52(t,J=7.8Hz,1H),7.49(t ,J=1.8Hz,1H),7.45(s,1H),7.40(d,J=8.0Hz,1H),7.30(d,J=8.8Hz,1H),6.26(s, 1H),3.81-3.66(m,2H),3.59(s,2H),3.55-3.41(m,2H),3.35(s,3H),2.84-2.69(m ,2H),1.97-1.80(m,1H),1.69-1.53(m,4H),1.52-1.38(m,1H),0.88-0.72(m,4H).

[1030] Example 96

[1031] 4-Chloro-6-(6-(ethylamino)-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1032] Reaction route:

[1033] Steps:

[1034] Step A: Dissolve 2,6-dichloro-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (170 mg, 0.57 mmol) in dimethyl sulfoxide (1.5 mL) at room temperature under nitrogen. Ethylamine hydrochloride (935 mg, 11.40 mmol) and N,N-diisopropylethylamine (1.47 g, 11.40 mmol) were then added to the solution. The reaction was stirred at 150°C for 6 hours.

[1035] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with ice water (40 mL). The mixture was extracted with dichloromethane (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 130 mg of 6-chloro-N-ethyl-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine.

[1036] MS (ESI) M / Z: 306.4 [M+H] + .

[1037] Step B: 6-chloro-N-ethyl-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine (95 mg, 0.31 mmol), (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (90 mg, 0.22 mmol), N,N'-dimethylethylenediamine (19 mg, 0.22 mmol), cuprous iodide (42 mg, 0.22 mmol), and potassium carbonate (61 mg, 0.44 mmol) were dissolved in N-methylpyrrolidone (1.2 mL) at room temperature under nitrogen. The reaction system was then stirred at 180°C for 6 hours.

[1038] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 83 mg of 4-chloro-6-(6-(ethylamino)-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1039] MS (ESI) M / Z: 340.4 [M / 2+H] + .

[1040] Step C: 4-chloro-6-(6-(ethylamino)-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (83 mg, 0.12 mmol) was dissolved in dichloromethane (0.6 mL) at room temperature. Trifluoroacetic acid (0.6 mL) was then added dropwise to the solution. The reaction was stirred for 2 hours.

[1041] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction mixture to adjust the pH to 8, and stirring was continued for 2 hours. Subsequently, water (25 mL) was added to the solution to dilute it. The mixture was extracted with ethyl acetate (15 mL x 3 times), and the organic phases were combined and washed with saturated brine (25 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC to yield 21.09 mg of 4-chloro-6-(6-(ethylamino)-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1042] MS (ESI) M / Z: 549.3 [M+H] + .

[1043] 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.40(s,1H),7.61(s,1H),6.83(t,J=5.4Hz,1H),6.74(d,J=1.2H z,1H),6.23(s,1H),6.19(d,J=0.8Hz,1H),3.58(s,2H),3.35(s,3H),3.26-3.16(m,2H),3.11-3.01(m, 2H),2.80-2.69(m,2H),2.39-2.27(m,1H),2.24-2.15(m,2H),1.94-1.83(m,1H ),1.66-1.52(m,4H),1.51-1.39(m,1H),1.13-1.08(m,6H),0.85-0.75(m,4H).

[1044] Example 97

[1045] 4-Chloro-6-(6-(cyclobutylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1046] Reaction route:

[1047] Steps:

[1048] Step A: Dissolve 2,6-dichloro-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (100 mg, 0.3 mmol) in dimethyl sulfoxide (1.7 mL) at room temperature under nitrogen. Then, add cyclobutylamine (240 mg, 3.4 mmol). The reaction mixture is stirred at 140°C for 4 hours.

[1049] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with ice water (15 mL) and then adjusted to pH 6 with 1 M dilute hydrochloric acid. The mixture was extracted with dichloromethane (10 mL x 2), and the organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg of 6-chloro-N-cyclobutyl-4-(1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine.

[1050] MS (ESI) M / Z: 332.3 [M+H] + .

