Bicyclic heteroaryl-containing compounds as IKZF2 degradation agents

Abstract

Described herein are compounds of Formula II and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, and their use in the treatment or prevention of diseases or conditions (e.g., as IKZF2 degrading agents).

Description

[0001] Related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 323,656, filed March 25, 2022, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0003] IKZF2 (also known as Helios), a zinc finger protein of the Ikaros family, is one of five members of the Ikaros transcription factor family found in mammals. IKZF2 contains four zinc finger domains near its N-terminus involved in DNA binding and two zinc finger domains at its C-terminus involved in protein dimerization. IKZF2 shares approximately 50% homology (80%+) with the Ikaros family members Ikaros (IKZF1), Aiolos (IKZF3), and Eos (IKZF4) in their zinc finger domains. These four Ikaros family transcription factors bind to the same shared DNA sites and can heterodimerize with each other when co-expressed in cells. The fifth Ikaros family protein, Pegasus (IKZF5), shares only 25% homology with IKZF2, binds to different DNA sites compared to other Ikaros family members, and is less prone to heterodimerization with other Ikaros family proteins. IKZF2, IKZF1, and IKZF3 are mainly expressed in hematopoietic cells, while IKZF4 and IKZF5 are expressed in a variety of tissues.

[0004] IKZF2 is a key regulator of T cell activity and function. Deletion of the Helios gene leads to enhanced anti-tumor immune responses. Notably, Helios is highly expressed in regulatory T cells, a subset of T cells that limit effector T cell activity. Selective deletion of Helios in regulatory T cells results in loss of inhibitory activity and gain of effector T cell function. Therefore, Helios is a key factor limiting T cell effector function in Tregs. Currently, anti-CTLA4 antibodies are used clinically to target Tregs in tumors. However, targeting CTLA4 often induces systemic activation of T effector cells, leading to excessive toxicity and limiting therapeutic efficacy. Up to three-quarters of patients treated with combination anti-PD-1 and anti-CTLA4 have reported grade 3 or higher adverse events. Therefore, there is an urgent need for compounds that target Tregs in tumors without inducing systemic activation of T effector cells. IKZF2-specific degraders have the potential to concentrate the enhanced immune response in or near the tumor, providing a potentially more tolerable and less toxic therapeutic agent for cancer treatment.

[0005] Helios expression has been reported to be upregulated in "exhausted" T cells in contexts of chronic viral infection and in dysfunctional chimeric antigen receptor (CAR) T cells. Overexpression or aberration of Helios and various splice isoforms has been reported in several hematologic malignancies, including T-cell leukemia and lymphoma. Furthermore, knockdown of Helios in a mixed lineage leukemia (MLL)-driven myeloid leukemia model effectively inhibited proliferation and increased cell death. Consistent with these results, genomic and chromatin accessibility analyses demonstrated that IKZF2 loss led to increased myeloid differentiation. These data suggest that myeloid leukemia cells have a different need for IKZF2 compared to normal cells. Therefore, IKZF2 deficiency has a preferential effect in leukemia stem cells compared to normal hematopoietic stem cells, thus providing a novel strategy for targeting leukemia stem cells. Summary of the Invention

[0006] In some respects, this disclosure provides compounds of formula II:

[0007]

[0008] And their pharmaceutically acceptable salts, solvates or stereoisomers, wherein the variables in Formula II are described, implemented and illustrated herein.

[0009] In some respects, this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein and pharmaceutically acceptable excipients.

[0010] In some aspects, this disclosure further provides methods for degrading IKZF2 protein in a subject or biological sample, which include administering the disclosed compound to a subject or contacting a biological sample with the disclosed compound.

[0011] In some respects, this disclosure further provides the use of the compounds disclosed herein in the preparation of medicaments for degrading IKZF2 protein in subjects or biological samples.

[0012] In some respects, this disclosure provides compounds disclosed herein for the degradation of IKZF2 protein in subjects or biological samples.

[0013] In some respects, this disclosure provides methods for treating IKZF2-mediated diseases or conditions, which include administering the disclosed compounds to a subject in need.

[0014] In some respects, this disclosure provides the use of the compounds disclosed herein in the preparation of medicaments for treating IKZF2-mediated diseases or conditions.

[0015] In some respects, this disclosure provides compounds disclosed herein for the treatment of IKZF2-mediated diseases or conditions.

[0016] In some respects, this disclosure provides methods for (a) increasing IL-2 production in a subject; (b) suppressing regulatory T cells; (c) enhancing effector T cells; (d) suppressing tumor growth; and / or (e) enhancing tumor regression, said methods comprising administering the compounds disclosed herein to a subject in need.

[0017] In some respects, this disclosure provides the use of the compounds disclosed herein in the preparation of medicaments for (a) increasing IL-2 production in subjects; (b) inhibiting regulatory T cells; (c) enhancing effector T cells; (d) inhibiting tumor growth; and / or (e) enhancing tumor regression. Detailed Implementation

[0018] This disclosure relates to compounds and methods for degrading the IKZF2 protein, the methods comprising contacting the IKZF2 protein with an IKZF2 degrading agent. The invention also relates to a method for treating an IKZF2 protein-mediated disease or condition in a patient by administering an IKZF2 degrading agent to the patient in need. The invention further relates to a method for treating an IKZF2-mediated disease or condition in a patient, comprising administering a pharmaceutical composition comprising an IKZF2 degrading agent to the patient in need.

[0019] The compounds disclosed herein

[0020] This disclosure provides compounds of formula II:

[0021]

[0022] and its pharmaceutically acceptable salts, solvates or stereoisomers, wherein:

[0023] W is -N(R) 1 )2, 3 to 12-membered heterocyclic groups or 5 to 10-membered heteroaryl groups, wherein the heterocyclic group or heteroaryl group is optionally surrounded by one or more R 1b replace;

[0024] Two Rs 1 Together with the nitrogen atoms to which they are attached, they form 3 to 12-membered heterocyclic groups or 5 to 10-membered heteroaryl groups, wherein the heterocyclic group or heteroaryl group is optionally surrounded by one or more R 1b replace;

[0025] Each R 1b Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u Replace; or

[0026] Two adjacent R 1b Together with the inserted atoms, they form C 6-10 Aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally surrounded by one or more R u Replace; or

[0027] Each R 1 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic groups, 3 to 12-membered heterocyclic groups, -(C 1-6 alkylene)-(C 6-10 aryl), -(C 1-6 alkylene)-(5 to 10-membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbonyl group), -(C 1-6 alkylene)-(3 to 12-membered heterocyclic groups), -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 1a replace;

[0028] Each R 1a Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)Ra -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace;

[0029] X is -[C(R) 2 )2]- m , O or NR X Where X is O or NR X When W is a 3- to 12-membered heterocyclic group or a 5- to 10-membered heteroaryl group, wherein the heterocyclic group or heteroaryl group is optionally surrounded by one or more R groups. 1b replace;

[0030] Each R 2 Independently, it is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c Rd -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace;

[0031] Two conjoined Rs 2 Together they form oxygen; or

[0032] Two conjoined Rs 2 Together with the carbon atoms they are attached to, they form C 3-6 A carbocyclic group or a 3- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally composed of one or more R groups. u replace;

[0033] m is an integer from 0 to 5;

[0034] R X It is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups.u replace;

[0035] Ring A is a 9- or 10-membered bicyclic fused ring system containing at least one 5- or 6-membered heteroaryl group;

[0036] Each R A Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace;

[0037] Where valence is permissible, n is an integer from 0 to 10; or

[0038] Two adjacent R A Together with the inserted atoms, they form C 3-12 A carbocyclic group or a 3- to 12-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally composed of one or more R groups. u replace;

[0039] Each R B Independently, it is a halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NRc R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace;

[0040] p is an integer from 0 to 3;

[0041] U is -C(R) 4 )2- or -C(=O)-;

[0042] Each R 4 Independently, it is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u Replace; or

[0043] Two Rs 4 Together with the carbon atoms they are attached to, they form C 3-6 A carbocyclic group or a 3- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally composed of one or more R groups. u replace;

[0044] Each R D Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace;

[0045] d is an integer selected from 0 to 4;

[0046] R 3 It is hydrogen, deuterium, and carbon. 1-6 Halogenated alkyl or C 1-6 Alkyl; and

[0047] q is an integer between 0 and 2;

[0048] in:

[0049] Each R uIndependently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from the following: oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, and 5- to 6-membered heteroaryl; or

[0050] Two Rs u Together with one or more inserted atoms, they form C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic or 3 to 12-membered heterocyclic groups;

[0051] Each R a C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl;

[0052] Each R b Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 aryl or 5- to 10-membered heteroaryl; and

[0053] Each R c and R d Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl; or

[0054] R c and R d Together with the nitrogen atoms to which they are attached, they form 3 to 12-membered heterocyclic groups or 5 to 10-membered heteroaryl groups, wherein the heterocyclic group or heteroaryl group is optionally substituted by one or more substituents selected from: oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic groups and 3- to 6-membered heterocyclic groups;

[0055] Where R a R b R c and R d Each independently and optionally by one or more R z replace;

[0056] Each R z Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, or 5- to 6-membered heteroaryl.

[0057] In some implementations, when ring A is a 10-membered bicyclic heteroaryl group, ring A is not an isoquinolinyl group.

[0058] In some implementations,

[0059] i) When ring A is

[0060] hour,

[0061] Then m is not 0;

[0062] ii) When each R 1 Independently, it is hydrogen and C 1-6 Alkyl, C 3-12 Carbocyclic group or -C(=O)(C 1-6 When alkyl), then 1) m is not 0; and 2) the two homologous Rs 2 They do not form oxygen together; and

[0063] iii) The compound is not

[0064]

[0065] In some embodiments, ring A is not pyrido[2,3-d]pyrimidinyl.

[0066] In some implementations, two R 1 Together with the nitrogen atoms to which they are attached, they form a group optionally bound by one or more R atoms. 1b If a piperazine group is substituted, then ring A is not a pyrido[2,3-d]pyrimidinyl group.

[0067] In some embodiments, the compound is a compound of formula II-1.

[0068]

[0069] Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0070] In some embodiments, the compound is a compound of formula II-2.

[0071]

[0072] Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0073] In some implementations, W is -N(R) 12, 3 to 12-membered heterocyclic groups (e.g., heterocyclic groups comprising one or two 3 to 8-membered rings and 1 to 5 heteroatoms selected from N, O, and S) or 5 to 10-membered heteroaryl groups (e.g., heteroaryl groups comprising one or two 5 or 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S), wherein said heterocyclic group or heteroaryl group is optionally composed of one or more R 1b replace.

[0074] In some implementations, two R 1 Together with the nitrogen atoms to which they are attached, they form 3 to 12-membered heterocyclic groups (e.g., heterocyclic groups comprising one or two 3 to 8-membered rings and 1 to 5 heteroatoms selected from N, O, and S) or 5 to 10-membered heteroaryl groups (e.g., heteroaryl groups comprising one or two 5 or 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S), wherein said heterocyclic or heteroaryl groups are optionally connected by one or more R 1b replace.

[0075] In some implementations, each R 1 Independently, it is hydrogen and C 1-6 Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10), 3- to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -(C 1-6 alkylene)-(C 6-10 aryl), -(C 1-6 alkylene)-(5 to 10-membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbonyl group), -(C 1-6 alkylene)-(3 to 12-membered heterocyclic groups), -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 1a replace.

[0076] In some implementations, each R 1 Independently, it is hydrogen and C 1-6 Alkyl, -(C 1-6 alkylene)-(C 6-10 aryl) or -(C 1-6 (alkylene)-(5 to 10-membered heteroaryl), wherein the alkyl, alkylene, aryl or heteroaryl group is optionally surrounded by one or more R 1a replace.

[0077] In some implementation files, each R 1a Independently, it is an oxo, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkyl groups (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6Alkylamino groups (e.g., dimethylamino, diethylamino, di-n-propylamino, di-isopropylamino, di-n-butylamino, di-isobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino) Ethyl-n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 ), 3- to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR b -S(=O)R a-S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0078] In some implementations, each R 1a Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 aryl, 5 to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0079] In some implementations, each R1a Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0080] In some implementations, each R 1a Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0081] In some implementations, each R 1a Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0082] In some implementations, each R 1a Independently, halogen, C 1-6 Alkyl, C 6-10 Aryl or 5 to 10-membered heteroaryl, wherein the alkyl, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0083] In some implementations, each R 1b Independently, it is an oxo, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkyl groups (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 Alkylamino groups (e.g., dimethylamino, diethylamino, di-n-propylamino, di-isopropylamino, di-n-butylamino, di-isobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino) Ethyl-n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 )), 3 to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3 to 8-membered rings and 1 to 5 heteroatoms selected from N, O, and S), C 6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0084] In some implementations, each R 1b Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 aryl, 5 to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0085] In some implementations, each R 1b Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0086] In some implementations, each R 1b Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0087] In some implementations, each R 1b Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0088] In some implementations, each R 1b Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, 5- to 6-membered heteroaryl, or -S(=O)2R a The alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0089] In some implementations, each R 1b Independently, it is oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C6 aryl, 5- to 6-membered heteroaryl, or -S(=O)2R a The alkyl, alkoxy, alkylamino, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0090] In some implementations, two adjacent R 1b Together with the inserted atoms, they form C 6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein said aryl or heteroaryl is optionally surrounded by one or more R u replace.

[0091] In some implementations, X is -[C(R 2 )2]- m , O or NR X .

[0092] In some implementations, X is -[C(R 2 )2]- m In some implementations, X is 0. In some implementations, X is NR. X In some implementations, when X is O or NR X When W is a 3- to 12-membered heterocyclic group or a 5- to 10-membered heteroaryl group, wherein the heterocyclic group or heteroaryl group is optionally surrounded by one or more R groups. 1b replace.

[0093] In some implementations, each R 2 Independently, it is hydrogen, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkyl groups (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 Alkylamino groups (e.g., dimethylamino, diethylamino, di-n-propylamino, di-isopropylamino, di-n-butylamino, di-isobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino) Ethyl-n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 )), 3 to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3 to 8-membered rings and 1 to 5 heteroatoms selected from N, O, and S), C 6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0094] In some implementations, each R 2 Independently, it is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 aryl, 5 to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0095] In some implementations, each R 2 Independently, it is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0096] In some implementations, each R 2 Independently, it is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0097] In some implementations, each R 2 Independently, it is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0098] In some implementations, each R 2 Independently hydrogen or C 1-6 Alkyl group. In some embodiments, each R 2It is hydrogen.

[0099] In some implementations, two co-occurring R 2 Together they form oxygen.

[0100] In some implementations, two co-occurring R 2 Together with the carbon atoms they are attached to, they form C 3-6 A carbocyclic group (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or a 3- to 6-membered heterocyclic group (e.g., a heterocyclic group comprising a 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein said carbocyclic or heterocyclic group is optionally surrounded by one or more R u replace.

[0101] In some implementations, m is an integer from 0 to 5. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, m is 4. In some implementations, m is 5.

[0102] In some implementations, R X It is hydrogen, C 1-6 Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 ), 3- to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0103] In some implementations, R X It is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, 5- to 6-membered heteroaryl, -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0104] In some implementations, R X It is hydrogen, C 1-6 Alkyl, C 3-6 Carbocyclic groups, 3- to 6-membered heterocyclic groups, -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NRc R d The alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0105] In some embodiments, ring A is a 9- or 10-membered bicyclic fused ring system containing at least one 5- or 6-membered heteroaryl group (e.g., a heteroaryl group containing a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S).

[0106] In some embodiments, ring A is a 9- or 10-membered bicyclic fused ring system comprising a 5- or 6-membered heteroaryl group (e.g., a heteroaryl group comprising a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S) and a C 5-6 Carbocyclic groups (e.g., cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6) or cyclohexadienyl (C6)) or 5- to 6-membered heterocyclic groups (e.g., heterocyclic groups comprising a 5- to 6-membered ring and 1-3 heteroatoms selected from N, O and S).

[0107] In some embodiments, ring A is a 9- or 10-membered bicyclic heteroaryl (e.g., a bicyclic heteroaryl comprising two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S).

[0108] In some embodiments, ring A is a 9-membered bicyclic heteroaryl (e.g., a bicyclic heteroaryl comprising a 5-membered ring and a 6-membered ring and 1-5 heteroatoms selected from N, O and S, wherein at least one of the 5-membered ring and the 6-membered ring is a heteroaryl).

[0109] In some embodiments, ring A is a 9-membered bicyclic heteroaryl group containing 1 to 4 nitrogen atoms.

[0110] In some embodiments, ring A is imidazo[1,5-a]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, imidazo[1,2-a]pyridyl, indolyl, benzo[d]imidazolyl, indazole, benzo[d]isoxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[d]thiazolyl, benzo[b]thiophenyl, or benzofuranyl.

[0111] In some implementations, yes

[0112]

[0113] in:

[0114] R 3a It is hydrogen, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl, 5- to 10-membered heteroaryl, -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0115] In some implementations, yes

[0116]

[0117] In some implementations, yes

[0118]

[0119] In some implementations, R 3a It is hydrogen, C 1-6 Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Heteroalkyl groups (e.g., C-type groups containing 1-3 heteroatoms selected from O, N, and S) 1-6 Alkyl), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 ), 3- to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -(C 1-3 alkylene)-(C 3-6 carbonyl group), -(C 1-3 alkylene)-(3 to 6-membered heterocyclic group), -(C 1-3 alkylene)-(C6 aryl), -(C 1-3 alkylene)-(5 to 6-membered heteroaryl), -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0120] In some implementations, R 3a It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, 5- to 6-membered heteroaryl, -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d-C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0121] In some implementations, R 3a It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Carbocyclic groups, 3- to 6-membered heterocyclic groups, -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0122] In some implementations, R 3a It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 aryl, 5- to 10-membered heteroaryl or -(C 1-3 (alkylene)-(C6 aryl), wherein the alkyl, alkylene, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0123] In some embodiments, ring A is a 10-membered bicyclic heteroaryl (e.g., a bicyclic heteroaryl comprising two 6-membered rings and 1-5 heteroatoms selected from N, O and S, wherein at least one of the two 6-membered rings is a heteroaryl).

[0124] In some embodiments, ring A is a 10-membered bicyclic heteroaryl group containing 1 to 3 nitrogen atoms.

[0125] In some implementations, yes

[0126]

[0127] In some embodiments, ring A is a 9- or 10-membered bicyclic fused ring system comprising a 5- or 6-membered heteroaryl group and a 5- or 6-membered heterocyclic group or C 5-6 Carbon cyclic group.

[0128] In some embodiments, ring A is a 9- or 10-membered bicyclic fused ring system comprising a 5- or 6-membered heteroaryl group and a C group. 5-6 Carbon cyclic group.

[0129] In some implementations, yes

[0130]

[0131] In some implementations, each R A Independently, it is an oxo, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkyl groups (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 Alkylamino groups (e.g., dimethylamino, diethylamino, di-n-propylamino, di-isopropylamino, di-n-butylamino, di-isobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino) Ethyl-n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 )), 3 to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3 to 8-membered rings and 1 to 5 heteroatoms selected from N, O, and S), C 6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d-OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0132] In some implementations, each R A Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 aryl, 5 to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0133] In some implementations, each R A Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0134] In some implementations, each R A Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0135] In some implementations, each R A Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0136] In some implementations, each R A Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic or 3 to 6-membered heterocyclic, C6 aryl, 5 to 6-membered heteroaryl or -NR c S(=O)R a The alkyl, alkoxy, alkylamino, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0137] In some implementations, each R A Independently, it is oxo, halogen, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, 5- to 6-membered heteroaryl or -NR c S(=O)R a The alkyl, alkoxy, alkylamino, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0138] In some implementations, n is an integer from 0 to 10, where valence is permissible.

[0139] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4, provided the valence allows. In some embodiments, n is 5, provided the valence allows. In some embodiments, n is 6, provided the valence allows. In some embodiments, n is 7, provided the valence allows. In some embodiments, n is 8. In some embodiments, n is 9, provided the valence allows. In some embodiments, n is 10, provided the valence allows.

[0140] In some implementations, two adjacent R A Together with the inserted atoms, they form C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 ), 3 to 12-membered heterocyclic groups (e.g., heterocyclic groups comprising one or two 3 to 8-membered rings and 1 to 5 heteroatoms selected from N, O, and S), wherein the carbocyclic or heterocyclic group is optionally surrounded by one or more R u replace.