[1051] Step B: 6-chloro-N-cyclobutyl-4-(1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine (100 mg, 0.3 mmol) was dissolved in N-methylpyrrolidone (1.1 mL) at room temperature under nitrogen. (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (88 mg, 0.2 mmol), N,N'-dimethylethylenediamine (19 mg, 0.2 mmol), cuprous iodide (41 mg, 0.2 mmol), and potassium carbonate (60 mg, 0.4 mmol) were then added to the solution. The reaction system was then stirred at 180°C for 3 hours.

[1052] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (15 mL). The mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 48 mg of 4-chloro-6-(6-(cyclobutylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1053] MS (ESI) M / Z: 353.5 [M / 2+H] + .

[1054] Step C: Dissolve 4-chloro-6-(6-(cyclobutylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (48 mg, 0.07 mmol) in dichloromethane (0.4 mL) at room temperature. Trifluoroacetic acid (0.2 mL) was then added dropwise to the solution and stirred for 2 hours. The mixture was then cooled to 0°C and aqueous ammonia (1.0 mL) was slowly added dropwise to adjust the pH to 8. The mixture was then warmed to room temperature and stirred for another 2 hours.

[1055] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was diluted with water (15 mL). The mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 10.69 mg of 4-chloro-6-(6-(cyclobutylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1056] MS (ESI) M / Z: 575.3 [M+H] + .

[1057] 1H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.33(s,1H),7.60(s,1H),7.15(d,J=6.8Hz ,1H),6.86(s,1H),6.29(s,1H),6.24(s,1H),4.27-4.13(m,1H),3.58(s,2H),3.28 (s,3H),2.86-2.69(m,4H),2.62-2.51(m,3H),2.28-2.19(m,2H),1.95-1.80(m,3H ),1.73-1.52(m,6H),1.51-1.39(m,1H),1.07(d,J=5.6Hz,3H),0.87-0.72(m,4H).

[1058] Example 98

[1059] 4-Chloro-6-(6-(cyclopentylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1060] Reaction route:

[1061] Steps:

[1062] Step A: Dissolve 2,6-dichloro-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (100 mg, 0.34 mmol) in dimethyl sulfoxide (1.7 mL) at room temperature under nitrogen. Cyclopentylamine (290 mg, 3.40 mmol) was then added to the solution. The reaction was stirred at 140°C for 16 hours.

[1063] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with ice water (25 mL). The mixture was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 88 mg of 6-chloro-N-cyclopentyl-4-(1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine.

[1064] MS (ESI) M / Z: 346.3 [M+H] + .

[1065] Step B: 6-chloro-N-cyclopentyl-4-(1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine (88 mg, 0.25 mmol), (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (74 mg, 0.18 mmol), N,N'-dimethylethylenediamine (16 mg, 0.18 mmol), cuprous iodide (34 mg, 0.18 mmol), and potassium carbonate (50 mg, 0.36 mmol) were dissolved in N-methylpyrrolidone (1.5 mL) at room temperature under nitrogen. The reaction system was then stirred at 180°C for 8 hours.

[1066] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (25 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 67 mg of 4-chloro-6-(6-(cyclopentylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1067] MS (ESI) M / Z: 719.4 [M+H] + .

[1068] Step C: 4-chloro-6-(6-(cyclopentylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (65 mg, 0.09 mmol) was dissolved in dichloromethane (0.6 mL) at room temperature. Trifluoroacetic acid (0.6 mL) was then added dropwise to the solution. The reaction was stirred at room temperature for 2 hours.

[1069] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction mixture to adjust the pH to 8, and stirring was continued for 2 hours. Subsequently, water (25 mL) was added to the above solution to quench the mixture. The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC to obtain 25.78 mg of 4-chloro-6-(6-(cyclopentylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1070] MS (ESI) M / Z: 589.2 [M+H] + .

[1071] 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.34(s,1H),7.62(s,1H),6.88(d,J=6. 4Hz,1H),6.84(d,J=1.2Hz,1H),6.36(d,J=1.2Hz,1H),6.24(s,1H),4.07-3.9 8(m,1H),3.59(s,2H),3.29(s,3H),2.83-2.69(m,4H),2.61-2.51(m,3H),1.9 4-1.83(m,3H),1.72-1.37(m,12H),1.07(d,J=6.0Hz,3H),0.86-0.72(m,4H).