[0141] In some implementations, each R B It is independently a halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkyl groups (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6Alkylamino groups (e.g., dimethylamino, diethylamino, di-n-propylamino, di-isopropylamino, di-n-butylamino, di-isobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino) Ethyl-n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 ), 3- to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR b -S(=O)R a-S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0142] In some implementations, each R B Independently, it is a halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 aryl, 5 to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0143] In some implementations, each RB Independently, it is a halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0144] In some implementations, each R B Independently, it is a halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0145] In some implementations, each R B Independently, it is a halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0146] In some implementations, each R B Independently, halogen, C 1-6 Alkyl or C 1-6 Alkyl group.

[0147] In some implementations, p is an integer from 0 to 3.

[0148] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0149] In some implementations, U is -C(R) 4 )2- or -C(=O)-.

[0150] In some implementations, each R4 Independently, it is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkyl groups (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 Alkylamino groups (e.g., dimethylamino, diethylamino, di-n-propylamino, di-isopropylamino, di-n-butylamino, di-isobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino) Ethyl-n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 3-6 A carbocyclic group (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or a 3- to 6-membered heterocyclic group (e.g., a heterocyclic group comprising a 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R u replace.

[0151] In some implementations, each R 4 Independently hydrogen or C 1-6 Alkyl group. In some embodiments, each R 4 It is hydrogen.

[0152] In some implementations, two R 4 Together with the carbon atoms they are attached to, they form C 3-6A carbocyclic group (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or a 3- to 6-membered heterocyclic group (e.g., a heterocyclic group comprising a 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclic group or heterocyclic group is optionally surrounded by one or more R u replace.

[0153] In some implementations, each R D Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkyl groups (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 Alkylamino groups (e.g., dimethylamino, diethylamino, di-n-propylamino, di-isopropylamino, di-n-butylamino, di-isobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino) Ethyl-n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 ), 3- to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0154] In some implementations, each R D Independently, it is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0155] In some implementations, each R D Independently, it is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0156] In some implementations, each R D Independently, it is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0157] In some implementations, d is an integer selected from 0 to 4.

[0158] In some implementations, d is 0. In some implementations, d is 1. In some implementations, d is 2. In some implementations, d is 3. In some implementations, d is 4.

[0159] In some implementations, R 3 It is hydrogen, deuterium, and carbon. 1-6 Haloalkyl groups (e.g., C-type alkyl groups containing 1-8 halogen atoms selected from -F, -Cl, and -Br) 1-6 alkyl) or C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5) or hexyl (C6)).

[0160] In some implementations, R 3 It is hydrogen.

[0161] In some implementations, q is an integer from 0 to 2. In some implementations, q is 0. In some implementations, q is 1. In some implementations, q is 2.

[0162] In some embodiments, the compound is a compound of formula II-2.

[0163]

[0164] Or its pharmaceutically acceptable salt, solvate or stereoisomer, wherein:

[0165] Two Rs 1 Together with the nitrogen atoms to which they are attached, they form a group optionally bound by one or more R atoms. 1b Substituted 3- to 12-membered heterocyclic groups;

[0166] Each R 1b Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u Replace; or

[0167] Two adjacent R 1b Together with the inserted atom, a C6 aryl or 5- to 6-membered heteroaryl group is formed, wherein the aryl or heteroaryl group is optionally surrounded by one or more R atoms. u replace;

[0168] Each R 2 It is hydrogen;

[0169] m is 1;

[0170] Ring A contains a 5- or 6-membered heteroaryl group and a C group. 5-6 9- or 10-membered bicyclic fused heteroaryl or 9- or 10-membered bicyclic fused ring systems of carbocyclic groups;

[0171] Each R A Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R dThe alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace;

[0172] n is an integer from 0 to 2;

[0173] Each R B Independently, it is a halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R dThe alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace;

[0174] p is an integer from 0 to 3;

[0175] U is -CH2-;

[0176] Each R D Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace;

[0177] d is an integer selected from 0 to 4;

[0178] R 3 It is hydrogen, deuterium, and carbon. 1-6 Halogenated alkyl or C 1-6 Alkyl; and

[0179] q is 1.

[0180] In some embodiments, the compound is a compound of formula I:

[0181]

[0182] Or its pharmaceutically acceptable salt, solvate or stereoisomer, wherein:

[0183] Each R 1 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, -(C 1-6 alkyl)-(C 6-14 aryl), -(C 1-6 alkyl)-(5 to 14-membered heteroaryl), -(C 1-6 alkyl)-(C 3-10 carbonyl group), -(C 1-6 (alkyl)-(3 to 10-membered heterocyclic group), wherein the alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R 1a replace;

[0184] Each R1a Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u Replace; or

[0185] Two Rs 1 Together with the nitrogen atoms to which they are attached, they form 3 to 12-membered heterocyclic groups, wherein the heterocyclic groups are optionally surrounded by one or more R atoms. 1b replace;

[0186] Each R 1b Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace;

[0187] Each R 2 Independently, it is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace;

[0188] Two Rs 2 Together they form oxygen; or

[0189] Two Rs 2 Together with the inserted carbon atom, they form C 3-10A carbocyclic group or a 3- to 10-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally composed of one or more R groups. u replace;

[0190] m is an integer from 1 to 5;

[0191] Ring A is a 9- or 10-membered bicyclic heteroaryl group;

[0192] Each R A Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R dThe alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace;

[0193] When valence is allowed, n is an integer from 0 to 10;

[0194] Each R B Independently, it is a halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-14 Aryl, 5- to 14-membered heteroaryl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R dThe alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace;

[0195] p is an integer from 0 to 3;

[0196] U is -CH2- or -C(=O)-;

[0197] R 3 It is hydrogen, deuterium, and carbon. 1-6 Halogenated alkyl or C 1-6 Alkyl groups; and

[0198] q is an integer between 0 and 2;

[0199] in:

[0200] Each R u Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)Ra -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from the following: oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-10 Carbocyclic groups and 3- to 6-membered heterocyclic groups; or

[0201] Two Rs u Together with one or more inserted atoms, they form C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Carbocyclic or 3 to 10-membered heterocyclic groups;

[0202] Each R a C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl or 5 to 10-membered heteroaryl;

[0203] Each R b Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl; and

[0204] Each R c and R d Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl; or

[0205] R c and R d Together with the nitrogen atoms they are attached to, they form 3- to 10-membered heterocyclic groups.

[0206] Where Ra R b R c and R d Each independently and optionally by one or more R z replace;

[0207] Each R z Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic or 3- to 6-membered heterocyclic groups

[0208] The conditions are:

[0209] When ring A is a 10-membered bicyclic heteroaryl group, ring A is not an isoquinolinyl group.

[0210] In some implementations, each R 1 Independently, it is hydrogen and C 1-6 Alkyl, C 3-6 Carbocyclic groups, 3- to 6-membered heterocyclic groups, -(C 1-6 alkyl)-(C 6-10 aryl), -(C 1-6 alkyl)-(5 to 10-membered heteroaryl), -(C 1-6 alkyl)-(C 3-6 (carbocyclic group) or -(C 1-6 Alkyl)-(3 to 6-membered heterocyclic group), wherein the alkyl, aryl, heteroaryl, carbocyclic or heterocyclic group is optionally surrounded by one or more R 1a replace.

[0211] In some implementations, each R 1 Independently, it is hydrogen and C 1-6 Alkyl, -(C 1-6 alkyl)-(C 6-14 aryl) or -(C 1-6 (alkyl)-(5 to 14-membered heteroaryl), wherein the alkyl, aryl, or heteroaryl group is optionally surrounded by one or more R 1a replace.

[0212] In some implementations, each R 1a Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0213] In some implementations, each R 1a Independently, it is halogen, C 1-6 Alkyl, C 6-14 Aryl or 5 to 14-membered heteroaryl, wherein the alkyl, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0214] In some implementations, two R 1 Together with the nitrogen atoms to which they are attached, they form 5- or 6-membered heterocyclic groups, wherein the heterocyclic groups are optionally surrounded by one or more R atoms. 1b replace.

[0215] In some implementations, each R 1b Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic groups, 3- to 6-membered heterocyclic groups, or -S(=O)2R a The alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0216] In some implementations, each R 1b Independently, halogen, C 1-6 Alkyl, C 6-14 Aryl or -S(=O)2R a The alkyl or aryl group is optionally surrounded by one or more R groups. u replace.

[0217] In some implementations, each R 2 It is hydrogen.

[0218] In some implementations, two R 2 Together they form oxygen.

[0219] In some implementations, two R 2 Together with the carbon atoms they are attached to, they form C 3-10 Carbon cyclic group or 3 to 10-membered heterocyclic group.

[0220] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0221] In some embodiments, ring A is a 9-membered bicyclic heteroaryl group containing 1 to 4 nitrogen atoms, optionally 0 to 2 sulfur atoms or 0 to 2 oxygen atoms.

[0222] In some embodiments, ring A is imidazo[1,5-a]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, imidazo[1,2-a]pyridyl, indolyl, benzo[d]imidazolyl, indazole, benzo[d]isoxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[d]thiazolyl, benzo[b]thiophenyl, or benzofuranyl.

[0223] In some embodiments, ring A is a 9-membered bicyclic heteroaryl group containing 1 to 3 nitrogen atoms.

[0224] In some implementations, yes

[0225]

[0226] In some implementations, yes

[0227]

[0228] In some embodiments, ring A is a 10-membered bicyclic heteroaryl group containing 1 to 3 nitrogen atoms, optionally 0 to 2 sulfur atoms or 0 to 2 oxygen atoms.

[0229] In some embodiments, ring A is a 10-membered bicyclic heteroaryl group containing 1 to 3 nitrogen atoms.

[0230] In some implementations, yes

[0231]

[0232] In some implementations, ring A is associated with a 5- to 6-membered heterocyclic group or a C-ring. 5-6 A 6-membered heteroaryl group fused with a carbocyclic group.

[0233] In some implementations, yes

[0234]

[0235] In some embodiments, the compound is a compound of formula Ia, Ib, Ic, Id, Ie, or If.

[0236]

[0237]

[0238] Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0239] In some embodiments, the compound is a compound of formula Ia-1, Ib-1, Ic-1, Id-1, Ie-1, or If-1.

[0240]

[0241] Or its pharmaceutically acceptable salt, solvate or stereoisomer.

[0242] In some implementations, each R A Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, wherein the alkyl, alkoxy, alkylamino, carbocyclic or heterocyclic group is optionally surrounded by one or more R u replace.

[0243] In some implementations, each R A C is independent 1-6 Alkyl groups, wherein the alkyl group is optionally composed of one or more R u replace.

[0244] In some embodiments, n is an integer from 0 to 8, depending on the valence. In some embodiments, n is an integer from 0 to 6, depending on the valence. In some embodiments, n is an integer from 0 to 5, depending on the valence. In some embodiments, n is an integer from 0 to 4, depending on the valence. In some embodiments, n is an integer from 0 to 3, depending on the valence. In some embodiments, n is an integer of 0 or 1, depending on the valence. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0245] In some implementations, each R B Independently, it is a halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C3-6 Carbocyclic, 3- to 6-membered heterocyclic, wherein the alkyl, alkoxy, alkylamino, carbocyclic or heterocyclic group is optionally surrounded by one or more R u replace.

[0246] In some implementations, each R B It is halogen or C independently 1-6 Alkyl groups, wherein the alkoxy group is optionally surrounded by one or more R groups u replace.

[0247] In some implementations, p is 0 or 1. In some implementations, p is 0. In some implementations, p is 1.

[0248] In some implementations, U is -CH2-. In some implementations, U is -C(=O)-.

[0249] In some implementations, R 3 It is hydrogen, deuterium, halogen, C 1-6 Halogenated alkyl or C 1-6 Alkyl group. In some embodiments, R 3 Is it hydrogen, deuterium, or carbon? 1-6 Alkyl group. In some embodiments, R 3 It is hydrogen. In some implementations, R 3 It is deuterium. In some implementations, R 3 It is C 1-6 alkyl.

[0250] In some implementations, q is 0. In some implementations, q is 1. In some implementations, q is 2.

[0251] In some implementations, each R a C is independent 1-6 Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 ), 3- to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10 Aryl (e.g., phenyl or naphthyl) or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein said alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0252] In some implementations, each R a C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, or 5- to 6-membered heteroaryl.

[0253] In some implementations, each R a C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbon cyclic group or 3 to 6-membered heterocyclic group.

[0254] In some implementations, each R a C is independent 1-6 Alkyl, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0255] In some implementations, each R b Independently, it is hydrogen and C 1-6Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 )), 3 to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3 to 8-membered rings and 1 to 5 heteroatoms selected from N, O, and S), C 6-10 Aryl (e.g., phenyl or naphthyl) or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein said alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0256] In some implementations, each R b Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, or 5- to 6-membered heteroaryl.

[0257] In some implementations, each R b Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-6 Carbon cyclic group or 3 to 6-membered heterocyclic group.

[0258] In some implementations, each R b Independently, it is hydrogen and C 1-6 Alkyl, C 3-6 Carbocyclic or 3- to 6-membered heterocyclic or C 2-6 Alkynyl, wherein the alkyl, carbocyclic, or heterocyclic group is optionally surrounded by one or more R u replace.

[0259] In some implementations, each R c and each R d Independently, it is hydrogen and C 1-6 Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 )), 3 to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3 to 8-membered rings and 1 to 5 heteroatoms selected from N, O, and S), C 6-10Aryl (e.g., phenyl or naphthyl) or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein said alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. u replace.

[0260] In some implementations, each R c and each R d Independently, it is hydrogen and C 1-6 Alkyl, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic, or heterocyclic group is optionally surrounded by one or more R groups. u replace.

[0261] In some implementations, R c and R d Together with the nitrogen atoms to which they are attached, they form 3 to 12-membered heterocyclic groups (e.g., heterocyclic groups comprising one or two 3 to 8-membered rings and 1 to 5 heteroatoms selected from N, O, and S), wherein said heterocyclic groups are optionally surrounded by one or more R atoms. u replace.

[0262] In some implementations, R a R b R c and R d Independently and optionally by one or more R z replace.

[0263] In some implementations, R z Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl, or 5- to 6-membered heteroaryl.

[0264] In some implementations, each R u Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl groups (e.g., methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), isobutyl (C4), sec-butyl (C4), tert-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6Alkyl groups (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1-6 Alkylamino groups (e.g., dimethylamino, diethylamino, di-n-propylamino, di-isopropylamino, di-n-butylamino, di-isobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, methyl-n-butylamino, methyl-isobutylamino, methyl-sec-butylamino, methyl-tert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-isopropylamino) Ethyl-n-butylamino, ethyl-sec-butylamino, ethyl-isobutylamino, ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-isobutylamino, propyl-sec-butylamino, propyl-tert-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 Alkenyl (e.g., vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ) or spirocyclic [4.5]decyl (C 10 ), 3- to 12-membered heterocyclic groups (e.g., heterocyclic groups containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 Aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SR b -S(=O)R a -S(=O)2R a -S(=O)2OR b -S(=O)2NR c R d -NR c S(=O)2R a -NR c S(=O)R a -NR c S(=O)2OR b -NR c S(=O)2NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -OS(=O)2R a -OS(=O)2OR b -OS(=O)2NR c R d -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -C(=O)R a -C(=O)OR b or -C(=O)NR c R d The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from the following: oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl and 5- to 6-membered heteroaryl.

[0265] In some implementations, each R uIndependently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Carbocyclic groups, 3- to 12-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from: oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl and 5- to 6-membered heteroaryl.

[0266] In some implementations, each R u Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from the following: oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl and 5- to 6-membered heteroaryl.

[0267] In some implementations, each R u Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally substituted by one or more substituents selected from: oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl and 5- to 6-membered heteroaryl.

[0268] In some implementations, each R u Independently, it is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 A carbocyclic or 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, alkylamino, carbocyclic, or heterocyclic group is optionally substituted by one or more substituents selected from: oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 3- to 6-membered heterocyclic, C6 aryl and 5- to 6-membered heteroaryl.

[0269] In some implementations, two R u Together with the carbon atoms they are attached to, they form C 3-6 Carbocyclic groups (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), 3- to 6-membered heterocyclic groups (e.g., heterocyclic groups comprising a 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), C6 aryl (i.e., phenyl), or 5- to 6-membered heteroaryl (e.g., heteroaryl groups comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R z replace.

[0270] In some implementations, two R u Together with the carbon atoms they are attached to, they form C 3-6A carbocyclic group (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or a 3- to 6-membered heterocyclic group (e.g., a heterocyclic group comprising a 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclic group or heterocyclic group is optionally surrounded by one or more R z replace.

[0271] In some implementations, two co-occurring R u Together with the carbon atoms they are attached to, they form C 3-6 A carbocyclic group (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or a 3- to 6-membered heterocyclic group (e.g., a heterocyclic group comprising a 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein said carbocyclic or heterocyclic group is optionally surrounded by one or more R z replace.

[0272] If applicable, the implementation of the variables in any formula described herein is as described above. Any of the variables can be any part as described in the above implementation. In addition, if applicable, combinations of any part described for any variable and any part described for any remaining variable are also considered.

[0273] When listing a range of values, also consider the discrete values ​​and subranges within that range. For example, "C 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0274] In some embodiments, the compounds are selected from the compounds in Table 1 and their pharmaceutically acceptable salts:

[0275] Table 1.

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336] Compared to known compounds (such as known IKZF2 degraders), the compounds disclosed herein may possess advantageous features. For example, the compounds disclosed herein may exhibit more potent IKZF2 activity and more favorable pharmacokinetic properties (e.g., as per C...). max T max The compounds exhibit fewer interactions (and / or AUC as measured) and / or with other cellular targets (e.g., hepatocyte transporters such as OATP1B1) and thus improve safety (e.g., drug-drug interactions). These beneficial properties of the compounds disclosed herein can be measured according to methods commonly available in the art (such as those exemplified herein).

[0337] Compared to other p300 degraders, the compounds disclosed herein may possess advantageous characteristics. For example, the compounds disclosed herein may exhibit greater selectivity for IKZF2 than for IKZF1, demonstrating more effective degradation activity against IKZF2 and more favorable pharmacokinetic properties (e.g., as per C...). max T max Less interaction with other cellular targets (e.g., hepatocyte transport proteins such as OATP1B1) and / or with AUC as measured by the drug and / or AUC, thus improving safety (e.g., drug-drug interactions).

[0338] In some embodiments, a compound disclosed herein is "selective" or "displayed" selective to IKZF2 when it selectively degrades IKZF2 or exhibits selective degradation of IKZF2 beyond IKZF1. For example, when the compound's DC value for IKZF2... 50 Lower than its DC for IKZF1 50 At this time, it exhibits selectivity for IKZF2. In some embodiments, when the compounds disclosed herein exhibit selectivity for IKZF2 D... max Greater than its D for IKZF1 maxAt that time, it showed selective degradation of IKZF2 exceeding that of IKZF1. In some embodiments, the compounds disclosed herein exhibit lower DC values ​​for IKZF2 compared to IKZF1. 50 and higher D max The combination of these compounds is used to demonstrate selective degradation of IKZF2 beyond IKZF1. In some embodiments, when the compounds disclosed herein exhibit selective degradation of IKZF2 by DC... 50 Compared to its DC version of IKZF1 50 At least 10 times lower and / or D of IKZF2 max Subtract D for IKZF1 max The value of (ΔD) max The compound exhibits selectivity when the concentration of the compound disclosed herein is at least 30, at least 35, at least 40, or at least 45 percentage points relative to the DC concentration of IKZF2. In some preferred embodiments, the compound exhibits selectivity when the concentration of the compound disclosed herein is at least 30, at least 35, at least 40, or at least 45 percentage points relative to the DC concentration of IKZF2. 50 Compared to its DC version of IKZF1 50 At least 30 times lower and / or D relative to IKZF2 max Subtract D for IKZF1 max The value of (ΔD) max The compound exhibits selectivity when the concentration of the compound disclosed herein is at least 50, at least 55, at least 60, or at least 65 percentage points relative to the DC concentration of IKZF2. In some more preferred embodiments, the compound exhibits selectivity when the concentration of the compound disclosed herein is at least 50, at least 55, at least 60, or at least 65 percentage points relative to the DC concentration of IKZF2. 50 Compared to its DC version of IKZF1 50 At least 100 times lower and / or D relative to IKZF2 max Subtract D for IKZF1 max The value of (ΔD) max The compound exhibits selectivity when the percentage is at least 70, at least 75, at least 80, at least 85, or at least 90 percentage points. These beneficial properties of the compounds disclosed herein can be measured according to methods commonly available in the art, such as those exemplified herein.

[0339] Due to the presence of double bonds, the compounds of this disclosure can be in cis or trans, or Z or E configurations. It should be understood that although one configuration may be depicted in the structure of the compounds or formulas of this disclosure, another configuration is also covered. For example, the compounds or formulas of this disclosure may be depicted in cis or trans, or Z or E configurations.

[0340] In one embodiment, the compound disclosed herein (e.g., any compound of any formula disclosed herein or any single compound) is a pharmaceutically acceptable salt. In another embodiment, the compound disclosed herein (e.g., any compound of any formula disclosed herein or any single compound) is a solvate. In yet another embodiment, the compound disclosed herein (e.g., any compound of any formula disclosed herein or any single compound) is a hydrate.

[0341] The details of this disclosure are set forth in the accompanying description. While methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, illustrative methods and materials are described hereafter. Other features, objects, and advantages of this disclosure will be apparent from the specification and claims. Unless the context clearly requires otherwise, the singular form also includes the plural form in the specification and appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents and publications referenced in this specification are incorporated herein by reference in their entirety.

[0342] Other forms of the compounds disclosed herein

[0343] Pharmaceutically acceptable salts

[0344] In some embodiments, the compounds disclosed herein are present in their pharmaceutically acceptable salt form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0345] In some embodiments, the compounds described herein have acidic or basic groups, and thus can react with a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting the purified free form of the compound with a suitable acid or base, respectively, and isolating the resulting salts.

[0346] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with minerals, organic acids, or inorganic bases. Such salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, disglucurons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucono-2-phosphates, glycerophosphates, glycolates, hemisulfates, heptahydrates, hexyn-1,6-dicitates, hydroxybenzoates, and gamma-hydroxybutyrates. Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0347] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the compounds in their free base form with a pharmaceutically acceptable inorganic or organic acid, including but not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzene Formic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid.

[0348] In some embodiments, those compounds comprising free acid groups described herein react with a suitable base (such as a pharmaceutically acceptable hydroxide, carbonate, bicarbonate, or sulfate of a metal cation), with ammonia, or a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2SO4. + (C 1-4 Alkyl)4, etc.

[0349] Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization yields water-soluble, oil-soluble, or dispersible products.

[0350] solvates

[0351] Those skilled in the art of organic chemistry will understand that many organic compounds can form complexes with solvents, which react in the solvent or precipitate or crystallize therefrom. These complexes are called "solvates." For example, complexes with water are called "hydrates." Solvates are within the scope of this invention.

[0352] Those skilled in organic chemistry will also understand that many organic compounds can exist in more than one crystalline form. For example, the crystalline form can vary depending on the solvate. Therefore, all crystalline forms or their pharmaceutically acceptable solvates are considered, and they are within the scope of this invention.

[0353] In some embodiments, the compounds described herein are present in the form of solvates. This disclosure provides a method of treating a disease by administering such solvates. This disclosure further provides a method of treating a disease by administering such solvates in the form of a pharmaceutical composition.

[0354] Solvates contain stoichiometric or non-stoichiometric amounts of solvents such as water and ethanol. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholysis is formed. Solvates of the compounds described herein can be readily prepared or formed during the methods described herein. Furthermore, the compounds provided herein can exist in both solvated and non-solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0355] Isomers / stereoisomers

[0356] It should also be understood that compounds with the same molecular formula but different atomic bonding properties or sequences, or different spatial arrangements of atoms, are called "isomers". Isomers with different spatial arrangements of atoms are called "stereoisomers".

[0357] In some embodiments, the compounds described herein are present in geometrical isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds disclosed herein include all cis, trans, cis-trans, iso-entgegen (E), and iso-entgegen (Z), and corresponding mixtures thereof. All geometrical forms of the compounds disclosed herein are considered, and they are within the scope of this invention.

[0358] In some embodiments, the compounds disclosed herein have one or more chiral centers, and each center is present in an R configuration or an S configuration. The compounds disclosed herein include all diastereomers, enantiomers, and epimers, as well as corresponding mixtures thereof. All diastereomers, enantiomers, and epimers of the compounds disclosed herein are considered and are within the scope of this invention.

[0359] In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared in separate stereoisomer forms by reacting a racemic mixture of the compounds with an optically active resolving agent to form diastereomeric compound pairs, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by a separation / resolution technique based on solubility differences. In some embodiments, the optically pure enantiomers are then recovered together with the resolving agent.

[0360] tautomer

[0361] In some embodiments, the compounds described herein are present as tautomers. The compounds described herein include all possible tautomers within the formulas described herein.

[0362] Tautomers are compounds that interconvert through the migration of hydrogen atoms, accompanied by the conversion of single bonds and adjacent double bonds. A chemical equilibrium of tautomers will exist in the bond arrangements in which tautomerization may occur. Consider all tautomer forms of the compounds disclosed herein, and they are within the scope of this invention. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0363] Pharmaceutical Composition

[0364] In some embodiments, the compound described herein is administered as a pure chemical substance. In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, such as as described, for example, in the following literature: Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition Mack Pub. Co., Easton, PA (2005)).

[0365] Therefore, this disclosure provides pharmaceutical compositions comprising the compounds described herein or their pharmaceutically acceptable salts, solvates or stereoisomers, and pharmaceutically acceptable excipients.

[0366] In some embodiments, the compounds provided herein are substantially pure because they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts generated, for example, in one or more steps of the synthetic method.

[0367] The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dose, duration, and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, an appropriate dose and treatment regimen provide an amount of composition sufficient to provide therapeutic and / or preventive benefits, such as improved clinical outcomes (e.g., more frequent complete or partial remissions, or longer disease-free survival and / or overall survival) or reduced symptom severity. Optimal doses are typically determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body mass, weight, or blood volume.

[0368] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, percutaneous, parenteral, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ocular administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as tablets, pills, capsules, liquids, inhalers, nasal spray solutions, suppositories, suspensions, gels, colloids, dispersions, solutions, emulsions, ointments, lotions, eye drops, or ear drops. In some embodiments, the pharmaceutical composition is formulated as tablets.

[0369] Appropriate dosage and administration regimens are determined using conventional dose range exploration techniques known to those skilled in the art. Typically, treatment begins with a smaller dose, less than the optimal dose of the compounds disclosed herein. The dose is then increased in small increments until optimal efficacy is achieved in this case. In some embodiments, the method of the invention involves administering about 0.1 μg to about 50 mg of at least one of the compounds described herein per kg of subject body weight. For a 70 kg patient, a more commonly used dose is about 10 μg to about 200 mg of the compounds disclosed herein, depending on the subject's physiological response.

[0370] For example only, the dosage of the compounds described herein for treating diseases as described herein is about 0.001 to about 1 mg / kg of the subject's body weight per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg / kg of body weight per day. In some embodiments, the compounds described herein are used in the method at a dose of about 1 to about 1000 mg / kg of the body weight of the subject being treated, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

[0371] Preparation of compounds

[0372] The compounds disclosed herein can be prepared using many methods well known to those skilled in the art of organic synthesis. For example, the compounds disclosed herein can be synthesized using the methods described below, as well as synthetic methods known in the field of organic chemical synthesis or variations thereof as understood by those skilled in the art. The compounds disclosed herein (i.e., the compounds of this application (e.g., any compound of any formula disclosed herein or any single compound)) can be synthesized by following the general synthetic schemes below and the steps outlined in the examples, schemes, procedures and / or synthesis described herein (e.g., embodiments).

[0373] General synthesis scheme

[0374] The exemplary compounds can be prepared by following the general synthetic procedure outlined in the following scheme.

[0375]

[0376] According to Scheme 1, in the presence of a halogen source (such as N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), etc.), in a suitable solvent (such as CCl4, benzene, etc.), at a temperature ranging from 60°C to 100°C, a commercially available or synthetically obtained substituted compound of formula (II, R is C 1-6 The phenyl carboxylic acid esters (where X is a halogen) react with free radical initiators (such as benzoyl peroxide (BPO), azobisisobutyronitrile (AIBN), etc.) to provide a compound of formula (III, where R is C). 1-6 Halogenated substituted phenyl carboxylate of formula (where X is a halogen) is used to treat the halogenated substituted phenyl carboxylate of formula III with a commercially available or synthetically available aminoglutarimide of formula IV in the presence of a suitable base (such as DIPEA, TEA, and the like) in an aprotic solvent (such as MeCN, DMF, etc.) at a temperature ranging from 0°C to 25°C (preferably 10°C) to provide a compound of formula (V). The compound of formula (V) is cyclized in the presence of a suitable acid (such as AcOH, TFA, etc.) in a suitable solvent (such as dichloromethane (DCM), dichloroethane (DCE), etc.) at a temperature ranging from 25°C to 80°C (preferably 60°C) to provide a cyclized compound of formula (VI). Under palladium-catalyzed boration conditions, in the presence of a suitable catalyst (such as Pd(dppf)Cl2, Pd(OAc)2, etc.), a suitable base (such as K3PO4, Cs2CO3, KOAc, etc.), and in a suitable solvent (such as dioxane, DMF, THF, etc.), at a temperature ranging from 60°C to about 120°C, the compound of formula (VI) is coupled with commercially available 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane).

[0377]

[0378] According to Scheme 2, in the presence of a suitable reducing agent (such as NaBCNH3, NaBH(OAc)3, etc.), in an alcohol solvent (such as MeOH, EtOH, etc.), at a temperature ranging from 0°C to about 50°C (preferably 25°C), a commercially available or synthetically available aldehyde or ketone of formula (VIII, X = halogen) is coupled to a commercially available or synthetically available amine compound of formula (IX) to provide a compound of formula (Xa).

[0379]

[0380] According to Scheme 3, in a solvent (such as diethyl ether, THF, etc.), at a temperature ranging from -20°C to about 25°C (preferably 0°C), a commercially available or synthetically available aldehyde or ketone of formula (VIII, X = halogen) is reacted with a commercially available or synthetically available Grignard reagent of formula (XI) to provide an alcohol compound of formula (XII); in the presence of a suitable base (such as DIPEA, TEA, etc.), in a solvent (such as DCM, THF, etc.), at a temperature ranging from -10°C to about 30°C (preferably 0°C), the compound of formula (XII) is reacted with a methanesulfonating agent (such as MsCl, etc.) to provide a compound of formula (XIII). In the presence of a suitable base (such as Cs2CO3, K2CO3, etc.), in a solvent (such as DMF, DMSO, etc.), at a temperature ranging from 25°C to about 100°C (preferably 80°C), the compound of formula (XIII) is reacted with a commercially available or synthetically available amine of formula (IX) to provide the compound of formula (Xb).

[0381]

[0382] According to Scheme 4, under Suzuki coupling conditions, a suitable catalyst (such as Pd(Ph3P)4, Pd2(dba)3, Pd(ddpf)Cl2, etc.), a suitable base (such as K3PO4, Cs2CO3, etc.), a suitable solvent (such as dioxane, DMF, etc.), in the presence of a co-solvent (such as water), and at a temperature ranging from 60°C to about 120°C (preferably 80°C), a borate ester compound of formula (VII) is reacted with a halogenated compound of formula (Xa) or (Xb) to provide the desired compound of formula (I).

[0383] Those skilled in the art can discern the presence of a stereocenter in the compounds disclosed herein (e.g., compounds of any formula disclosed herein or any single compound). Therefore, this disclosure includes two possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but also single enantiomers and / or diastereomers. When it is desired that the compound be a single enantiomer or diastereomer, the compound can be obtained by stereooriented synthesis or by resolving the final product or any convenient intermediate. The resolving of the final product, intermediate, or starting material may be influenced by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E.L.E.L., S.H.Wilen, and L.N.Mander (Wiley-Interscience, 1994).

[0384] The compounds used in the reactions described herein are prepared from commercially available chemicals and / or compounds described in chemical literature, according to organic synthesis techniques known to those skilled in the art. "Commercially available compounds" were obtained from standard commercial sources, including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), and Maybridge Chemical. Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD) and Wako Chemicals USA, Inc. (Richmond, VA).

[0385] Suitable reference books and papers that describe in detail the synthesis of reactants used to prepare the compounds described herein or provide reference to articles describing such preparations include, for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; SRSandler et al., “Organic Functional Group Preparations,” 2nd ed., Academic Press, New York, 1983; HO House, “Modern Synthetic Reactions”, 2nd ed., WABenjamin, Inc., Menlo Park, Calif., 1972; TL Gilchrist, “Heterocyclic Chemistry”, 2nd ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th ed., Wiley-Interscience, New York, 1992. Other suitable references and papers that describe in detail the synthesis of reactants used to prepare the compounds described herein or provide reference to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin G., “Organic Synthesis: Concepts, Methods, Starting Materials”, 2nd ed. (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV., “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC., “Comprehensive Organic Transformations: A Guide to Functional Group Preparations”, 2nd ed. (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J., “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure”, 4th ed. (1992) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV., “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC., “Comprehensive Organic Transformations: A Guide to Functional Group Preparations”, 2nd ed. (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J., “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure”, 4th ed. (1992) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV., “Organic Chemistry, An Intermediate Text” (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman Wiley & Sons, ISBN: 0-471-60180-2; Otera, J.(Editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's "Encyclopedia" (1999) by John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942-2000) by John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups" by John Wiley & Sons, 73 volumes.

[0386] Specific and similar reactants are optionally identified by means of an index of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, which is available in most public and university libraries as well as online. Known but not listed in commercially available catalogues are optionally prepared by conventional chemical synthesis facilities, many of which provide routine synthesis services to standard chemical suppliers (e.g., those listed above). References for the preparation and selection of pharmaceutical salts of the compounds described herein are found in PHStahl and CGWermuth, “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002.

[0387] Analytical methods, materials and instruments

[0388] Unless otherwise specified, reagents and solvents were used as is from the commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained at 400 MHz on a Bruker or Varian spectrometer. Spectra are given in ppm (δ), and the coupling constant J is reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC / MS) was collected using a SHIMADZU LCMS-2020EV or an Agilent 1260-6125B LCMS. Purity and low-resolution mass spectrometry data were measured using an Agilent 1260-6125B LCMS system (with a diode array detector and an Agilent G6125BA mass spectrometer) or a Waters Acquity UPLC system (with a diode array detector and a Waters 3100 mass spectrometer). Purity was characterized by UV wavelengths at 214 nm, 220 nm, 254 nm, and ESI. Column: Poroshell 120EC-C18 2.7μm 4.6X 100mm; flow rate 0.8mL / min; solvent A (100 / 0.1 water / formic acid), solvent B (100 acetonitrile); gradient: hold 5% B to 0.3min, 5%-95% B from 0.3 to 2min, hold 95% B to 4.8min, 95%-5% B from 4.8 to 5.4min, then hold 5% B to 6.5min. Alternatively, column: Acquity UPLC BEH C18 1.7μm 2.1X 50mm; flow rate 0.5mL / min; solvent A (0.1% formic acid in water), solvent B (acetonitrile); gradient: hold 5% B for 0.2min, 5%-95% B from 0.2 to 2.0min, hold 95% B to 3.1min, then hold 5% B for 3.5min.

[0389] Biological assay

[0390] The biological activity of the compounds of this application can be evaluated using methods and assays known in the art.

[0391] The binding potency of the compound to CRBN / DDB1 was determined using HTRF assays. The HTRF signal was measured by replacing the Cy5-labeled thalidomide with the test compound, which was then replaced with His-labeled CRBN+DDB-DLS7+CXU4. The data were analyzed using XLfit with four-parameter dose-response curves to determine the IC50. 50 .

[0392] The cellular degradation activity of IKZF2 in Jurkat cells was measured by FACS at compound concentrations of 0.001, 0.01, 0.1, 1 to 10 μM for 24 hours. Protein concentration was assessed by immunoblotting using PVDF membranes and antibodies against IKZF2. Band intensity was quantified and analyzed using XLfit.

[0393] Alternatively, the cellular degradation activity of IKZF2 in Jurkat cells was measured by FACS at compound concentrations ranging from 0.05 to 10 μM for 24 hours. Cells were stained with primary and secondary antibodies against IKZF2, then imaged on an iQue flow cytometer, and IKZF2 levels were quantified using iQue software.

[0394] Alternatively, the cellular degradation activity of IKZF2 was measured using the HiBit IKZF2 assay, in which the HiBiT protein labeling system was applied to modified HEK293T Flp-in-HiBiT cells. Test and reference compounds were diluted 3-fold starting at 1 mM, for a total of 11 doses. A HiBiT lysis detection system was used to detect the bioluminescence of HiBiT tags in treated cells to determine the correlation between tag abundance and luminescence level. After DMSO normalization, dose-response curves (GraphPad Prism) were plotted to determine the concentration point at which each compound achieved 50% HiBiT-Helios degradation.

[0395] Alternatively, the cellular degradation activity of IKZF1 was measured using the HiBit IKZF1 assay, in which the HiBiT protein labeling system was applied to modified HEK293T Flp-in-HiBiT cells. Test and reference compounds were diluted 3-fold starting at 1 mM, for a total of 11 doses. A HiBiT lysis detection system was used to detect the bioluminescence of HiBiT tags in treated cells to determine that tag abundance is proportional to luminescence level. After DMSO normalization, dose-response curves (GraphPad Prism) were plotted to determine the concentration point at which each compound achieved 50% HiBiT-Ikaros degradation.

[0396] How to use

[0397] In some respects, this disclosure provides a method for degrading the IKZF2 protein in a subject, comprising administering the compound disclosed herein to the subject.

[0398] In some respects, this disclosure provides the use of the compounds disclosed herein in the preparation of a medicament for degrading IKZF2 protein in a subject.

[0399] In some respects, this disclosure provides compounds disclosed herein for the degradation of IKZF2 protein in subjects.

[0400] In some respects, this disclosure provides methods for treating or preventing a disease or condition in a subject in need, comprising administering to said subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0401] In some respects, this disclosure provides a method for treating a disease or condition in a subject in need, comprising administering to said subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0402] In some respects, this disclosure provides for the use of the compounds disclosed herein in the preparation of a medicament for the treatment or prevention of a disease or condition in a subject in need.

[0403] In some respects, this disclosure provides for the use of the compounds disclosed herein in the preparation of a medicament for treating a disease or condition in a subject in need.

[0404] In some respects, this disclosure provides the compounds disclosed herein for the treatment or prevention of a disease or condition in a subject of need.

[0405] In some respects, this disclosure provides the compounds disclosed herein for use in treating diseases or conditions in subjects in need.

[0406] In some implementations, the disease or condition is an IKZF2-mediated disease or condition.

[0407] In some implementations, the disease or condition is selected from T-cell leukemia, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid tumor, and gastrointestinal stromal tumor (GIST).

[0408] In some respects, this disclosure provides methods for (a) increasing IL-2 production in a subject; (b) suppressing regulatory T cells; (c) enhancing effector T cells; (d) suppressing tumor growth; and / or (e) enhancing tumor regression, said methods comprising administering the compounds disclosed herein to a subject in need.

[0409] In some respects, this disclosure provides the use of the compounds disclosed herein in the preparation of medicaments for (a) increasing IL-2 production in subjects; (b) inhibiting regulatory T cells; (c) enhancing effector T cells; (d) inhibiting tumor growth; and / or (e) enhancing tumor regression.

[0410] In some implementations, the subjects are mammals.

[0411] In some implementations, the subjects are humans.

[0412] definition

[0413] Unless otherwise stated, the following terms have the meanings as used in the specification and appended claims.

[0414] Chemical definition

[0415] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS version of the Periodic Table of the Elements on the inner cover of the 75th edition of the Handbook of Chemistry and Physics, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry, as well as specific functional parts and reactivity, are described in the following references: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0416] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of isomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched with one or more stereoisomers). Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (edited by Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0417] The present invention further covers the compounds described herein in the form of a single isomer that is substantially free of other isomers, as well as alternatively in the form of a mixture of various isomers.