[1072] Example 99

[1073] 4-Chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(oxetan-3-ylamino)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

[1074] Reaction route:

[1075] Steps:

[1076] Step A: At room temperature, under nitrogen protection, compound 6-(3-bromo-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (60 mg, A mixture of 2-(di-tert-butylphosphino)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1,1'-biphenyl (8 mg, 0.017 mmol), tris(dibenzylideneacetone)dipalladium (15 mg, 0.017 mmol), and potassium tert-butoxide (19 mg, 0.17 mmol) was dissolved in toluene (0.6 mL). The reaction was then stirred at 100°C for 16 hours.

[1077] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 25 mg of 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(oxetan-3-ylamino)phenyl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

[1078] MS (ESI) M / Z: 706.4 [M+H] + .

[1079] Step B: Compound 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(oxetane-3-ylamino)phenyl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (25 mg, 0.035 mmol) was dissolved in dichloromethane (0.5 mL) at room temperature. Subsequently, trifluoroacetic acid (0.2 mL) was added to the above solution and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added to the reaction solution to adjust the pH to 8 and stirring was continued for 1 hour.

[1080] After LCMS monitoring showed the disappearance of the intermediate, the reaction mixture was diluted with water (10 mL), and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 1.02 mg of 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(oxetan-3-ylamino)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

[1081] MS (ESI) M / Z: 576.3 [M+H] + .

[1082] 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),8.28(s,1H),7.34(s,1H),6.70(d,J=6.4Hz,1H),6.64 (s,1H),6.42(s,1H),6.34(s,1H),6.24(s,1H),4.78(t,J=6.4Hz,2H),4.55-4.45(m,1H),4. 38(t,J=6.0Hz,2H),3.58(s,2H),3.25(s,3H),2.86-2.69(m,4H),2.58-2.51(m,3H),1.94-1 .81(m,1H),1.69-1.51(m,4H),1.49-1.38(m,1H),1.06(d,J=5.6Hz,3H),0.89-0.72(m,4H).

[1083] Example 100

[1084] 2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)acetonitrile

[1085] Reaction route:

[1086] Steps:

[1087] Step A: (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (115 mg, 0.28 mmol), 3-bromo-5-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenol (90 mg, 0.28 mmol), N,N'-dimethylethylenediamine (30 mg, 0.33 mmol), cuprous iodide (54 mg, 0.28 mmol), and potassium carbonate (78 mg, 0.56 mmol) were dissolved in dimethyl sulfoxide (1.4 mL) at room temperature under nitrogen. The reaction system was then stirred at 150°C for 4 hours.

[1088] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 60 mg of 4-chloro-6-(3-hydroxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1089] MS (ESI) M / Z: 651.4 [M+H] + .

[1090] Step B: 4-chloro-6-(3-hydroxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (60 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (0.6 mL) at 0°C under nitrogen. 60% wt sodium hydride (11 mg, 0.27 mmol) was added to the solution and stirred for 20 minutes. Bromoacetonitrile (68 mg, 0.30 mmol) was then added, the mixture was warmed to room temperature, and stirring was continued for 2 hours.

[1091] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with saturated aqueous ammonium chloride (3 mL). The mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined and washed with saturated brine (5 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 12 mg of 2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)acetonitrile.

[1092] MS (ESI) M / Z: 690.4 [M+H] + .

[1093] Step C: Compound 2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)acetonitrile (12 mg, 0.02 mmol) was dissolved in dichloromethane (0.5 mL) at room temperature. Trifluoroacetic acid (1 mL) was then added dropwise to the solution and stirring was continued for 2 hours. After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added to the reaction solution to adjust the pH to 8 and stirring was continued for 2 hours.

[1094] After LCMS monitoring showed the disappearance of the intermediate, the reaction mixture was quenched with water (5 mL). The mixture was extracted with dichloromethane (5 mL x 2), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography to yield 2.7 mg of 2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)acetonitrile.

[1095] MS (ESI) M / Z: 560.2 [M+H] + .

[1096] 1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.29(s,1H),7.43(s,1H),7.12(s,1H), 7.11(s,1H),7.00(s,1H),6.26(s,1H),5.22(s,2H),3.59(s,2H),3.26(s,3H), 2.96-2.83(m,2H),2.81-2.70(m,2H),2.61-2.52(m,3H),1.95-1.82(m,1H),1 .68-1.51(m,4H),1.50-1.39(m,1H),1.07(d,J=4.8Hz,3H),0.87-0.71(m,4H).

[1097] Example 101

[1098] 6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

[1099] Reaction route:

[1100] Steps:

[1101] Step A: (S)-2-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (70 mg, 0.16 mmol), 2-chloro-6-cyclopropyl-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (72 mg, 0.24 mmol), cuprous iodide (30 mg, 0.16 mmol), N,N'-dimethylethylenediamine (14 mg, 0.16 mmol), and potassium carbonate (44 mg, 0.32 mmol) were dissolved in N-methylpyrrolidone (0.7 mL) at room temperature under nitrogen. The reaction system was then stirred at 180°C for 5 hours.

[1102] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 50 mg of 6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1103] MS (ESI) M / Z: 710.4 [M+H] + .

[1104] Step B: Compound 6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (50 mg, 0.07 mmol) was dissolved in dichloromethane (1.0 mL) at room temperature. Trifluoroacetic acid (0.5 mL) was then added dropwise to the solution and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added to the reaction solution to adjust the pH to 8 and stirring was continued for 1 hour.

[1105] After LCMS monitoring showed the disappearance of the intermediate, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL x 3), and the organic phases were combined. The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to yield 14.17 mg of 6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

[1106] MS (ESI) M / Z: 580.3 [M+H] + .

[1107] 1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.34(s,1H),7.92(s,1H),7.48(s,1H),7.35(s, 1H),6.27(s,1H),3.60(s,2H),3.28(s,3H),2.95-2.83(m,2H),2.81-2.69(m,2H),2.6 3-2.51(m,3H),2.25-2.16(m,1H),1.95-1.83(m,1H),1.68-1.53(m,4H),1.50-1.38(m ,1H),1.08(d,J=5.2Hz,3H),1.02-0.95(m,2H),0.94-0.89(m,2H),0.86-0.72(m,4H).

[1108] Example 102

[1109] 4-Chloro-6-(3-((1S,3R)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1110] Reaction route:

[1111] Steps:

[1112] Step A: Dissolve (1s,3s)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol (92 mg, 0.3 mmol) in N,N-dimethylformamide (1.5 mL) at 0°C under nitrogen. Slowly add sodium hydride (21.6 mg, 0.5 mmol) to the solution and stir for 20 minutes. Then, add deuterated iodomethane (87 mg, 0.6 mmol), warm to room temperature, and continue stirring for 2 hours.

[1113] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added dropwise to ice water (20 mL) to quench the mixture. The mixture was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 98 mg of 3-((1S,3S)-1-(3-bromophenyl)-3-(methoxy-d3)cyclobutyl)-4-methyl-4H-1,2,4-triazole.

[1114] MS (ESI) M / Z: 325.0 [M+H] + .

[1115] Step B: 3-((1S,3S)-1-(3-bromophenyl)-3-(methoxy-d3)cyclobutyl)-4-methyl-4H-1,2,4-triazole (98 mg, 0.3 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) at room temperature under nitrogen. (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (88 mg, 0.2 mmol), copper iodide (41 mg, 0.2 mmol), dimethylethylenediamine (19 mg, 0.2 mmol), and potassium carbonate (59 mg, 0.4 mmol) were then added to the solution. The reaction mixture was stirred at 150°C for 3 hours.

[1116] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 94 mg of 4-chloro-6-(3-((1S,3R)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1117] MS (ESI) M / Z: 654.4 [M+H] + .