[0418] When listing a series of values, the aim is to cover every value within that range and every subrange. For example, "C 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0419] The following terms are intended to have the meanings presented below and to aid in understanding the description and intended scope of the invention. In describing inventions that may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms (if present) shall have the following meanings unless otherwise stated. It should also be understood that, when described herein, any portion defined below may be substituted with various substituents, and the respective definitions are intended to include those substituted portions within the scope described below. Unless otherwise stated, the term “substituted” shall be defined as set forth below. It should be further understood that the terms “groups” and “radicals” are considered interchangeable when used herein. The article “an” may be used herein to refer to one or more (e.g., at least one) grammatical object of the article. For example, “an analogue” means one or more analogues.

[0420] As used herein, "alkyl" refers to a group having 1 to 20 carbon atoms, either a straight-chain or branched saturated hydrocarbon group ("C"). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 12 carbon atoms (“C12”). 1-12 Alkyl group (“C10”). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C”). 1-7 Alkyl group). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C6”). 1-6 Alkyl group, also referred to herein as "lower alkyl group"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C1 to 5 C2"). 1-5 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C”). 1-4 Alkyl group (“C1”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has one carbon atom (“C1 alkyl”). 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl group is an unsubstituted C1. 1-10 Alkyl group (e.g., -CH3). In some embodiments, the alkyl group is a substituted C-molecule. 1-10 Alkyl. Common alkyl abbreviations include Me(-CH3), Et(-CH2CH3), i-Pr(-CH(CH3)2), n-Pr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0421] As used herein, “alkylene” refers to an alkyl group in which two hydrogens have been removed to provide a divalent group. When providing a range or number of carbons for a particular “alkylene,” it should be understood that the range or number refers to the range or number of carbons in a linear divalent carbon chain. An “alkylene” may be substituted or unsubstituted by one or more substituents as described herein. Exemplary unsubstituted divalent alkylenes include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2-), etc. Exemplary substituted dialkylene groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0422] As used herein, “alkenyl” refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). 2-20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C”). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 Alkenyl (“C2-alkenyl”). In some embodiments, the alkenyl group has two carbon atoms (“C2-alkenyl”). One or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the C group mentioned above. 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise stated, each example of an alkenyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkenyl group is an unsubstituted C10. 2-10 Alkenyl. In some embodiments, the alkenyl group is a substituted C. 2-10 Alkenyl group.

[0423] As used herein, “alkenylene” refers to an alkenyl group in which two hydrogens have been removed to provide a divalent group. When providing a range or number of carbons for a particular “alkenylene”, it should be understood that the range or number refers to the range or number of carbons in a linear divalent carbon chain. An “alkenylene” may be substituted or unsubstituted by one or more substituents as described herein. Exemplary unsubstituted divalent alkenylenes include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted dialkylene groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-) and substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-) groups, etc.

[0424] As used herein, “alkynyl” refers to a group (“C”) of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds). 2-20 The alkynyl group (“Alynyl”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 10 carbon atoms (“C”). 2-10 The alkynyl group (“Alynyl”) has 2 to 9 carbon atoms in some embodiments. 2-9 The alkynyl group (“acetylation”) has 2 to 8 carbon atoms in some embodiments. 2-8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“acetylation”) has 2 to 6 carbon atoms in some embodiments. 2-6 The alkynyl group (“H”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 5 carbon atoms (“C”). 2-5 The alkynyl group (“H”) has 2 to 4 carbon atoms in some embodiments. 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. One or more carbon-carbon triple bonds may be internal (as in 2-butynyl) or terminal (as in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), and 2-propynyl (C3).、 1-Butynyl (C4), 2-Butynyl (C4), etc. C 2-6 Examples of alkenyl groups include the C group mentioned above. 2-4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl groups include heptynyl (C7), octyynyl (C8), etc. Unless otherwise stated, each example of an alkynyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkynyl group is an unsubstituted C5 group. 2-10 Alkyne group. In some embodiments, the alkynyl group is a substituted C- group. 2-10 Alkyne group.

[0425] As used herein, “ynynyl” refers to an ynyl group in which two hydrogens have been removed to provide a divalent group. When providing a range or number of carbons for a particular “ynynyl”, it should be understood that the range or number refers to the range or number of carbons in a linear carbon divalent chain. An “ynynyl” may be substituted or unsubstituted with one or more substituents as described herein. Exemplary divalent ynynyls include, but are not limited to, substituted or unsubstituted ethynyl groups, substituted or unsubstituted propynyl groups, etc.

[0426] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more heteroatoms are inserted between carbon atoms and the parent molecule, i.e., between connection points. In some embodiments, a heteroalkyl group refers to a saturated group ("heteroalkyl") having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms. 1-10 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1-9 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1-8 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1-7 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2 or 3 heteroatoms (“heteroalkyl”). 1-6 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroalkyl”). 1-5Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms (“heteroalkyl”). 1-4 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroalkyl”). 1-3 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroalkyl”). 1-2 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having two to six carbon atoms and one or two heteroatoms (“heteroC1 alkyl”). 2-6 Alkyl group”. Unless otherwise stated, each example of a heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”). In some embodiments, the heteroalkyl group is an unsubstituted heteroalkyl group. 1-10 Alkyl group. In some embodiments, the heteroalkyl group is a substituted heteroC. 1-10 alkyl.

[0427] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein that comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or between carbon atoms and the parent molecule, i.e., between connection points. In some embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl group"). 2-10 In some embodiments, the heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroalkenyl”). 2-9 In some embodiments, the heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroalkenyl”). 2-8 In some embodiments, the heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroalkenyl”). 2-7 In some embodiments, the heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroalkenyl”). 2-6 In some embodiments, the heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroalkenyl”). 2-5 In some embodiments, the heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroalkenyl”). 2-4In some embodiments, the heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroalkenyl”). 2-3 In some embodiments, the heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroalkenyl”). 2-6 ("alkenyl"). Unless otherwise stated, each example of a heteroalkenyl is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl"). In some embodiments, the heteroalkenyl is an unsubstituted hetero-C 2-10 Alkenyl. In some embodiments, the heteroalkenyl group is a substituted heteroC. 2-10 Alkenyl group.

[0428] As used herein, the term "heteroyne" refers to an alkynyl group as defined herein that comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or between carbon atoms and the parent molecule, i.e., between connection points. In some embodiments, a heteroyne refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroyne-C"). 2-10 The ethynyl group ("ethynyl group") has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroylated C"). In some embodiments, the ethynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroylated C"). 2-9 ("Hydynyl"). In some embodiments, the heteroynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("Hydynyl"). 2-8 The kyne group ("ynyl group") has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroylated C"). In some embodiments, the kyne group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroylated C"). 2-7 The kyne group ("ynyl group") has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroyne group"). In some embodiments, the kyne group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroyne group"). 2-6 The alkynyl group ("heteroyne") has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroyne"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroyne"). 2-5 ("Hydynyl"). In some embodiments, the heteroynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("Hydynyl"). 2-4 ("Hydynyl group"). In some embodiments, the heteroynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom ("Hydynyl group"). 2-3 ("Hydynyl group"). In some embodiments, the heteroynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("Hydynyl group"). 2-6(The text appears to be incomplete and contains several tyneylyl groups. A more accurate translation would require the full context.) 2-10 Alkynyl group. In some embodiments, the heteroyne group is a substituted hetero-C group. 2-10 Alkyne group.

[0429] Similar to "alkylene", "alkenylene", and "ynynein" as defined above, "heteroalkylene", "heteroalkenyl", and "heteroynyne" as used herein refer to the divalent groups of heteroalkyl, heteroalkenyl, and heteroynyl groups, respectively. When a range or number of carbons is provided for a particular "heteroalkylene", "heteroalkenyl", and "heteroynyne", it should be understood that the range or number refers to the range or number of carbons in a linear divalent chain. "Heteroalkylene", "heteroalkenyl", and "heteroynyne" may be substituted or unsubstituted by one or more substituents as described herein.

[0430] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a cyclic array), which provides 6-14 ring carbon atoms and zero heteroatoms ("C"). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C14”). 14 "Aromatic"; for example, anthracene.

[0431] Typical aryl groups include, but are not limited to, those derived from the following groups: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azurite, benzene, etc. Benzene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-dicyclopentadienzene, s-dicyclopentadienzene, indene, indene, naphthalene, octacene, octaphene, octalene, oleophane, pentane-2,4-diene, pentane, pentaphenene, pentaphenyl, perylene, phenanthracene, sepium, pyrene, pyrane, rubicene, triphenylene, and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indene, and tetrahydronaphthyl. Unless otherwise stated, each example of an aryl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted aryl”) or substituted by one or more substituents (“substituted aryl”). In some embodiments, the aryl group is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0432] As used herein, “arylene” refers to an aryl group in which two hydrogens have been removed to provide a divalent group. When providing a range or number of carbons for a particular “arylene”, it should be understood that the range or number refers to the range or number of carbons in the aryl group. An “arylene” may be substituted or unsubstituted by one or more substituents as described herein.

[0433] "Heteroaryl" refers to a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a cyclic array), which provides a cyclic carbon atom and 1 to 8 cyclic heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, where the valence allows. Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.

[0434] "Heteroaryl" also includes ring systems in which a heteroaryl group as defined above is fused with one or more aryl groups, wherein the linking point is on the heteroaryl group or one or more aryl groups, and in such cases, the number of ring members represents the total number of ring members in the fused (aryl / heteroaryl) ring system. When substitution is indicated in such cases, unless otherwise stated, substitution may occur on the heteroaryl group or one or more aryl groups. For bicyclic heteroaryl groups (e.g., indolyl, quinolinyl, carbazolyl, etc.) where one ring does not contain a heteroatom, the linking point may be on either ring, i.e., the ring carrying the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0435] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 9-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has 1 to 2 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, each example of a heteroaryl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl group.

[0436] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroloyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, aza-aryl. azepinyl, oxygen oxepinyl and thiohexyl Thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinel. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0437] As used herein, “heteroaryl” refers to a heteroaryl group in which two hydrogens have been removed to provide a divalent group. When a range or number of ring members is provided for a particular “heteroaryl”, it should be understood that the range or number refers to the number of ring members in the heteroaryl group. A “heteroaryl” may be substituted or unsubstituted by one or more substituents as described herein.

[0438] "Carbocyclic group" refers to a non-aromatic ring system having 3 to 12 ring carbon atoms ("C"). 3-12 A group consisting of a carbocyclic group (“C”) and a non-aromatic hydrocarbon group with zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 10 cyclic carbon atoms (“C”). 3-10 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3-8 The carbocyclic group ("CCO") has 3 to 6 cyclic carbon atoms in some embodiments. 3-6 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 5 to 12 cyclic carbon atoms (“C”). 5-12 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 5 to 8 cyclic carbon atoms (“C”). 5-8 The carbocyclic group (“CCR”) is used in some embodiments. In some embodiments, the carbocyclic group has 5 or 6 cyclic carbon atoms (“C”). 5-6 (Carbocyclic group). Example C 3-6 The carbocyclic group includes, but is not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Example C 3-8 Carbocyclic groups include, but are not limited to, the C groups mentioned above. 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Example C 3-10 Carbocyclic groups include, but are not limited to, the C groups mentioned above.3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spirocyclic [4.5]decyl (C 10 )wait.

[0439] In some embodiments, "carbocyclic group" is a monocyclic saturated carbocyclic group ("C") having 3 to 12 ring carbon atoms. 3-12 "Carbocyclic group"). In some embodiments, "carbocyclic group" is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C"). 3-10 "Carbocyclic group"). In some embodiments, "carbocyclic group" is a monocyclic saturated carbocyclic group having 3 to 8 ring carbon atoms ("C"). 3-8 "Carbocyclic group"). In some embodiments, "carbocyclic group" is a monocyclic saturated carbocyclic group ("C") having 3 to 6 ring carbon atoms. 3-6 "Carbocyclic group"). In some embodiments, "carbocyclic group" is a monocyclic saturated carbocyclic group ("C") having 5 to 12 ring carbon atoms. 5-12 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 5 to 8 cyclic carbon atoms (“C”). 5-8 "Carbocyclic group"). In some embodiments, "carbocyclic group" is a monocyclic saturated carbocyclic group having 5 or 6 ring carbon atoms ("C"). 5-6 (Carbocyclic group). C 5-6 Examples of carbocyclic groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of carbocyclic groups include the C mentioned above. 5-6 Carbocyclic groups, as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of carbocyclic groups include the C mentioned above. 3-6 Carbocyclic groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise stated, each example of a carbocyclic group is independently unsubstituted (“unsubstituted carbocyclic group”) or substituted with one or more substituents (“substituted carbocyclic group”). In some embodiments, the carbocyclic group is an unsubstituted C7 group. 3-12 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3-12 Carbon cyclic group.

[0440] As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is a monocyclic (“monocyclic carbocyclic”) or a polycyclic (“polycyclic carbocyclic”) containing a fused, bridged, or spirocyclic system, and may be saturated or partially unsaturated. Unless otherwise stated, each example of the carbocyclic group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted carbocyclic”) or substituted with one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group is an unsubstituted C 3-12 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3-12 Carbon cyclic group.

[0441] "Fused carbocyclic group" or "fused carbocyclic ring" refers to a ring system in which a carbocyclic group as defined above is fused with one or more carbocyclic groups as defined above, i.e., sharing two common atoms (and therefore, sharing a common bond), with the bonding point located on either fused ring. In such cases, the number of carbon atoms indicates the total number of carbon atoms in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on either fused ring.

[0442] "Spirocyclic carbide" or "spirocyclic" refers to a ring system in which a carbide group as defined above forms a spirocyclic structure with one or more carbide groups as defined above, i.e., sharing a common atom, with the bonding point located on the carbide group ring into which the spirocyclic structure is embedded. In such cases, the number of carbon atoms represents the total number of carbon atoms in the carbide group ring into which the spirocyclic structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on the carbide group ring into which the spirocyclic structure is embedded.

[0443] "Bridged carbocyclic group" or "bridged carbocyclic ring" refers to a ring system in which a carbocyclic group as defined above forms a bridged structure with one or more carbocyclic groups as defined above, i.e., sharing more than two atoms (and therefore more than one bond), with the connection point located on any of the carbocyclic rings with the bridged structure. In such cases, the number of carbon atoms represents the total number of carbon atoms in the carbocyclic ring with the bridged structure. When substitution is indicated, unless otherwise specified, substitution can occur on any carbocyclic ring with the bridged structure.

[0444] As used herein, a “carbocyclic group” refers to a carbocyclic group in which two hydrogens have been removed to provide a divalent group. The divalent group may be present on different atoms or on the same atom of the carbocyclic group. When providing a range or number of carbons for a particular “carbocyclic group,” it should be understood that the range or number refers to the range or number of carbons in the carbocyclic group. A “carbocyclic group” may be substituted or unsubstituted by one or more substituents as described herein.

[0445] "Heterocyclic group" refers to a group having a cyclic carbon atom and 1 to 4 cyclic heteroatoms in a 3 to 12-membered nonaromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3 to 12-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linking point can be a carbon or nitrogen atom, where the valence allows. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolane, oxothiofuran, dithiofuran, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thioalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazine, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azoheptanyl, oxecanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused with an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0446] In some embodiments, the heterocyclic group is a 5- to 12-membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5- to 8-membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5- to 6-membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclic group”). In some embodiments, the 5- to 6-membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0447] As illustrated in the foregoing examples, in some embodiments, the heterocyclic group may be a monocyclic (“monocyclic heterocyclic group”) or a polycyclic (“polycyclic heterocyclic group”) containing a fused, bridged, or spirocyclic system, and may be saturated or partially unsaturated. The heterocyclic polycyclic system may include one or more heteroatoms in one or two rings. “Hypercyclic group” also includes ring systems in which the heterocyclic group as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring, and in such cases, the number of ring members represents the total number of ring members in the entire ring system. When substitution is indicated in such cases, unless otherwise stated, substitution may occur on the heterocyclic group or on one or more carbocyclic groups. Unless otherwise stated, each example of a heterocyclic group is optionally substituted independently, i.e., unsubstituted (“unsubstituted heterocyclic group”) or substituted with one or more substituents (“substituted heterocyclic group”). In some embodiments, the heterocyclic group is an unsubstituted 3- to 12-membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3- to 12-membered heterocyclic group.

[0448] A “fused heterocyclic group” or “fused heterocycle” refers to a ring system in which a heterocyclic group as defined above is fused with one or more heterocyclic groups or carbocyclic groups as defined above, i.e., sharing two common atoms (and therefore, sharing a common bond), with the connection point located on either fused ring. In such cases, the number of ring members indicates the total number of ring members in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on either fused ring.

[0449] "Spirocyclic heterogroup" or "spirocyclic" refers to a ring system in which a heterocyclic group as defined above forms a spirocyclic structure with one or more heterocyclic or carbocyclic groups as defined above, i.e., sharing a common atom, with the bonding point located on the heterocyclic or carbocyclic ring in which the spirocyclic structure is embedded. In such cases, the number of ring members indicates the total number of ring members in the heterocyclic or carbocyclic ring in which the spirocyclic structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclic or carbocyclic rings in which the spirocyclic structure is embedded.

[0450] A “bridged heterocyclic group” or “bridged heterocycle” refers to a ring system in which a heterocyclic group as defined above forms a bridged structure with one or more heterocyclic groups or carbocyclic groups as defined above, i.e., sharing more than two atoms (and therefore more than one bond), with the connection point located on the heterocyclic group or carbocyclic ring with the bridged structure. In such cases, the number of ring members indicates the total number of ring members of the heterocyclic group or carbocyclic ring with the bridged structure. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclic groups or carbocyclic rings with the bridged structure.

[0451] As used herein, a “hybridized group” refers to a heterocyclic group in which two hydrogens have been removed to provide a divalent group. The divalent group may be present on different atoms or on the same atom of the hybridized group. When a range or number of ring members is provided for a particular “hybridized group,” it should be understood that the range or number refers to the number of ring members in the hybridized group. A “hybridized group” may be substituted or unsubstituted by one or more substituents as described herein.

[0452] As used herein, "alkoxy" refers to the group -OR, where R is an alkyl group as defined herein. 1-6 Alkoxy groups refer to the -OR group, where each R is a C as defined herein. 1-6 Alkyl, C 3-4 Carbocyclic or 3- to 4-membered heterocyclic groups. Example C 1-6 Alkyl groups are as described above.

[0453] As used herein, “alkylamino” refers to the group -NHR or -NR2, where each R is independently an alkyl group as defined herein. 1-6 Alkylamino refers to the group -NHR or -NR2, where each R is independently a C as defined herein. 1-6 Alkyl, C 3-4 Carbocyclic or 3- to 4-membered heterocyclic groups. Example C 1-6 Alkyl groups are as described above.

[0454] "Oxidation" refers to the =O group. When a group or atom other than aryl and heteroaryl is substituted with oxygen, it is intended to indicate that the two geminal groups on that group or atom form a double bond with an oxygen radical. When a heteroaryl group is substituted with oxygen, it is intended to indicate that the resonance structure / tautomer of the heteroatom provides a carbon atom capable of forming two geminal groups that form a double bond with an oxygen radical.

[0455] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen is fluorine or chlorine.

[0456] As used herein, "protecting group" is a term recognized in the art and refers to a chemical moiety introduced into a molecule by chemically modifying a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to achieve chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups requiring protection include, but are not limited to, hydroxyl, amino, thiols, and carboxylic acids. Therefore, protecting groups are referred to as hydroxyl protecting groups, amino protecting groups, thiol protecting groups, and carboxylic acid protecting groups, respectively.

[0457] Common types of hydroxyl protecting groups include, but are not limited to, ethers (e.g., methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p-methoxyphenyl (PMP), tert-butyl, triphenylmethyl / trityl, allyl and benzyl (Bn) ethers), silyl ethers (e.g., tert-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), triisopropylsilyloxymethyl (TOM) and tert-butyldimethylsilyl (TBDMS) ethers) and esters (e.g., neopentanoate (Piv) and benzoic acid ester / benzoate (Bz)).

[0458] Common types of amino protecting groups include, but are not limited to, urethane esters (e.g., tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzylcarbonyl (Moz or MeOZ), 2,2,2-trichloroethoxycarbonyl (Troc) and benzyl urethane ester (Cbz)), esters (e.g., acetyl (Ac), benzoyl (Bz), trifluoroacetyl and phthalimide), amines (e.g., benzyl (Bn), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP) and triphenylmethyl (triphenylmethyl / trityl)) and sulfonamides (e.g., toluenesulfonyl (Ts), N-alkylnitrobenzenesulfonamide (nitrobenzenesulfonyl (Nosyl)) and 2-nitrobenzenethio (Nps)).