[1118] Step C: 4-chloro-6-(3-((1S,3R)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (94 mg, 0.2 mmol) was dissolved in dichloromethane (0.7 mL) at room temperature. Trifluoroacetic acid (0.7 mL) was then added to the solution. The reaction was stirred for 2 hours.

[1119] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated sodium chloride aqueous solution (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This yielded 16.12 mg of 4-chloro-6-(3-((1S,3R)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1120] MS (ESI) M / Z: 524.3 [M+H] + .

[1121] 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),8.31(s,1H),7.50(t,J=7.8Hz,1H),7. 46-7.42(m,2H),7.38-7.34(m,1H),7.30(d,J=8.4Hz,1H),6.27(s,1H),4.11- 4.01(m,1H),3.60(s,2H),3.27(s,3H),3.12-3.05(m,2H),2.84-2.70(m,4H) ,1.98-1.80(m,1H),1.68-1.53(m,4H),1.52-1.38(m,1H),0.87-0.71(m,4H).

[1122] Example 103

[1123] 4-Chloro-6-(3-((1S,3R)-3-(difluoromethoxy)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1124] Reaction route:

[1125] Steps:

[1126] Step A: Dissolve (1S,3S)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutan-1-ol (307.0 mg, 1.0 mmol) in acetonitrile (5.0 mL) at room temperature under nitrogen. Then, add 2,2-difluoro-2-(fluorosulfonyl)acetic acid (534.0 mg, 3.0 mmol) and cuprous iodide (38.0 mg, 0.2 mmol) sequentially to the solution. The reaction system is then stirred at 45°C for 5 hours.

[1127] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3 times), and the organic phases were combined and washed with saturated brine (10 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 90 mg of 3-((1S,3S)-1-(3-bromophenyl)-3-(difluoromethoxy)cyclobutyl)-4-methyl-4H-1,2,4-triazole.

[1128] MS (ESI) M / Z: 358.0 [M+H] + .

[1129] Step B: (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (83.0 mg, 0.20 mmol) was dissolved in dimethyl sulfoxide (2.0 mL) at room temperature under nitrogen. 3-((1S,3S)-1-(3-bromophenyl)-3-(difluoromethoxy)cyclobutyl)-4-methyl-4H-1,2,4-triazole (87.0 mg, 0.25 mmol), potassium carbonate (55.2 mg, 0.4 mmol), N,N'-dimethylethylenediamine (21.0 mg, 0.24 mmol), and cuprous iodide (38.0 mg, 0.20 mmol) were then added to the solution. The reaction system was then stirred at 180°C for 2 hours.

[1130] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 50 mg of 4-chloro-6-(3-((1S,3R)-3-(difluoromethoxy)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1131] MS (ESI) M / Z: 687.2 [M+H] + .

[1132] Step C: 4-chloro-6-(3-((1S,3R)-3-(difluoromethoxy)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (50.0 mg, 0.07 mmol) was dissolved in dichloromethane (1.0 mL) at 0°C. Trifluoroacetic acid (0.5 mL) was then added dropwise to the solution. The reaction was stirred at room temperature for 2 hours.

[1133] After LCMS monitoring showed the disappearance of the starting material, aqueous ammonia was added dropwise to the reaction mixture to adjust the pH to 8, and stirring was continued for 30 minutes. Subsequently, water (15 mL) was added to dilute the solution, and the mixture was extracted with ethyl acetate (15 mL × 3 times). The organic phases were combined and washed with saturated brine (25 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to yield 18 mg of 4-chloro-6-(3-((1S,3R)-3-(difluoromethoxy)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

[1134] MS (ESI) M / Z: 557.2 [M+H] + .

[1135] 1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.33(s,1H),7.54-7.48(m,2H),7.47(s,1H),7. 38(d,J=8.4Hz,1H),7.31(d,J=8.0Hz,1H),6.67(t,J=75.4Hz,1H),6.27(s,1H),4.86- 4.76(m,1H),3.61(s,2H),3.27(s,3H),3.25-3.18(m,2H),3.07-2.98(m,2H),2.83-2. 72(m,2H),1.99-1.82(m,1H),1.67-1.52(m,4H),1.51-1.38(m,1H),0.88-0.73(m,4H).

[1136] Example 104

[1137] 4-Chloro-6-(3-((1R,3S)-3-(methoxymethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1138] 4-Chloro-6-(3-((1S,3R)-3-(methoxymethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1139] Reaction route:

[1140] Steps:

[1141] Step A: Dissolve (methoxymethyl)triphenylphosphonium chloride (1.4 g, 3.9 mmol) in tetrahydrofuran (6.6 mL) at 0°C under nitrogen. Add sodium hydride (157 mg, 6.5 mmol) and stir for 1 hour. Then, add 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-one (400 mg, 1.3 mmol) and continue stirring for 1 hour.

[1142] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with ice water (10 mL) and adjusted to pH 6 with 1 M dilute hydrochloric acid. The mixture was extracted with dichloromethane (20 mL x 2), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 123 mg of 3-(1-(3-bromophenyl)-3-(methoxymethylene)cyclobutyl)-4-methyl-4H-1,2,4-triazole.

[1143] MS (ESI) M / Z: 334.1 [M+H] + .

[1144] Step B: 3-(1-(3-bromophenyl)-3-(methoxymethylene)cyclobutyl)-4-methyl-4H-1,2,4-triazole (123 mg, 0.4 mol) was dissolved in methanol (0.2 mL) at room temperature under a hydrogen atmosphere. 10% wt palladium on carbon (120 mg) was then added to the solution. The reaction was stirred for 5 minutes.

[1145] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with dichloromethane (8 mL x 2). The organic phases were combined and washed with saturated brine (10 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This yielded 73 mg of 3-(1-(3-bromophenyl)-3-(methoxymethyl)cyclobutyl)-4-methyl-4H-1,2,4-triazole.

[1146] MS (ESI) M / Z: 336.1 [M+H] + .

[1147] Step C: 3-(1-(3-bromophenyl)-3-(methoxymethyl)cyclobutyl)-4-methyl-4H-1,2,4-triazole (73 mg, 0.2 mmol) was dissolved in dimethyl sulfoxide (1.1 mL) at room temperature under nitrogen. (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (85 mg, 0.2 mmol), cuprous iodide (40 mg, 0.2 mmol), N,...

Claims

1. A compound represented by formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, or a hydrate thereof, in, Ring A is selected from 6-10 membered aryl, 5-6 membered heteroaryl; The bond "--" between X1 and X2 represents a single bond or a double bond; X1 is selected from -C(=CH2), CR a1 R a2 , N, NH, CR a3 ; R a1 , R a2 , R a3 Each independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkylamino, nitro, substituted or unsubstituted C 2--4 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Alkylene-OC 1-4 Alkyl, -NRe1Re2, -CORe3, -SO2CH3; Re1, Re2, and Re3 are each independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 alkyl; X2 Selected from CR b1 R b2 , CR b3 ; R b1 , R b2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl, or the R a1 and R b1 , or R a1 and R b2 , or R a2 and R b1 , or R a2 and R b2 With the common linked carbon atom to form a substituted or unsubstituted C 3-6 Cycloalkyl; R b3 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, -WC 3-6 Cycloalkyl; R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, cyano, nitro, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-4 Alkyl-C 1-4 Haloalkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 deuterated alkoxy; or R1 and X1 combine to form a substituted or unsubstituted 5-6 membered heterocyclic group; L1 is selected from C 1-4 Alkylene, C 1-4 Deuterated alkylene, -NH-C 1-4 Alkylene, C 3-6 Cycloalkylene; Ring B is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group; R2 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OC 1-4 Alkyl, deuterium, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy, NH=; m is selected from 0, 1, 2, 3, 4. When there are multiple R2, adjacent R2 and the atoms connected thereto optionally form a substituted or unsubstituted C 3-6 Cycloalkyl; Y1 and Y2 are each independently selected from CH, N, CR c , the R c Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkylamino, C 3- 6-cycloalkylamino, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -NH2, -NH-C 1-4 Alkyl, -NH-C 1-4 Alkylene-C 1-4 Haloalkyl, -NH-C 1-4 Alkylene -CONH2, -OC 1-4 Alkylene -CN, -OC 3-6 Cycloalkylene -CN, -WC 3-6 Cycloalkyl, -W-(3-6 membered heterocyclic group), C 2-6 Alkenyl-CN, cyano, -CO-NH-C 1-4 Alkyl, the C 3-6 Cycloalkyl, 3-6 membered heterocyclic group may be optionally substituted with halogen, C 1-4 Alkyl, cyano, C 1-4 Alkylene-CN substitution; W is selected from O, NH, S; Z is selected from CR d1 R d2 , O, S, N, R d1 , R d2 are independently hydrogen, halogen, C 1-4 Alkyl, cyano, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Alkyl-C 1-4 Haloalkyl, C 1-4 Alkyl-cyano, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy, C 2-4 Alkenyl, OC 1-4 Haloalkyl, oxo, or R d1 , R d2 With the common linked carbon atom to form a substituted or unsubstituted C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that Ring A is selected from phenyl, Preferably, ring A is selected from phenyl, or R a1 , R a2 , R a3 Each independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -CHF2, -NH-CH3, -CH=CH2, -C(CH3)=CH2, -CH2CH3、-CH(CH3)2、-OCF3、-OCH3、-N(CH3)2、 -CH2OCH3, -CONH2, -SO2CH3, -CHO, -CONHCH3; or R b1 , R b2 Each independently selected from H, -CH3; or R b3 Selected from 3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that R1 is selected from H, -Br, -F, -Cl, -CF3, -CH3, -C2H5, -CH2-CF3, -CHF2.