[0459] Common types of thiol protecting groups include, but are not limited to, sulfides (e.g., p-methylbenzyl (Meb), tert-butyl, acetamylmethyl (Acm), and triphenylmethyl / Trityl).

[0460] Common types of carboxylic acid protecting groups include, but are not limited to, esters (e.g., methyl esters, triphenylmethyl / Trityl esters, tert-butyl esters, benzyl esters (Bn), S-tert-butyl esters, silyl esters, and orthoesters) and oxazolines.

[0461] These and other exemplary substituents are described in more detail in the detailed description, embodiments, and claims. This invention is not intended to be limited in any way by the above list of exemplary substituents.

[0462] Other definitions

[0463] "Pharmaceutical acceptable" means approved or permitted by a federal or state regulatory agency or a corresponding agency in a country outside the United States, or listed in the United States Pharmacopeia for animal (more particularly, human) or other recognized pharmacopoeias.

[0464] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be addition salts of inorganic or organic acids and addition salts of bases. Specifically, such salts include: (1) acid addition salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or salts formed with organic acids (such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid). (1) Acid addition salts formed by the formation of acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or coordinated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc.). By way of example only, salts further include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium salts, etc.; and when the compound contains a basic functional group, salts further include salts of non-toxic organic acids or inorganic acids, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc.

[0465] The term “pharmaceutically acceptable cation” refers to an acceptable cationic counterion with an acidic functional group. Examples of such cations include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, etc. (see, for example, Berge et al., J. Pharm. Sci. 66(1):1-79(1 / 77)).

[0466] "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or carrier that is administered together with the compounds of the present invention.

[0467] A “pharmaceutically acceptable metabolically cleavable group” is a group that can be cleaved in vivo to produce a parent molecule with the structure shown herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONR2, and -CH2OR groups, wherein R, each time it appears, is independently selected from alkyl, trialkylsilyl, carbocyclic aryl, or a carbocyclic aryl group substituted with one or more of alkyl, halogen, hydroxyl, or alkoxy groups. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl, and trimethylsilyl.

[0468] "Solventrolyte" refers to a compound that typically associates with a solvent or water (also called "hydrate") via a solvent decomposition reaction. This physical association includes hydrogen bonding. Common solvents include water, ethanol, acetic acid, etc. The compounds of this invention can be prepared, for example, in crystalline form and can be solvated or hydrated. Suitable solvventrolytes include pharmaceutically acceptable solvventrolytes, such as hydrates, and further include both stoichiometric and non-stoichiometric solvventrolytes. In some cases, solvventrolytes will be separable, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solventrolyte" includes both solution phases and separable solvventrolytes. Representative solvventrolytes include hydrates, ethanolates, and methanolates.

[0469] The intended "subject" includes, but is not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0470] "Effective dose" refers to the amount of a compound that, when administered to a subject for the treatment or prevention of a disease, is sufficient to achieve such treatment or prevention. The "effective dose" can vary depending on the compound, the disease and its severity, and the age and weight of the subject being treated. "Therapeutic effective dose" refers to an effective dose for therapeutic treatment. "Prophylactic effective dose" refers to an effective dose for preventative treatment.

[0471] "Preventing," "prevention," or "prophylactic treatment" refers to reducing the risk of acquiring or developing a disease or condition (i.e., the absence of at least one clinical symptom of the disease in subjects who have not been exposed to the causative agent or in subjects who are susceptible to the disease before the onset of the disease).

[0472] The term “prophylaxis” is related to “prevention” and refers to measures or procedures whose purpose is to prevent rather than treat or cure a disease. Non-limiting examples of preventive measures may include: administering vaccines; administering low molecular weight heparin to hospitalized patients at risk of thrombosis (e.g., due to lack of mobility); and administering antimalarial agents (such as chloroquine) before visiting geographical areas where malaria is endemic or where the risk of malaria infection is high.

[0473] In one implementation, “treating,” “treatment,” or “therapeutic treatment” refers to improving any disease or condition (i.e., curbing the disease or reducing the manifestation, extent, or severity of at least one clinical symptom). In another implementation, “treating” or “treatment” refers to improving at least one bodily parameter that may not be discernible by the subject. In yet another implementation, “treating” or “treatment” refers to modulating a disease or condition physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing bodily parameters), or both. In yet another implementation, “treating” or “treatment” involves slowing the progression of a disease.

[0474] It should also be understood that compounds with the same molecular formula but different atomic bonding properties or sequences, or different spatial arrangements of atoms, are called "isomers". Isomers with different spatial arrangements of atoms are called "stereoisomers".

[0475] Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and described by the R and S sequence rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarization and is designated as dextrorotatory or levorotatory (i.e., (+)- or (-)- isomers, respectively). Chiral compounds can exist as a single enantiomer or a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0476] "Tautomers" are compounds with specific structures that have interchangeable forms and vary in terms of hydrogen atom and electron shifts. Thus, the two structures can be kept in equilibrium through the movement of electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with an acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with an acid or base. The tautomer form may be related to obtaining optimal chemical reactivity and biological activity of the desired compound.

[0477] As used herein, a pure enantiomer is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer excess). In other words, the “S” form of the compound is substantially free of the “R” form of the compound, and therefore the “R” form enantiomer is in excess. The terms “enantiomerically pure” or “pure enantiomer” mean that the compound contains more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% of the enantiomers by weight. In some embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0478] As used herein and unless otherwise stated, the term "enantiomerically pure (R)-compound" means at least about 95% (R)-compound and at most about 5% (S)-compound by weight, at least about 99% (R)-compound and at most about 1% (S)-compound by weight, or at least about 99.9% (R)-compound and at most about 0.1% (S)-compound by weight. In some embodiments, the weight is based on the total weight of the compounds.

[0479] As used herein and unless otherwise stated, the terms "enantiomerically pure (S)-compound" or "(S)-compound" mean at least about 95% (S)-compound and at most about 5% (R)-compound by weight, at least about 99% (S)-compound and at most about 1% (R)-compound by weight, or at least about 99.9% (S)-compound and at most about 0.1% (R)-compound by weight. In some embodiments, the weight is based on the total weight of the compounds.

[0480] In the compositions provided herein, enantiomerically pure compounds or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure (R)-compound may comprise, for example, about 90% excipients and about 10% enantiomerically pure (R)-compound. In some embodiments, the enantiomerically pure (R)-compound in such a composition may, for example, comprise at least about 95% (R)-compound by weight and at most about 5% (S)-compound by weight, based on the total weight of the compounds. For example, a pharmaceutical composition comprising an enantiomerically pure (S)-compound may comprise, for example, about 90% excipients and about 10% enantiomerically pure (S)-compound. In some embodiments, the enantiomerically pure (S)-compound in such a composition may, for example, comprise at least about 95% (S)-compound by weight and at most about 5% (R)-compound by weight, based on the total weight of the compounds. In some implementations, the active ingredient can be formulated with minimal or no excipients or carriers.

[0481] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be produced as individual (R)- or (S)- stereoisomers or mixtures thereof.

[0482] Unless otherwise stated, the description or naming of specific compounds in this specification and claims is intended to include both their individual enantiomers and mixtures (racemic or otherwise). Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0483] When referring to a number or range of values, the term “about” means that the number or range of values ​​mentioned is an approximation within experimental variability (or within statistical experimental error), and therefore in some cases, the number or range of values ​​will vary between 1% and 15% of the stated number or range of values.

[0484] The term “comprising” (and related terms such as “comprise”, “comprise”, “having”, or “including”) is not intended to exclude other embodiments, such as any embodiment of a substance composition, composition, method, or process described herein, from being “composed of the described features” or “substantially composed of the described features”.

[0485] The phrase “and / or” as used herein in the specification and claims should be understood to mean “any one or both” of the elements so combined, that is, elements that are combined in some cases and uncombined in others. Multiple elements listed with “and / or” should be interpreted in the same way, that is, “one or more” elements so combined. In addition to the elements specifically identified by the “and / or” clause, other elements may optionally be present, whether or not they are related to those specifically identified. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “comprising”, reference to “A and / or B” may refer only to A in one embodiment (optionally including elements other than B); only to B in another embodiment (optionally including elements other than A); both A and B in yet another embodiment (optionally including other elements); and so on.

[0486] As used herein in the specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” should be interpreted as inclusive, that is, including at least one of the number or list of elements and, optionally, more than one, of items not listed. Only terms that expressly indicate the opposite, such as “only one of…” or “exact one of…”, or when used in the claims, “consisting of…” will refer to the number or list of elements including exactly one element. In general, the term “or” as used herein, when used before exclusive terms (such as “any one,” “one of…,” “only one of…,” or “exact one of…”), should be interpreted only as indicating an exclusive alternative (i.e., “one or another but not two”). When used in the claims, “consisting substantially of…” should have its ordinary meaning as used in the field of patent law.

[0487] As used herein in the specification and claims, the phrase “at least one” in relation to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase “at least one,” whether or not they are related to those specifically identified elements. Thus, as a non-limiting example, “at least one of A and B” (or equivalently, “at least one of A or B,” or equivalently, “at least one of A and / or B”) in one embodiment may refer to at least one (optionally including more than one) A, without B (and optionally including elements other than B); in another embodiment, it refers to at least one (optionally including more than one) B, without A (and optionally including elements other than A); in yet another embodiment, it refers to at least one (optionally including more than one) A and at least one (optionally including more than one) B (and optionally including other elements); and so on.

[0488] While this teaching has been described in conjunction with various implementations and examples, it is not intended to limit this teaching to such implementations or examples. Rather, as those skilled in the art will understand, this teaching encompasses various alternatives, modifications, and equivalents.

[0489] While various inventive embodiments have been described and illustrated herein, those skilled in the art will readily envision various other ways and / or structures to perform the functions and / or obtain the results and / or one or more advantages described herein, and each of such variations and / or modifications is considered to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily understand that all parameters, dimensions, materials, and configurations described herein are intended to be exemplary, and actual parameters, dimensions, materials, and / or configurations will depend on one or more specific applications using the teachings of this invention. Those skilled in the art will recognize many equivalents of the specific inventive embodiments described herein. Therefore, it should be understood that the above embodiments are presented by way of example only, and that inventive embodiments may be practiced in ways other than those specifically described and claimed within the scope of the appended claims and their equivalents. The inventive embodiments of this disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. Furthermore, any combination of two or more such features, systems, articles, materials, kits, and / or methods is included within the scope of this disclosure if such features, systems, articles, materials, kits, and / or methods are not inconsistent with each other.

[0490] Unless described as having that effect, the claims should not be construed as being limited to the order or elements described. It should be understood that various changes in form and detail may be made by those skilled in the art without departing from the spirit and scope of the appended claims. All embodiments within the spirit and scope of the following claims and their equivalents are claimed.

[0491] Example

[0492] To provide a fuller understanding of the invention described herein, the following embodiments are illustrated. The embodiments described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting their scope in any way.

[0493] I. Synthesis and Characterization of Intermediates and Compounds 1-318

[0494] In the following examples, the chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Company) and used without further purification.

[0495] When obtaining the compounds and corresponding analytical data described in the following examples, unless otherwise stated, the following experimental and analytical protocols were followed.

[0496] Unless otherwise specified, the reaction mixture is magnetically stirred at room temperature (rt) under a nitrogen atmosphere. When solutions are “dried,” they are typically dried with a drying agent such as Na₂SO₄ or MgSO₄. When mixtures, solutions, and extracts are “concentrated,” they are typically concentrated on a rotary evaporator under reduced pressure.

[0497] Compounds can be purified using a variety of traditional methods as needed, including but not limited to preparative chromatography using normal-phase or reversed-phase HPLC, fast columns, or preparative TLC plates under acidic, neutral, or alkaline conditions.

[0498] Rapid chromatography was performed on a Biotage Isolera One column with 200-300 mesh silica gel particles. Analytical and preparative thin-layer chromatography were performed using silica gel 60GF254 plates. Normal-phase silica gel chromatography (FCC) was also performed on silica gel (SiO2) using pre-packed cylindrical columns.

[0499] Preparative reversed-phase high-performance liquid chromatography (RP HPLC) was performed on any of the following:

[0500] Method A

[0501] Preparative HPLC, YMC-Actus Triart 18C (5μm, 20x250mm), mobile phase: 5%-99% ACN in water (0.1% HCOOH) solution, for 10 min, followed by 2 min at 100% ACN, flow rate: 25 mL / min; or

[0502] Method B

[0503] Preparative supercritical fluid high-performance liquid chromatography (SFC) was performed on a Thar 80Prep-SFC system or a Waters 80Q Prep-SFC system from Waters. ABPR was set to 100 bar to maintain CO2 under SF conditions, and the flow rate was validated based on compound characterization, ranging from 50 g / min to 70 g / min. Column temperature was ambient temperature.

[0504] Unless otherwise specified, nuclear magnetic resonance (NMR) spectra were recorded using a Brucker AVANCE NEO 400 MHz spectrometer at approximately 20–30 °C. The following abbreviations were used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet; ddd, double doublet; dt, double triplet; bs, broad peak signal. Chemical shifts were reported in parts per million (ppm, δ) from the low field of tetramethylsilane. It should be understood that for compounds containing exchangeable protons, these protons may be visible or invisible on the NMR spectrum, depending on the choice of solvent used to operate the NMR spectra and the concentration of the compound in solution.

[0505] Unless otherwise specified, mass spectra (MS) were obtained on a SHIMADZU LCMS-2020MSD using positive mode electrospray ionization (ESI). Calculated (calcd.) masses correspond to exact masses.

[0506] Use ChemDraw Ultra 12.0, ChemDraw Ultra 14.0 (CambridgeSoft Corp., Cambridge, MA) or ACD / Name version 10.01 (Advanced Chemistry) to generate chemical names.

[0507] Compounds designated as R* or S* are enantiomeric pure compounds with indeterminate absolute configuration.

[0508] Intermediate 1: 5-Clomidazolo[1,5-a]pyridine-7-carboxaldehyde

[0509]

[0510] Step A: Methyl 2-(bromomethyl)-6-chloropyridine-4-carboxylate

[0511] A solution of methyl 2-chloro-6-methylpyridine-4-carboxylate (9 g, 48.489 mmol, 1.0 equivalent), NBS (11.22 g, 63.036 mmol, 1.3 equivalent), and AIBN (0.717 mL, 4.849 mmol, 0.1 equivalent) in CCl4 (180 mL) was stirred at 90 °C for 12 h under nitrogen. After cooling to room temperature, the mixture was diluted with cold water (300 mL) and extracted with DCM (300 mL x 3). The combined organic extracts were washed with water (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residues were purified by rapid column chromatography on silica gel (PE solution of EA, from 0 to 10%) to give a mixture (20 g). DIPEA (25.3 mL, 145.467 mmol, 3.0 equivalent) and diethyl phosphite (18.7 mL, 145.467 mmol, 3.0 equivalent) were added to a solution of the mixture (20 g) in THF (300 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 4 h. The mixture was diluted with (300 mL) and extracted with EA (300 mL x 3). The organic layer was washed with water (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE solution of EA, from 0 to 4%) to give methyl 2-(bromomethyl)-6-chloroisonicotinic acid (10 g, 78% yield) as a white solid.

[0512] LC-MS (ESI): Computed mass of C8H7BrClNO2, 262.93; Measured m / z, 264.3 [M+H] + .

[0513] Step B: Methyl 2-(azidomethyl)-6-chloropyridine-4-carboxylate

[0514] A solution of methyl 2-(bromomethyl)-6-chloropyridin-4-carboxylate (8 g, 30.245 mmol, 1.0 equivalent) and sodium azide (3.93 g, 60.489 mmol, 2.0 equivalent) in DMF (80 mL) was stirred at room temperature for 12 h. The mixture was diluted with cold water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with brine (150 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide crude methyl 2-(azidomethyl)-6-chloropyridin-4-carboxylate (6 g, 87% yield) as a yellow oil.

[0515] LC-MS (ESI): Calculated mass of C8H7ClN4O2, 226.03; Measured m / z, 227.1 [M+H] + .

[0516] Step C: Methyl 2-(aminomethyl)-6-chloropyridine-4-carboxylate

[0517] A solution of methyl 2-(azidomethyl)-6-chloropyridin-4-carboxylate (6 g, 26.476 mmol, 1.0 equivalent) and PPh3 (10.42 g, 39.714 mmol, 1.5 equivalent) in THF (80 mL) and H2O (8 mL) was heated at 50 °C for 1 h. After evaporation, the mixture was dissolved in an aqueous HCl solution (2 N) (50 mL) and extracted with DCM (50 mL x 3). The organic layer was discarded and the aqueous layer was concentrated under reduced pressure to obtain methyl 2-(aminomethyl)-6-chloropyridin-4-carboxylate hydrochloride (4.4 g, 70% yield) as a white solid.

[0518] LC-MS (ESI): Calculated mass of C8H9ClN2O2, 200.04; Measured m / z, 201.1 [M+H] + .

[0519] Step D: Methyl 2-chloro-6-(formamidomethyl)pyridine-4-carboxylate

[0520] A solution of methyl 2-(aminomethyl)-6-chloropyridin-4-carboxylate hydrochloride (1.5 g, 7.476 mmol, 1.0 equivalent) in ethyl formate (30 mL) was mixed with NaHCO3 (0.31 g, 3.738 mmol, 0.5 equivalent) and triethylamine (1.6 mL, 11.214 mmol, 1.5 equivalent), and the mixture was refluxed for 10 h. After filtration, the filtrate was concentrated to give crude methyl 2-chloro-6-(formamidomethyl)pyridin-4-carboxylate (1.20 g, 70% yield) as a brown oil. The crude product was used in the next step without further purification.

[0521] LC-MS (ESI): Calculated mass of C9H9ClN2O3, 228.03; Measured m / z, 229.2 [M+H] + .

[0522] Step E: Methyl 5-chloroimidozolo[1,5-a]pyridine-7-carboxylate

[0523] To a solution of methyl 2-chloro-6-(formamidomethyl)pyridine-4-carboxylate (1.2 g, 5.249 mmol, 1.0 equivalent) in dioxane (20 mL), POCl3 (0.978 mL, 10.497 mmol, 2.0 equivalent) was added, and the mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature, quenched with a saturated aqueous solution of NaHCO3 (50 mL) at 0 °C, and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (petroleum ether solution of EtOAc, 30%) to give methyl 5-chloroimidazolo[1,5-a]pyridine-7-carboxylate (340 mg, 28% yield) as a yellow solid.

[0524] LC-MS (ESI): Calculated mass of C9H7ClN2O2, 210.02; Measured m / z, 211.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.69(s,1H),8.41(s,1H),7.94(s,1H),7.25(s,1H),3.87(s,3H).

[0525] Step F: {5-chloroimidazolo[1,5-a]pyridin-7-yl}methanol

[0526] At -78°C under N2, DIBAL-H (1N THF solution) (2.4 mL, 2.421 mmol, 1.5 equivalent) was added dropwise to a solution of methyl 5-chloroimidazolo[1,5-a]pyridin-7-carboxylate (340 mg, 1.614 mmol, 1.0 equivalent) in anhydrous THF (15 mL), and the mixture was stirred at room temperature for 30 min. The mixture was diluted with THF (30 mL) and slowly quenched with Na2SO4·10H2O, and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (petroleum ether solution of EtOAc, 50%) to give {5-chloroimidazolo[1,5-a]pyridin-7-yl}methanol (250 mg, 76.33% yield) as a yellow solid.

[0527] LC-MS (ESI): Computed mass of C8H7ClN2O, 182.02; Measured m / z, 183.2 [M+H] + .

[0528] Step G: 5-Clomidazolo[1,5-a]pyridine-7-carboxaldehyde

[0529] Add Desmond-Martin periodane (1.279 mL, 4.107 mmol, 3.0 equivalent) to a solution of {5-chloroimidazolo[1,5-a]pyridin-7-yl}methanol (250 mg, 1.369 mmol, 1.0 equivalent) in DCM (5 mL) and stir the reaction at room temperature for 1 h. Quench the reaction mixture with an aqueous solution of Na₂SO₃ (20 mL) and extract with EtOAc (30 mL x 3). Wash the organic layer with brine (20 mL), dry to anhydrous Na₂SO₄, filter, and concentrate under reduced pressure. Purify the crude product by rapid column chromatography on silica gel (petroleum ether solution of EtOAc, 50%) to give 5-chloroimidazolo[1,5-a]pyridin-7-carboxaldehyde (200 mg, 73% yield) as a yellow solid.

[0530] LC-MS (ESI): Computed quality of C8H5ClN2O, 180.01; Measured m / z, 181.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ9.82 (s, 1H), 8.71 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.15 (d, J = 1.0hz, 1H).

[0531] Intermediate 2: 8-Bromoimidazolo[1,2-a]pyridine-6-carboxaldehyde

[0532]

[0533] Step A: Methyl 8-bromoimidazolo[1,2-a]pyridine-6-carboxylate

[0534] A solution of methyl 6-amino-5-bromopyridine-3-carboxylate (2 g, 8.656 mmol, 1.0 equivalent), 2-chloroacetaldehyde (2.062 mL, 12.984 mmol, 1.5 equivalent), and NaHCO3 (1.09 g, 12.984 mmol, 1.5 equivalent) in EtOH (40 mL) was stirred at 80 °C under nitrogen for 12 h. After evaporation, the mixture was diluted with cold water (100 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic extracts were washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (EA / PE = 1 / 2) to obtain methyl 8-bromoimidazolo[1,2-a]pyridine-6-carboxylate (1.5 g, 61% yield) as a yellow solid.

[0535] LC-MS (ESI): Computed mass of C9H7BrN2O2, 253.97; Measured m / z, 254.4 [M+H] + .1 HNMR (400MHz, CDCl3) δ8.90 (s, 1H), 8.01 (s, 1H), 7.76 (d, J = 6.8Hz, 2H), 3.96 (s, 3H).

[0536] Step B: {8-bromoimidazolo[1,2-a]pyridin-6-yl}methanol

[0537] Under N2 at -78°C, DIBAL-H (1N THF solution) (88.2 mL, 88.210 mmol, 1.5 equivalents) was added dropwise to a solution of methyl 8-bromoimidazolo[1,2-a]pyridin-6-carboxylate (15 g, 58.807 mmol, 1.0 equivalent) in THF (300 mL). The mixture was then heated to 0°C and stirred for 1 hour. The reaction mixture was diluted with THF (150 mL) and slowly quenched with Na2SO4·10H2O. After filtration, the filtrate was concentrated and purified by rapid column chromatography on silica gel (EA / PE = 1 / 1) to obtain {8-bromoimidazolo[1,2-a]pyridin-6-yl}methanol (10 g, yield 67.4%) as a white solid.

[0538] LC-MS (ESI): Computed quality of C8H7BrN2O, 225.97; Measured m / z, 227.4 [M+H] + .

[0539] Step C: 8-Bromoimidazolo[1,2-a]pyridine-6-carboxaldehyde

[0540] Add Desmond-Martin periodane (41.145 mL, 132.124 mmol, 3.0 equivalent) to a solution of {8-bromoimidazolo[1,2-a]pyridin-6-yl}methanol (10 g, 44.041 mmol, 1.0 equivalent) in DCM (100 mL), and stir the mixture at room temperature for 1 hour. Pour the residue into water (60 mL) and extract with EtOAc (60 mL x 4). Dry the organic layer over anhydrous MgSO4, filter, and concentrate under reduced pressure. Purify the residue on silica gel (EA / PE = 1 / 1) by rapid column chromatography to obtain 8-bromoimidazolo[1,2-a]pyridin-6-carboxaldehyde (8 g, 73% yield) as a yellow solid.

[0541] LC-MS (ESI): Computed quality of C8H5BrN2O, 223.96; Measured m / z, 225.5 [M+H] + .

[0542] Intermediate 3: 5-chloro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxaldehyde

[0543]

[0544] Step A: tert-butyl 2-chloro-6-hydrazinopyridine-4-carboxylate

[0545] Hydrazine (3.23 g, 100.762 mmol, 5.0 equivalent) was added to a solution of tert-butyl 2,6-dichloropyridine-4-carboxylate (3.912 mL, 20.152 mmol, 1.0 equivalent) in EtOH (20 mL). The mixture was stirred at 75 °C for 18 h. The mixture was cooled to room temperature, concentrated to half its volume under reduced pressure, and a solid precipitated. The solid was filtered off and the filtrate was concentrated to dryness to give crude tert-butyl 2-chloro-6-hydrazidopyridine-4-carboxylate (4.1 g, 83% yield) as a yellow solid.

[0546] LC-MS (ESI): C 10 H 14 The calculated mass of ClN3O2 is 243.08; the measured m / z value is 244.0 [M+H]. + .

[0547] Step B: tert-butyl 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate

[0548] The mixture of tert-butyl 2-chloro-6-hydrazinopyridine-4-carboxylate (4.1 g, 16.825 mmol, 1.0 equivalent) in trimethyl orthoformate (15 mL) was stirred at 85 °C for 5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography on silica gel (petroleum ether solution of ethyl acetate, from 0 to 50%) to provide tert-butyl 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (1.8 g, 42% yield).

[0549] LC-MS (ESI): C 11 H 12 The calculated mass of ClN3O2 is 253.06; the measured m / z value is 254.1 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ9.61 (s, 1H), 8.33 (s, 1H), 7.47 (d, J = 1.0Hz, 1H), 1.59 (s, 9H).

[0550] Step C: 7-Chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid

[0551] TFA (20 mL) was added to a solution of tert-butyl 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid (4.2 g, 16.556 mmol, 1.0 equivalent) in DCM (20 mL). The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure to give 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid (1.8 g, 55% yield) as a crude yellow solid.

[0552] LC-MS (ESI): Calculated mass of C7H4ClN3O2, 197.00; Measured m / z, 198.1 [M+H] + .

[0553] Step D: (5-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol

[0554] At 0 °C, a borane-tetrahydrofuran complex (1N) (45.5 mL, 45.551 mmol, 5.0 equivalent) was added dropwise to a solution of 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid (1.8 g, 9.110 mmol, 1.0 equivalent) in THF (20 mL). The reaction mixture was heated at room temperature for 24 h. After cooling to 0 °C, the mixture was slowly quenched with methanol (50 mL) and refluxed for 1 h. After evaporation, the residue was partitioned between ethyl acetate (200 mL) and an aqueous solution of NaOH (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (a chloroform solution of methanol, from 0 to 5%) to give {7-chloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl}methanol (760 mg, 45% yield) as a yellow solid.

[0555] LC-MS (ESI): Computed quality of C7H6ClN3O, 183.02; Measured m / z, 184.1 [M+H] + .

[0556] Step E: 7-Chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxaldehyde

[0557] Add Desmond-Martin periodane (2.15 g, 5.065 mmol, 1.5 equivalent) to a solution of {7-chloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl}methanol (620 mg, 3.377 mmol, 1.0 equivalent) in DCM (20 mL) and stir the mixture at room temperature for 2 h. Dilute the mixture with EtOAc (60 mL), wash with saturated Na2S2O3 aqueous solution (30 mL), saturated NaHCO3 aqueous solution (20 mL), and brine (20 mL). Dry the organic layer with anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the crude product by rapid chromatography on silica gel (petroleum ether / EtOAc = 50 / 1) to provide 7-chloro-[1,2,4]triazolo[4,3-a]pyridin-5-carboxaldehyde (350 mg, 57% yield) as a yellow oil.

[0558] LC-MS (ESI): Computed quality of C7H4ClN3O, 181.02; Measured m / z, 182.1 [M+H] + .

[0559] Intermediate 4: 4-Bromo-1-methyl-1H-benzo[d]imidazol-6-carboxaldehyde

[0560]

[0561] Step A: 4-Bromo-1-methyl-1H-1,3-benzodiazole-6-carboxynitrile

[0562] Under nitrogen atmosphere at 0 °C, NaH (60% suspended in oil) (0.27 g, 6.756 mmol, 1.5 equivalent) was added to a solution of 4-bromo-1H-1,3-benzodiazole-6-carboxynitrile (1.0 g, 4.504 mmol, 1.0 equivalent) in DMF (20 mL). The reaction mixture was stirred at 0 °C for 1 h, and then methyl iodoform (0.83 g, 5.855 mmol, 1.3 equivalent) was added dropwise to the mixture, and the mixture was stirred at 0 °C for 1 h. The mixture was diluted with cold water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (30 mL x 4), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (10% petroleum ether solution of ethyl acetate) to give 4-bromo-1-methyl-1H-benzo[d]imidazolium-6-carboxynitrile (0.314 g, 29% yield) as a white solid.

[0563] LC-MS (ESI): Computed quality of C9H6BrN3, 234.97; Measured m / z, 235.98 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.56 (s, 1H), 8.31 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H), 3.92 (s, 3H).

[0564] Step B: 4-Bromo-1-methyl-1H-1,3-benzodiazole-6-carboxaldehyde

[0565] Under nitrogen atmosphere at 0 °C, DIBAL-H (1.5N THF solution) (0.63 mL, 0.953 mmol, 1.5 equivalent) was added dropwise to a solution of 4-bromo-1-methyl-1H-1,3-benzodiazole-6-carboxynitrile (150 mg, 0.635 mmol, 1.0 equivalent) in toluene (10 mL). The reaction mixture was stirred at room temperature for 1 h, diluted with aqueous NH4Cl solution (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 4-bromo-1-methyl-1H-1,3-benzodiazole-6-carboxaldehyde (45 mg, 29% yield) as a white solid.

[0566] LC-MS (ESI): Computed quality of C9H7BrN2O, 237.97; Measured m / z, 238.98 [M+H] + .

[0567] Intermediate 5: 3-Iodo-7-(pyrrolidone-1-ylmethyl)imidazo[1,5-a]pyridine

[0568]

[0569] Step A: Imidazolo[1,5-a]pyridin-7-yl(pyrrolidine-1-yl) methyl ketone

[0570] HATU (3.52 g, 9.251 mmol, 1.5 equivalents) and TEA (2.572 mL, 18.501 mmol, 3.0 equivalents) were added to a solution of imidazo[1,5-a]pyridine-7-carboxylic acid (1 g, 6.167 mmol, 1.0 equivalents) and pyrrolidine (0.608 mL, 7.400 mmol, 1.2 equivalents) in DMF (25 mL). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (a solution of methanol in dichloromethane, from 0% to 10%) to provide imidazo[1,5-a]pyridin-7-yl(pyrrolidine-1-yl) methyl ketone as a yellow oil (1.3 g, 98% yield).

[0571] LC-MS (ESI): C 12 H 13 The calculated mass of N3O is 215.11; the measured m / z value is 216 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.35(d,J=7.2Hz,1H),7.81(s,1H),7.50(s,1H),6.78(d,J=7.2Hz,1H),3.52-3.47(m,4H),1.85(s,4H)

[0572] Step B: 7-(pyrrolidone-1-ylmethyl)imidazo[1,5-a]pyridine

[0573] A solution of imidazo[1,5-a]pyridin-7-yl(pyrrolidine-1-yl) methyl ketone (1 g, 4.646 mmol, 1.0 equivalent) and B₂H₆ solution (2N THF solution) (11.614 mL, 23.228 mmol, 5.0 equivalent) in THF (20 mL) was stirred overnight at 70°C under N₂. The reaction mixture was cooled to 0°C, quenched with MeOH (20 mL), and the solution was stirred at 70°C under N₂ for 1 hour. The reaction mixture was cooled to room temperature and concentrated, diluted with water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (methanol in dichloromethane solution, from 0% to 10%) to provide 7-(pyrrolidone-1-ylmethyl)imidazo[1,5-a]pyridine as a yellow oil (800 mg, 85% yield).

[0574] LC-MS (ESI): C 12 H 15 The calculated quality of N3 is 201.13; the measured m / z value is 202.3 [M+H]. + .

[0575] Step C: 3-Iodo-7-(pyrrolidone-1-ylmethyl)imidazo[1,5-a]pyridine

[0576] To a solution of 7-(pyrrolidone-1-ylmethyl)imidazo[1,5-a]pyridine (800 mg, 3.97 mmol, 1.0 equivalent) in THF (20 mL), nBuLi (2N n-hexane solution) (2.385 mL, 5.96 mmol, 1.5 equivalent) was added (2.385 mL, 5.96 mmol, 1.5 equivalent) in THF (20 mL). The mixture was stirred at -78 °C under N2 for 0.5 h. Then, a solution of iodine (1010 mg, 3.97 mmol, 1.0 equivalent) in THF (5 mL) was added dropwise to the above solution. The resulting mixture was stirred at room temperature at -78 °C for 0.5 h. The mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to provide 3-iodo-7-(pyrrolidone-1-ylmethyl)imidazo[1,5-a]pyridine (500 mg, 38% yield) as a yellow oil.

[0577] LC-MS (ESI): C 12 H 14 The calculated quality of IN3 is 327.02; the measured m / z value is 328 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ7.98 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 5.0 Hz, 2H), 6.78 (d, J = 7.2 Hz, 1H), 3.53 (s, 2H), 2.45 (s, 4H), 1.70 (s, 4H).

[0578] Intermediate 6: 3-Iodo-6-(pyrrolidone-1-ylmethyl)imidazo[1,5-a]pyridine

[0579]

[0580] Step A: Imidazolo[1,5-a]pyridin-6-yl(pyrrolidine-1-yl) methyl ketone

[0581] TEA (2.6 mL, 18.5 mmol, 3.0 equivalence) and pyrrolidine (0.76 mL, 9.3 mmol, 1.5 equivalence) were added to a solution of imidazo[1,5-a]pyridine-6-carboxylic acid (1 g, 6.2 mmol, 1.0 equivalence) and HATU (3.5 g, 9.3 mmol, 1.5 equivalence) in DMF (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (40 mL x 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EA = 1 / 1) to provide 1-{imidazo[1,5-a]pyridine-6-carbonyl}pyrrolidine as a yellow solid (900 mg, 68% yield).

[0582] LC-MS (ESI): C 12 H 13 The calculated mass of N3O is 215.11; the measured m / z value is 216.12 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.42(s,1H),7.57(d,J=9.4Hz,1H),7.40(s,1H),6.90(d,J=9.4Hz,1H),3.53-3.47(m,4H),1.88-1.83(m,4H).

[0583] Step B: 6-(pyrrolidone-1-ylmethyl)imidazo[1,5-a]pyridine

[0584] B2H6-Me2S complex (2M THF solution) (7 mL, 14.0 mmol, 5.0 equivalent) was added to a solution of 1-{imidazo[1,5-a]pyridine-6-carbonyl}pyrrolidine (600 mg, 2.8 mmol, 1.0 equivalent) in THF (5 mL) at room temperature. The reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with MeOH (5 mL), and then stirred at 70 °C for 30 min. The reaction mixture was diluted with dilute aqueous HCl (1N) (10 mL) and stirred for 30 min, the pH was adjusted to 8 with saturated NaHCO3 solution, and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (DCM / MeOH = 5 / 1) to give 1-({imidazo[1,5-a]pyridin-6-yl}methyl)pyrrolidine (300 mg, yield 53%) as a yellow solid.

[0585] LC-MS (ESI): C 12 H 15 The calculated quality of N3 is 201.13; the measured m / z value is 202.13 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),8.35(s,1H),7.56(d,J=9.4Hz,1H),7.35(s,1 H), 6.83 (d, J = 9.0Hz, 1H), 3.88-3.78 (m, 2H), 2.93-2.74 (m, 4H), 1.86-1.79 (m, 4H).

[0586] Step C: 3-Iodo-6-(pyrrolidone-1-ylmethyl)imidazo[1,5-a]pyridine

[0587] Under N2 at -78°C, n-BuLi (1.6M hexane solution) (0.894 mL, 2.3 mmol, 1.5 equivalence) was added dropwise to a solution of 1-({imidazo[1,5-a]pyridin-6-yl}methyl)pyrrolidine (300 mg, 1.5 mmol, 1.0 equivalence) in anhydrous THF (5 mL). The reaction mixture was stirred at -78°C for 1 h. A solution of I2 (661.2 mg, 1.5 mmol, 1.0 equivalence) in THF (5 mL) was added dropwise to the above mixture, and the resulting reaction mixture was stirred at -78°C for 0.5 h. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (40 mL x 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (DCM / MeOH = 5 / 1) to provide 1-({3-iodoimidazole[1,5-a]pyridin-6-yl}methyl)pyrrolidine (150 mg, 31% yield) as a yellow solid.

[0588] LC-MS (ESI): C 12 H 14 The calculated quality of IN3 is 327.02; the measured m / z value is 328.03 [M+H]. + . 1 HNMR(400MHz,DMSO-d6)δ7.90(s,1H),7.53(d,J=9.4Hz,1H),7.48(s,1H),6.8 5(d,J=9.0Hz,1H),3.61(s,2H),3.42(s,2H),3.04-2.89(m,2H),1.72(s,4H).

[0589] Intermediate 7: 5-Clomidazolo[1,5-a]pyridine-8-carboxaldehyde

[0590]

[0591] Step A: 3-Bromo-2-(Bromomethyl)-6-chloropyridine

[0592] BPO (0.94 g, 3.875 mmol, 0.1 equivalent) and NBS (8.97 g, 50.371 mmol, 1.3 equivalent) were added to a solution of 3-bromo-6-chloro-2-methylpyridine (8 g, 38.747 mmol, 1.0 equivalent) in carbon tetrachloride (130 mL) at room temperature. The reaction mixture was heated to 95 °C overnight. After cooling to room temperature, the reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with water (200 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EA = 80 / 1) to provide 3-bromo-2-(bromomethyl)-6-chloropyridine (7.1 g, 55% yield) as a yellow oil.

[0593] LC-MS (ESI): Computed mass of C6H4Br2ClN, 282.84; Measured m / z, 283.85 [M+H] + .

[0594] Step B: 2-(azidomethyl)-3-bromo-6-chloropyridine

[0595] Sodium azide (3.23 g, 49.760 mmol, 2.0 equivalent) was added to a solution of 3-bromo-2-(bromomethyl)-6-chloropyridine (7.1 g, 24.880 mmol, 1.0 equivalent) in DMF (100 mL) at room temperature. The reaction mixture was stirred at 30 °C for 1 h. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic extracts were washed with brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(azidomethyl)-3-bromo-6-chloropyridine (6.0 g, 83% yield) as a yellow oil. The oil was used directly in the next step without further purification.

[0596] LC-MS (ESI): Computed quality of C6H4BrClN4, 245.93; Measured m / z, 246.94 [M+H] + .

[0597] Step C: (3-bromo-6-chloropyridin-2-yl)methylamine

[0598] PPh3 (9.54 g, 36.366 mmol, 1.5 equivalent) was added to a solution of 2-(azidomethyl)-3-bromo-6-chloropyridine (6.0 g, 24.244 mmol, 1.0 equivalent) in THF (70 mL) and H2O (8 mL) at room temperature. The reaction mixture was stirred at 50 °C for 2 h. After evaporation, the residue was diluted with water (30 mL), acidified to pH 2-3 with HCl solution (2N), and extracted with DCM (50 mL x 2). After discarding the organic layer, the aqueous phase was concentrated under reduced pressure to give (3-bromo-6-chloropyridin-2-yl)methylamine hydrochloride (3.35 g, 56% yield) as a red oil.

[0599] LC-MS (ESI): Computed quality of C6H6BrClN2, 219.94; Measured m / z, 220.95 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.61 (s, 3H), 8.24 (d, J = 8.4Hz, 1H), 7.56 (d, J = 8.4Hz, 1H), 4.24 (s, 2H).

[0600] Step D: N-[(3-bromo-6-chloropyridin-2-yl)methyl]formamide

[0601] To a solution of (3-bromo-6-chloropyridin-2-yl)methylamine (3.35 g, 15.125 mmol, 1.0 equivalent) in ethyl formate (80 mL) at room temperature, NaHCO3 (2.54 g, 30.250 mmol, 2.0 equivalent) and triethylamine (10.5 mL, 75.624 mmol, 5.0 equivalent) were added. The reaction mixture was stirred overnight at 70 °C. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to give N-[(3-bromo-6-chloropyridin-2-yl)methyl]formamide (3.0 g, 64% yield) as a pink solid, which was used directly in the next step.