4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that Structural unit Selected from 5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that L1 is selected from -CH2-, -CH(CH3)-, -CD2-, -NH-CH2-, 6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that Ring B is selected from 7. The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that R2 is selected from -F, -CH3, -CH2CH3, -CH(CH3)2, -(CH2)2OCH3, deuterium, NH=.

8. The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that Structural unit Selected from 9. The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that R c Selected from -CF3, cyclopropyl, methylamino, cyclopropylamino, -OC2H5, -OCF3, -NH2, -NH-C2H5, -NH-CH2-CHF2, -NH-CH2-CONH2, -OCH2-CN, -OCH2F, CN, or R d1 , R d2 Selected from hydrogen, -F, -CH3, -CN, -OCH3, -CH2F, -CHF2, -CH2-CHF2, -CH2-CN, -CH2-OCH3, -OCD3, -OCHF2, -CH=CH2, OCF3, C2H5, CH2CH2F; or R d1 , R d2 With the carbon atoms linked together to form 10. The compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that Structural unit Selected from 11. The compound according to any one of claims 1 to 10, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that R3 is selected from -CH3, -CD3.

12. The compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate, selected from: in, X1, X2, Y2, R1, R2, R3, L1, Ring B, Z, m are as defined in any one of claims 1 to 11; Among them, X1, X2, Y2, R1, R2, R3, L1, Ring B, Z, m, R d1 , R d2 As defined in any one of claims 1 to 11; Among them, X1, X2, Y2, R1, R2, R3, L1, Ring B, m, R d1 , R d2 As defined in any one of claims 1 to 11.

13. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, or a hydrate thereof, 14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, its hydrate and a pharmaceutically acceptable carrier.

15. A compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, a hydrate thereof or a pharmaceutical composition according to claim 14 for use in treating a CBL-B target-mediated related disease, preferably wherein the CBL-B target-mediated related disease is a CBL-B-mediated cancer, such as urogenital tract cancer, uterine cancer, cervical cancer, ovarian cancer, breast cancer, gastrointestinal cancer, bone tumor, myeloma, skin cancer, head and neck cancer, liver cancer, gallbladder cancer, bile duct cancer, heart cancer, lung cancer, pancreatic cancer, salivary gland cancer, adrenal cancer, thyroid cancer, brain tumor, ganglion cancer, central nervous system tumor, peripheral nervous system tumor, hematopoietic system tumor and immune system tumor.

Images