[0602] LC-MS (ESI): Computed mass of C7H6BrClN2O, 247.94; Measured m / z, 248.94 [M+H] + .

[0603] Step E: 8-Bromo-5-chloroimidozolo[1,5-a]pyridine

[0604] POCl3 (2.2 mL, 24.048 mmol, 2.0 equivalent) was added to a solution of N-[(3-bromo-6-chloropyridin-2-yl)methyl]formamide (3.0 g, 12.024 mmol, 1.0 equivalent) in dioxane (60 mL) at room temperature. The reaction mixture was stirred at 115 °C for 3 h. After cooling to room temperature, the mixture was slowly quenched with an aqueous solution of NaHCO3 and extracted with EtOAc (50 mL x 2). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (PE / EA = 10 / 1) to provide 8-bromo-5-chloroimidazolo[1,5-a]pyridine (1.57 g, 56% yield) as a yellow solid.

[0605] LC-MS (ESI): Computed quality of C7H4BrClN2, 229.92; Measured m / z, 230.93 [M+H] + .

[0606] Step F: Methyl 5-chloroimidozop[1,5-a]pyridine-8-carboxylate

[0607] Triethylamine (1.5 mL, 10.800 mmol, 5 equivalents) and Pd(dppf)Cl2 (0.16 g, 0.216 mmol, 0.1 equivalents) were added to a solution of 8-bromo-5-chloroimidazolo[1,5-a]pyridine (0.5 g, 2.160 mmol, 1.0 equivalent) in DMF (20 mL) and MeOH (20 mL) at room temperature. The reaction mixture was stirred at 80 °C for 6 hours under CO (1 atm). After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with water (30 mL x 2) and brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EA = 6 / 1) to provide methyl 5-chloroimidozopyridine-8-carboxylate as a yellow solid (0.21 g, 46% yield).

[0608] LC-MS (ESI): Calculated mass of C9H7ClN2O2, 210.02; Measured m / z, 211.03 [M+H] + .

[0609] Step G: {5-chloroimidazolo[1,5-a]pyridin-8-yl}methanol

[0610] DIBAL-H (1M) (3 mL, 2.991 mmol, 3 equivalents) was added dropwise to a solution of methyl 5-chloroimidozop[1,5-a]pyridin-8-carboxylate (210 mg, 0.997 mmol, 1.0 equivalent) in THF (8 mL) under nitrogen at -70 °C. The reaction mixture was then stirred at 0 °C for 1 h, slowly diluted with saturated NH4Cl aqueous solution (10 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (100% EA) to provide {5-chloroimidozop[1,5-a]pyridin-8-ylmethanol (100 mg, 55% yield) as a yellow solid.

[0611] LC-MS (ESI): Computed mass of C8H7ClN2O, 182.02; Measured m / z, 183.03 [M+H] + .

[0612] Step H: 5-Clonimidozono[1,5-a]pyridine-8-carboxaldehyde

[0613] Des Martin periodane (302.16 mg, 0.712 mmol, 1.5 equivalent) was added to a solution of {5-chloroimidazolo[1,5-a]pyridin-8-yl}methanol (100 mg, 0.548 mmol, 1.0 equivalent) in DCM (8 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (30 mL), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (100% EA) to give 5-chloroimidazolo[1,5-a]pyridin-8-carboxaldehyde (90 mg, 87% yield) as a yellow solid.

[0614] LC-MS (ESI): Computed quality of C8H5ClN2O, 180.01; Measured m / z, 181.02 [M+H] + .

[0615] Intermediate 8: 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxaldehyde

[0616]

[0617] Step A: Methyl 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate

[0618] NaH (60% suspended in oil) (341.8 mg, 5.7 mmol, 1.5 equivalent) and CH3I (0.36 mL, 5.7 mmol, 1.5 equivalent) were added to a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (800 mg, 3.8 mmol, 1.0 equivalent) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (40 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EA = 10 / 1) to provide methyl 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (700 mg, 82% yield) as a yellow solid.

[0619] LC-MS (ESI, m / z): C 10 The calculated mass of H9ClN2O2 was 224.04; the measured mass was 224.9 [M+H]. + .

[0620] Step B: (6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol

[0621] LiAlH4 (118.3 mg, 3.1 mmol, 1.0 equivalent) was added fractionally to a solution of methyl 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-carboxylate (700 mg, 3.1 mmol, 1.0 equivalent) in anhydrous THF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min. The reaction mixture was slowly quenched with aqueous NaOH (1 N) solution (40 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (40 mL x 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EA = 1 / 1) to provide {6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl}methanol (500 mg, 82% yield) as a yellow solid.

[0622] LC-MS (ESI, m / z): Computed quality of C9H9ClN2O, 196.04; Measured quality, 196.9 [M+H] + .

[0623] Step C: 6-Chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxaldehyde

[0624] IBX (2.1 g, 7.5 mmol, 3.0 equivalent) was added fractionally to a solution of {6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl}methanol (500 mg, 2.5 mmol, 1.0 equivalent) in DMSO (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (40 mL x 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EA = 2 / 1) to provide 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-carboxaldehyde (350 mg, 71% yield) as a yellow solid.

[0625] LC-MS (ESI, m / z): Computed quality of C9H7ClN2O, 194.02; Measured quality, 195.2 [M+H] + .

[0626] Intermediate 9: 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxaldehyde

[0627]

[0628] Step A: (6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol

[0629] LiAlH4 (21.6 mg, 570 μmol, 1.0 equivalent) was added fractionally to a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridin-4-carboxylate (120 mg, 570 μmol, 1.0 equivalent) in THF (5.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min. The reaction mixture was slowly quenched with aqueous NaOH (1 N) solution (5 mL) and extracted with EtOAc (5 mL x 3). The organic layer was washed with brine (5 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EA = 1 / 1) to provide (6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (100 mg, 96% yield) as a yellow solid.

[0630] LC-MS (ESI): Computed mass of C8H7ClN2O, 182.02; Measured m / z, 183.02 [M+H] + .

[0631] Step B: 6-Chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxaldehyde

[0632] IBX (383 mg, 1.4 mmol, 2.5 equivalents) was added fractionally to a solution of (6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (100 mg, 548 μmol, 1.0 equivalent) in DMSO (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (10 mL x 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EA = 2 / 1) to provide 6-chloro-1H-pyrrolo[2,3-b]pyridin-4-carboxaldehyde (80 mg, 81% yield) as a yellow solid.

[0633] LC-MS (ESI): Computed quality of C8H5ClN2O, 180.01; Measured m / z, 181.01 [M+H] + .

[0634] Intermediate 10: 6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridine-4-carboxaldehyde

[0635]

[0636] Step A: Methyl 6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate

[0637] Sodium hydride (60% suspended in oil) (0.19 g, 4.75 mmol, 2.0 equivalent) was added to a stirred solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (500 mg, 2.37 mmol, 1.0 equivalent) in DMF (6.00 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. Then, ethane iodoform (444 mg, 2.85 mmol, 1.2 equivalent) was added to the mixture, and the reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 30 min. The reaction mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (30 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EtOAc = 10 / 1) to obtain methyl 6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate as a white solid (215 mg, yield 38%).

[0638] LC-MS (ESI): C 11 H 11 The calculated mass of ClN₂O₂ is 238.05; the measured m / z value is 239.05 [M+H].+ .

[0639] Step B: (6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol

[0640] Lithium aluminum hydride (34.2 mg, 901 μmol, 1.0 equivalent) was added to a solution of methyl 6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridin-4-carboxylate (215 mg, 901 μmol, 1.0 equivalent) in THF (4.00 mL) at 0 °C, and the reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 5 min. The reaction mixture was quenched with saturated NaOH solution (5 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were concentrated under reduced pressure to obtain (6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (170 mg, 89.6% yield) as a red oil. LC-MS (ESI): C 10 H 11 The calculated mass of ClN₂O was 210.06; the measured m / z value was 211.06 [M+H]. + .

[0641] Step C: 6-Chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridine-4-carboxaldehyde

[0642] IBX (678 mg, 2.42 mmol, 3.0 equivalent) was added to a stirred solution of (6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (170 mg, 807 μmol, 1.0 equivalent) in DMSO (4.00 mL), and the reaction mixture was stirred at 30 °C under a nitrogen atmosphere for 20 min. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EtOAc = 10 / 1) to obtain 6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridin-4-carboxaldehyde (110 mg, 65% yield) as a yellow solid.

[0643] LC-MS (ESI): C 10 The calculated mass of H9ClN2O was 208.04; the measured m / z value was 209.04 [M+H]. + . 1H NMR (400MHz, DMSO-d6) δ 10.28 (s, 1H), 7.90 (d, J = 3.4Hz, 1H), 7.70 (s, 1H), 7.00 (d, J = 3.4Hz, 1H), 4.31 (q, J = 7.2Hz, 2H), 1.39 (t, J = 7.2Hz, 3H).

[0644] Intermediate 11: 5-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxaldehyde

[0645]

[0646] Step A: (5-chloro-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol

[0647] LiAlH4 (94.6 mg, 2.49 mmol, 1.5 equivalent) was added to a solution of methyl 5-chloro-1H-pyrrolo[3,2-b]pyridin-7-carboxylate (350 mg, 1.66 mmol, 1.0 equivalent) in THF (10.0 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The mixture was quenched with Na2SO4·10H2O and filtered. The filtrate was concentrated under reduced pressure to provide (5-chloro-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol (250 mg, 82% yield) as a pale yellow solid.

[0648] LC-MS (ESI): Computed mass of C8H7ClN2O 182.6; Measured m / z value 183.2 [M+H] +

[0649] Step B: 5-Chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxaldehyde

[0650] Add IBX (575 mg, 2.05 mmol, 1.5 equivalent) to a solution of (5-chloro-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol (250 mg, 1.37 mmol, 1.0 equivalent) in DMSO (5.00 mL). Stir the mixture at 30 °C for 3 h. Quench the reaction mixture with ice water (20 mL) and extract with EA (15 mL x 3). Wash the organic layer with brine (10 mL x 4), dry to anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by rapid column chromatography on silica gel (petroleum ether solution of ethyl acetate, from 0 to 30%) to provide 5-chloro-1H-pyrrolo[3,2-b]pyridin-7-carboxaldehyde (180 mg, 73% yield) as a pale yellow solid.

[0651] LC-MS (ESI): Computed mass of C8H5ClN2O 180.01; Measured m / z value 181.1 [M+H] +

[0652] Intermediate 12: 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-7-carboxaldehyde

[0653]

[0654] Step A: Methyl 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

[0655] NaH (60% suspended in oil) (51 mg, 2.14 mmol, 3.0 equivalent) was added to a mixture of methyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxylate (150 mg, 0.71 mmol, 1.0 equivalent) in DMF (3.00 mL) at 0°C, and the mixture was stirred at N2 atmosphere for 1 hour. Then, MeI (355 mg, 2.14 mmol, 3.0 equivalent) was added to the above mixture, and the resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc (15 mL x 3). The organic layer was washed with brine (20 mL x 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE solution of EtOAc, from 0 to 50%) to provide methyl 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylate as a white solid (50.0 mg, 30% yield).

[0656] LC-MS (ESI): C 10 The calculated mass of H9ClN2O2 is 223.2; the measured m / z value is 225.2 [M+H]. +

[0657] Step B: (5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol

[0658] LiAlH4 (93.8 mg, 2.47 mmol, 1.5 equivalent) was added to a solution of methyl 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-7-carboxylate (370 mg, 1.65 mmol, 1.0 equivalent) in THF (10.0 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, then quenched with Na2SO4·10H2O and stirred at room temperature for 10 min. After filtration, the filtrate was concentrated under reduced pressure to provide (5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol (280 mg, 1.42 mmol, 86.5%) as a pale yellow solid.

[0659] LC-MS (ESI): Computed quality of C9H9ClN2O 196.6; Measured m / z value 197 [M+H] + .

[0660] Step C: 5-Chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-7-carboxaldehyde

[0661] IBX (598 mg, 2.14 mmol, 1.5 equivalent) was added to a solution of (5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol (280 mg, 1.42 mmol, 1.0 equivalent) in DMSO (8.00 mL) at 0 °C. The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with ice water (10 mL) and extracted with EA (15 mL x 3). The organic layer was washed with brine (10 mL x 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE solution of EA, from 0 to 30%) to provide 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-7-carboxaldehyde (160 mg, 58% yield) as a pale yellow solid.

[0662] LC-MS (ESI): Computed mass of C9H7ClN2O 194.02; Measured m / z value 195.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),7.86(d,J=3.4Hz,1H),7.60(s,1H),6.70(d,J=3.4Hz,1H),4.11(s,3H)

[0663] Intermediate 13: 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0664]

[0665] Step A: 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0666] 3-aminopiperidine-2,6-dione hydrochloride (10.7 g, 65.1 mmol, 1.0 equivalent) and DIPEA (25.2 g, 195.3 mmol, 3.0 equivalent) were added to a solution of methyl 4-bromo-2-(bromomethyl)benzoate (20 g, 65.1 mmol, 1.0 equivalent) in ACN (500 mL) at room temperature. The reaction mixture was stirred at 85 °C for 12 h. After evaporation, the residue was diluted with a mixture of ACN and H₂O (160 mL, 3 / 1 v / v) and filtered to give a blue solid. The solid was dried to give 3-(5-bromo-1-oxoisoindoline-2-yl)piperidine-2,6-dione (10.5 g, 50% yield).

[0667] LC-MS (ESI): C 13 H 11 The calculated mass of BrN₂O₃ is 322.00; the measured m / z value is 323.00 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),7.89(s,1H),7.73-7.66(m,2H),5.14-5.09(m,1H),4.47(d,J=16.8H z, 1H), 4.34 (d, J = 16.8Hz, 1H), 3.02-2.77 (m, 1H), 2.62-2.58 (m, 1H), 2.45-2.36 (m, 1H), 2.13-1.92 (m, 1H).

[0668] Step B: 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0669] To a solution of methyl 3-(5-bromo-1-oxoisoindolin-2-yl)piperidin-2,6-dione (10.5 g, 32.5 mmol, 1.0 equivalent) in anhydrous dioxane (150 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane-2,2'-dioxane) (9.9 g, 39.0 mmol, 1.2 equivalent), Pd(dppf)Cl2 (1.2 g, 1.62 mmol, 0.05 equivalent), and KOAc (9.5 g, 97.5 mmol, 3.0 equivalent) were added. The reaction mixture was stirred at 100 °C under N2 for 12 h. After evaporation, the residue was diluted with H2O (150 mL) and filtered to give a blue solid. The blue solid was washed with EA (50 mL x 3) and dried to give 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindololin-2-yl)piperidine-2,6-dione (9.2 g, 71% yield) in blue solid form.

[0670] LC-MS (ESI): C 19 H 23 BN₂O₅, 370.17; measured m / z, 371.21 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),7.90(s,1H),7.80(d,J=7.6Hz,1H),7.73(d,J=7.6Hz,1H),5.15-5.10(m,1H),4.47(d,J= 16.8Hz,1H),4.35(d,J=16.8Hz,1H),3.08-2.80(m,1H),2.62-2.58(m,1H),2.45-2.33(m,1H),2.18-1.94(m,1H),1.24(s,12H).

[0671] Intermediate 14: 3-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindolin-2-yl)piperidin-2,6-dione

[0672]

[0673] The title compound was prepared in a manner similar to intermediate 13 by brominating methyl 4-bromo-3-fluoro-2-methylbenzoate, coupling it with 3-aminopiperidine-2,6-dione, cyclizing it, and then borating it with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane).

[0674] LC-MS (ESI): C 19 H 22 The calculated mass of BFN2O5 is 388.16; the measured m / z value is 389.3 [M+H]. + .

[0675] Intermediate 15: 3-(6-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0676]

[0677] The title compound was prepared in a manner similar to intermediate 13 by brominating methyl 4-bromo-5-fluoro-2-methylbenzoate, coupling it with 3-aminopiperidine-2,6-dione, cyclizing it, and then borating it with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane).

[0678] LC-MS (ESI): C 19 H 22 The calculated mass of BFN2O5 is 388.20; the measured m / z value is 389.1 [M+H]. + . 1 HNMR (400MHz, DMSO-d6) δ11.02(s,1H),7.89(d,J=4.0Hz,1H),7.45(d,J=8.0Hz,1H),5.15-5.11(m,1H),4.45(d,J=17.6H z,1H),4.33(d,J=17.6Hz,1H),2.93-2.91(m,1H),2.62-2.58(m,1H),2.41-2.36(m,1H),2.03-1.99(m,1H),1.32(s,12H).

[0679] Intermediate 16: 3-(7-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0680]

[0681] The title compound was prepared in a manner similar to intermediate 13 by brominating methyl 4-bromo-6-fluoro-2-methylbenzoate, coupling it with 3-aminopiperidine-2,6-dione, cyclizing it, and then borating it with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane).

[0682] LC-MS (ESI): C 19 H 22 The calculated mass of BFN2O5 is 388.20; the measured m / z value is 389.1 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),7.71(s,1H),7.39(d,J=8.0Hz,1H),5.12-5.07(m,1H),4.49(d,J=17.6Hz,1H) ,4.37(d,J=17.6Hz,1H),2.94-2.91(m,1H),2.62-2.59(m,1H),2.50-2.48(m,1H),2.01-1.99(m,1H),1.32(s,12H).

[0683] Intermediate 17: 3-(4-methoxy-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0684]

[0685] The title compound was prepared in a manner similar to intermediate 13 by brominating methyl 4-bromo-3-methoxy-2-methylbenzoate, coupling it with 3-aminopiperidine-2,6-dione, cyclizing it, and then borating it with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane).

[0686] Intermediate 18: 3-(6-methoxy-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0687]

[0688] The title compound was prepared in a manner similar to intermediate 13 by brominating methyl 4-bromo-5-methoxy-2-methylbenzoate, coupling it with 3-aminopiperidine-2,6-dione, cyclizing it, and then borating it with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane).

[0689] Intermediate 19: 3-(7-methoxy-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0690]

[0691] The title compound was prepared in a manner similar to intermediate 13 by brominating methyl 4-bromo-6-methoxy-2-methylbenzoate, coupling it with 3-aminopiperidine-2,6-dione, cyclizing it, and then borating it with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane).

[0692] Intermediate 20: 2-(3-chloro-4-methylphenyl)ethyl-1-amine

[0693]

[0694] Step A: Methyl (3-chloro-4-methylphenyl) methanesulfonate

[0695] MsCl (0.741 mL, 9.578 mmol, 1.5 equivalence) was added dropwise to a solution of (3-chloro-4-methylphenyl)methanol (1 g, 6.385 mmol, 1.0 equivalence) and TEA (1.8 mL, 12.77 mmol, 2.0 equivalence) in DCM (15 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The residue was poured into water (30 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (10% petroleum ether solution of ethyl acetate) to give methyl (3-chloro-4-methylphenyl)methanesulfonate (0.6 g, 36% yield) as a yellow oil.

[0696] Step B: 2-(3-chloro-4-methylphenyl)acetonitrile

[0697] To a solution of methyl (3-chloro-4-methylphenyl)methanesulfonate (500 mg, 2.130 mmol, 1.0 equivalent) in DMF (1 mL), NaCN (0.131 mL, 4.261 mmol, 2.0 equivalent) was added, and the mixture was stirred overnight at 50 °C. The mixture was poured into water (6 mL) and extracted with DCM (15 mL x 3). The organic layer was washed with brine (15 mL x 4), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (10% petroleum ether solution of ethyl acetate) to give 2-(3-chloro-4-methylphenyl)acetonitrile (300 mg, 76% yield) as a yellow oil.

[0698] Step C: 2-(3-chloro-4-methylphenyl)ethyl-1-amine

[0699] Add BH to a solution of 2-(3-chloro-4-methylphenyl)acetonitrile (300 mg, 1.811 mmol, 1.0 equivalent) in THF (5 mL).3- THF (1M THF solution) (5.4 mL, 5.433 mmol, 3.0 equivalent) was prepared and the mixture was stirred overnight at 40°C. The residue was quenched with MeOH (6 mL) and stirred for 30 min. Then concentrated HCl (3 mL) was added to the mixture and stirred for 30 min. After evaporation, the residue was diluted with H2O (10 mL), adjusted to pH 9-10, and extracted with DCM (15 mL x 3). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (40% petroleum ether solution of ethyl acetate) to give 2-(3-chloro-4-methylphenyl)ethyl-1-amine (100 mg, yield 29.3%) as a yellow oil.

[0700] LC-MS (ESI): C9H 12 The calculated quality of ClN is 169.07; the measured m / z value is 170.3 [M+H]. + .

[0701] Intermediate 21: (1-methyl-1H-indol-7-yl)methylamine

[0702]

[0703] Step A: 1-Methyl-1H-indole-7-carboxaldehyde

[0704] To a solution of 1H-indole-7-carboxaldehyde (1.4 g, 9.645 mmol, 1.0 equivalent) in DMF (10 mL), NaH (60% suspended in oil) (0.46 g, 11.574 mmol, 1.2 equivalent) was added, and the mixture was stirred for 20 min. Then, methyl iodoform (1.64 g, 11.574 mmol, 1.2 equivalent) was added dropwise to the mixture, and the mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution (30 mL) and extracted with EA (40 mL x 3). The combined organic phases were washed with brine (30 mL x 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (MeOH / DCM = 1 / 10) to give 1-methyl-1H-indole-7-carboxaldehyde (700 mg, 46% yield) as a yellow oil.

[0705] LC-MS (ESI): C 10 The calculated quality of H9NO is 159.07; the measured m / z value is 160.10 [M+H]. + .

[0706] Step B: 2-Methyl-N-((1-methyl-1H-indol-7-yl)methyl)propane-2-sulfinamide

[0707] Ti(OEt)₄ (0.922 mL, 4.397 mmol, 1.0 equivalent) was added to a solution of 1-methyl-1H-indole-7-carboxaldehyde (700 mg, 4.397 mmol, 1.0 equivalent) and 2-methylpropane-2-sulfinamide (1065.83 mg, 8.794 mmol, 2.0 equivalent) in THF (20 mL), and the mixture was stirred at 70 °C for 30 min. After cooling to room temperature, NaBH₄ (250 mg, 6.596 mmol, 1.5 equivalent) was added to the above mixture at 0 °C, and the mixture was stirred at 50 °C for 24 h. After cooling to room temperature, the mixture was quenched with saturated NH₄Cl aqueous solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with 5% KH₂PO₄ aqueous solution (50 mL, pH 5, to disrupt the borane complex) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) under reflux, cooled to 22 °C, and heptane (50 mL) was added in a single addition. The solution was stirred at 22 °C for 30 min, during which crystallization began. The solution was then cooled to 5 °C and stirred for 30 min. The solid was filtered off, washed with EtOAc / Hep (20 mL, 1 / 1) and pentane (20 mL), and dried to give 2-methyl-N-[(1-methyl-1H-indol-7-yl)methyl]propane-2-sulfinamide (800 mg, yield 68.81%) as a white solid.

[0708] LC-MS (ESI): Computational quality of C14H20N2OS, 264.13; Measured m / z value, 265.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.46(dd,J=7.8,0.8Hz,1H),7.22(d,J=3.2Hz,1H),7.06(d,J=7.0Hz,1H),6.94(t,J=7.4Hz,1H),6.39 (d, J=3.2Hz, 1H), 5.64 (t, J=5.2Hz, 1H), 4.63 (dd, J=13.8, 4.6Hz, 1H), 4.52 (dd, J=13.8, 5.6Hz, 1H), 4.05 (s, 3H), 1.36 (s, 9H).

[0709] Step C: (1-Methyl-1H-indol-7-yl)methylamine

[0710] Hydrochloric acid (4N dioxane solution) (3.1 mL, 12.500 mmol, 4.0 equivalent) was added to a solution of 2-methyl-N-[(1-methyl-1H-indol-7-yl)methyl]propane-2-sulfinamide (800 mg, 3.026 mmol, 1.0 equivalent) in dioxane (5 mL) at 0 °C, and the resulting reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to obtain (1-methyl-1H-indol-7-yl)methylamine hydrochloride (460 mg, 95% yield) as a grayish-white solid.

[0711] LC-MS (ESI): Chemical formula C 10 H 12 The calculated quality of N2 is 160.10; the measured m / z value is 161.0 [M+H]. + .

[0712] Intermediate 22: 2-Chloroquinoline-4-carboxaldehyde

[0713]

[0714] Step A: (2-chloroquinoline-4-yl)(pyrrolidine-1-yl)methyl ketone

[0715] HATU (2.20 g, 1.2 equivalence, 5.78 mmol), DIEA (2.52 mL, 3.0 equivalence, 14.5 mmol), and pyrrolidine (603 μL, 1.5 equivalence, 7.23 mmol) were added to a mixture of 2-chloroquinoline-4-carboxylic acid (1.00 g, 1.0 equivalence, 4.82 mmol) in anhydrous DMF (10 mL) at 20 °C. The mixture was stirred at 20 °C for 30 min to obtain a yellow solution. The reaction solution was poured into saturated NH4Cl and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel, PE solution of 0-67% EtOAc) to provide (2-chloroquinoline-4-yl)(pyrrolidine-1-yl) methyl ketone (1.20 g, 95.6%) as a yellow solid.

[0716] LC-MS (ESI): Chemical formula C 14 H 13 The calculated mass of ClN₂O is 260.7; the measured m / z value is 261.5 [M+H]. + . 1HNMR(400MHz,DMSO-d6)δ8.03(d,J=8.4Hz,1H),7.91–7.83(m,2H),7.72(dd,J=11.2,4.0Hz,1H),7 .66(s,1H),3.62(t,J=7.0Hz,2H),3.10(t,J=6.7Hz,2H),1.96–1.88(m,2H),1.80(p,J=6.7Hz,2H).

[0717] Step B: 2-Chloroquinoline-4-carboxaldehyde

[0718] LAH (116 mg, 2.0 equivalent, 3.07 mmol) was added to a mixture of (2-chloroquinoline-4-yl)(pyrrolidone-1-yl) methyl ketone (400 mg, 1.0 equivalent, 1.53 mmol) in THF (6 mL) under ice-water bath conditions. The reaction mixture was stirred at 0 °C for 5 min. The reaction solution was poured into saturated NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-30% EtOAc in PE) to provide 2-chloroquinoline-4-carboxaldehyde (150 mg, 51.0%) as a yellow solid.

[0719] LC-MS (ESI): Chemical formula C 10 The calculated mass of H6ClNO was 191.0; the measured m / z value was 192.2 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.99(d,J=8.4Hz,1H),8.21(s,1H),8.16(d,J=8.1Hz,1H),8.03–7.97(m,1H),7.93–7.86(m,1H).

[0720] Intermediate 23: 2-chloro-4-(pyrrolidone-1-ylmethyl)-5,6,7,8-tetrahydroquinoline

[0721]

[0722] Step A: Ethyl 3-cyano-2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylate

[0723] Cyclohexanone (8.0 g, 1.0 wt, 81.5 mmol) was added dropwise to a mixture of sodium ethoxide (26.6 g, 25% wt, 1.2 equivalents, 97.8 mmol) in EtOH (30 mL) and diethyl oxalate (11.9 g, 1.0 equivalent, 81.5 mmol). The mixture was stirred at 25 °C for 3 h, and then 2-cyanoacetamide (6.85 g, 1.0 equivalent, 81.5 mmol) was added. The reaction was stirred at 80 °C for 2 h, and then concentrated under vacuum. The residue was absorbed in 150 mL of boiling water and 12 mL of acetic acid and stirred at 0 °C for 10 min. A precipitate appeared, and the solid was separated by filtration and dried under vacuum to provide ethyl 3-cyano-2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylate (12.6 g, 62.8% yield) as a brown solid.

[0724] LC-MS (ESI): Chemical formula C 13 H 14 The calculated mass of N₂O₃ is 246.3; the measured m / z value is 247.2 [M+H]. + .

[0725] Step B: 2-O-1,2,5,6,7,8-hexahydroquinoline-4-carboxylic acid

[0726] A mixture of ethyl 3-cyano-2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylic acid (12.5 g, 1 equivalent, 50.8 mmol) and a 36% aqueous hydrochloric acid solution (34.5 mL, 10 equivalent, 508 mmol) was stirred overnight at 115 °C. Then, 2 mL of 6M hydrochloric acid was added to the mixture, and the reaction was further heated to 115 °C overnight. The hot reaction solution was poured onto ice to form a precipitate, and the solid was filtered. The solid was dried under vacuum at 65 °C to give 2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylic acid (8.60 g, 44% yield).

[0727] LC-MS (ESI): Chemical formula C 10 H 11 The calculated quality of NO3 is 193.2; the measured m / z value is 194.1 [M+H]. + .

[0728] Step C: (2-chloro-5,6,7,8-tetrahydroquinoline-4-yl)(pyrrolidine-1-yl)methyl ketone

[0729] A solution of 2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylic acid (4.0 g, 1.0 equivalent, 10.4 mmol) in POCl3 (18.2 mL, 18.9 equivalent, 196 mmol) was stirred at 100 °C for 2 h. The reaction mixture was concentrated under vacuum to give a crude product. It was then added to DCM (50 mL) at 0 °C, followed by TEA (2.89 mL, 2.0 equivalent, 20.7 mmol). The mixture was then stirred at room temperature for 2 h. The reaction mixture was quenched with water (15 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the crude product. The crude product was then purified by rapid chromatography with EA / PE = 48% to provide (2-chloro-5,6,7,8-tetrahydroquinoline-4-yl)(pyrrolidine-1-yl) methyl ketone as a yellow oil (1.00 g, 36.5% yield).

[0730] LC-MS (ESI): Chemical formula C 14 H 17 The calculated mass of ClN₂O is 264.1; the measured m / z value is 265.1 [M+H]. + . 1 HNMR (400MHz, DMSO-d6) δ7.23 (s, 1H), 3.45 (t, J = 6.7Hz, 2H), 3.08 (t, J = 6.3Hz, 2H), 2.81 (t, J = 6.3Hz, 2H), 2.55 (t, J = 6.0Hz, 2H), 1.91–1.68 (m, 9H).

[0731] Step D: 2-Chloro-4-(pyrrolidone-1-ylmethyl)-5,6,7,8-tetrahydroquinoline

[0732] LAH (143 mg, 2.0 equivalent, 3.78 mmol) was added to a solution of (2-chloro-5,6,7,8-tetrahydroquinoline-4-yl)(pyrrolidine-1-yl) methyl ketone (500 mg, 1.0 equivalent, 1.89 mmol) in THF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The reaction solution was added to saturated NH4Cl at 0 °C. The mixed solution was filtered and the filtrate was partitioned between water (3 mL) and EA (5 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, and purified by preparative TLC (PE:EA = 1:1) to give 2-chloro-4-(pyrrolidine-1-ylmethyl)-5,6,7,8-tetrahydroquinoline (40 mg, 8.45% yield) as a yellow solid.

[0733] LC-MS (ESI): Chemical formula C 14H 19 The calculated quality of ClN is 193.2; the measured m / z value is 251 [M+H]. + .

[0734] Intermediate 24: 2-Chloro-6,7-dihydro-5H-cyclopentyl[b]pyridine-4-carboxaldehyde

[0735]

[0736] Step A: 3-Cyano-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxylate

[0737] Diethyl oxalate (8.69 g, 1.0 equivalent, 59.4 mmol) was added dropwise to a mixture of sodium ethoxide (20%, 27.9 mL, 1.2 equivalent, 71.3 mmol) in ethanol and cyclopentanone (5.00 g, 1.0 equivalent, 59.4 mmol). The mixture was stirred at 25 °C for 3 hours. Then 2-cyanoacetamide (5.00 g, 1.0 equivalent, 59.4 mmol) was added. The reaction was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was absorbed at 0 °C in 250 mL of boiling water and 20 mL of acetic acid. The solid precipitated and was separated by filtration, and the collected solid was dried under vacuum to give ethyl 3-cyano-2-oxo-2,5,6,7-tetrahydro-1H-cyclopentan[b]pyridine-4-carboxylate (4.90 g, 35.5% yield) as a green solid.

[0738] LC-MS (ESI): Chemical formula C 12 H 12 The calculated mass of N₂O₃ is 232.2; the measured m / z value is 233.1 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ13.22(s,1H),4.38(q,J=7.1Hz,2H),2.87(t,J=7.7Hz,2H),2.79(t,J=7.3Hz,2H),2.09–1.99(m,2H),1.32(t,J=7.1Hz,3H).

[0739] Step B: 2-O-2,5,6,7-Tetrahydro-1H-cyclopenta[b]pyridine-4-carboxylic acid

[0740] Ethyl 3-cyano-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxylic acid (4.90 g, 1.0 equivalent, 21.1 mmol) was added to an aqueous solution of 6N HCl (35.2 mL, 211 mmol). The mixture was stirred at 115 °C for 16 hours. The hot reaction solution was poured onto ice to precipitate a solid. The solid was then filtered. The filter cake was dried under vacuum at 45 °C to give 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxylic acid (3.00 g, 79.4%) as a red solid.

[0741] LC-MS (ESI): Calculated mass of chemical formula C9H9NO3, 179.2; measured m / z, 180.2 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ6.64 (s, 1H), 2.89 (t, J = 7.4Hz, 2H), 2.76 (t, J = 7.7Hz, 2H), 2.05–1.95 (m, 2H).

[0742] Step C: Methyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carboxylate

[0743] To a solution of 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxylic acid (600 mg, 1.0 equivalent, 3.35 mmol) in POCl3 (6.00 mL, 64.4 mmol), the mixture was stirred at 90 °C for 16 hours. The reaction mixture was concentrated under vacuum to give a crude product, 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbonyl chloride (600 mg, 82.9%), as a brown oil.

[0744] Methanol (600 mL, 18.5 mmol) was added to a solution of 2-chloro-6,7-dihydro-5H-cyclopentyl[b]pyridine-4-carbonyl chloride (600 mg, 1.85 mmol) in DCM (3.0 mL) at -40 °C. The mixture was stirred at room temperature for 20 min. The reaction mixture was quenched with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with aqueous brine and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide a crude product. The crude product was then purified by rapid chromatography with EA / PE = 20% to provide methyl 2-chloro-6,7-dihydro-5H-cyclopentyl[b]pyridine-4-carboxylate (300 mg, 76.6%) as a yellow solid.

[0745] LC-MS (ESI): Chemical formula C 10 H 10The calculated quality of ClNO2 is 211.6; the measured m / z value is 198.4 (M-19). + . 1 HNMR (400MHz, DMSO-d6) δ7.57 (s, 1H), 3.88 (s, 3H), 3.16 (t, J = 7.6 Hz, 2H), 2.97 (t, J = 7.8 Hz, 2H), 2.09 (p, J = 7.7 Hz, 2H).

[0746] Step D: (2-chloro-6,7-dihydro-5H-cyclopentan[b]pyridin-4-yl)methanol

[0747] LiAlH4 (53.8 mg, 1.0 equivalent, 1.42 mmol) was added to a solution of methyl 2-chloro-6,7-dihydro-5H-cyclopentan[b]pyridin-4-carboxylate (300 mg, 1.0 equivalent, 1.42 mmol) in THF (5.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. Na2SO4·10H2O was added to the mixture at 0 °C. The mixed solution was filtered and the filtrate was divided between water (3 mL) and EA (5 mL x 3). The organic layer was washed with brine, dried with anhydrous Na2SO4, and concentrated under vacuum to give (2-chloro-6,7-dihydro-5H-cyclopentan[b]pyridin-4-yl)methanol (250 mg, 96.0%) as a yellow solid.

[0748] LC-MS (ESI): Chemical formula C9H 10 The calculated quality of ClNO is 183.6; the measured m / z value is 184.5 [M+1]. + .

[0749] Step E: 2-Chloro-6,7-dihydro-5H-cyclopentyl[b]pyridine-4-carboxaldehyde

[0750] DMP (866 mg, 1.5 equivalent, 2.04 mmol) was added to a solution of (2-chloro-6,7-dihydro-5H-cyclopentyl[b]pyridin-4-yl)methanol (250 mg, 1 equivalent, 1.36 mmol) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched dropwise by adding saturated NaHCO3 aqueous solution (20 mL). The mixture was filtered through a diatomaceous earth pad and the filtrate was extracted with DCM (15 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was then purified by preparative TLC with PE / EA = 2.5:1 to give 2-chloro-6,7-dihydro-5H-cyclopentyl[b]pyridin-4-carboxaldehyde (150 mg, 60.7% yield) as a yellow solid.

[0751] LC-MS (ESI): Computed quality of C9H8ClNO, 181.0; Measured m / z, 182.1 [M+1] + .

[0752] Intermediate 25: 5-chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxaldehyde

[0753]

[0754] Step A: 4-Bromo-6-chloro-2-methylpyridine-3-amine

[0755] Br2 (26 mL, 0.504 mol, 1.8 equivalent) was added dropwise to a solution of 6-chloro-2-methylpyridin-3-amine (40 g, 0.28 mol, 1.0 equivalent) and AcOH (30.4 mL, 0.53 mol, 1.9 equivalent) in MeOH (400 mL) at 0 °C, and the mixture was stirred at 0 °C for 6 h. After evaporation, the reaction mixture was diluted with EA (1 L), washed with saturated sodium thiosulfate aqueous solution (500 mL x 2), saturated NaHCO3 aqueous solution (500 mL x 2), and brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EA = 10 / 1 v / v) to provide 4-bromo-6-chloro-2-methylpyridin-3-amine (55 g, 90% yield) as a yellow solid. LC-MS (ESI): Computed quality of C6H6BrClN2, 219.94; Measured m / z, 221.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.41(s,1H),5.39(s,2H),2.33(s,3H).

[0756] Step B: 7-Bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine

[0757] Potassium acetate (22.2 g, 226 mmol, 2.0 equivalent) and AcOH (210 mL) were added to a solution of 4-bromo-6-chloro-2-methylpyridin-3-amine (25 g, 113 mmol, 1.0 equivalent) in toluene (625 mL) at 0 °C. Then, isoamyl nitrite (19.8 g, 22.7 mL, 169 mmol, 1.5 equivalent) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for 6 h. After evaporation, the mixture was poured into ice water (300 mL), adjusted to pH 7-8 with solid NaHCO3, and extracted with EA (300 mL x 3). The organic layer was washed with water (300 mL) and brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (ethyl acetate in petroleum ether solution, from 2% to 15% v / v) to give 7-bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine as a yellow solid (8.4 g, 32% yield). LC-MS (ESI): calculated mass of C6H3BrClN3, 230.92; m / z found, 232.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ14.14(s,1H),8.43(s,1H),7.87(s,1H).

[0758] Step C: 7-Bromo-5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine

[0759] To a solution of 7-bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine (15.0 g, 64.5 mmol, 1.0 equivalent) in concentrated H₂SO₄ (48 mL) at 0 °C, concentrated H₂SO₄ / concentrated HNO₃ (96 mL, 1 / 1 v / v) was added dropwise (concentrated HNO₃ was added to concentrated H₂SO₄ at 0 °C). The mixture was then stirred at 110 °C for 2 h. After cooling to room temperature, the mixture was poured into ice water (300 mL) and stirred for 0.5 h. The mixture was extracted with EA (200 mL x 3). The organic layer was washed with H₂O (300 mL x 4) and brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 7-bromo-5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (17.9 g, 100% yield) as a yellow solid. LC-MS (ESI): Calculated mass of C6H2BrClN4O2, 275.90; measured m / z, 276.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),8.13(s,1H).

[0760] Step D: 7-Bromo-5-chloro-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine (4a) and 7-Bromo-5-chloro-3-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine

[0761] Sodium hydride (60% suspended in oil) (9.29 g, 232 mmol, 1.8 equivalent) was added dropwise to a solution of 7-bromo-5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (35.8 g, 129 mmol, 1.0 equivalent) in anhydrous DMF (500 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, 2-(trimethylsilyl)ethoxymethyl chloride (25.8 g, 27.4 mL, 155 mmol, 1.2 equivalent) was added dropwise to the above mixture, and the resulting mixture was stirred at 0 °C for 30 min. The mixture was quenched with saturated NH4Cl aqueous solution (1000 mL) at 0 °C and extracted with EA (800 mL x 3). The organic layer was washed with H2O (500 mL x 4) and brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (petroleum ether solution of ethyl acetate, from 0% to 10%) to give 7-bromo-5-chloro-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine (28.2 g, 54% yield) and 7-bromo-5-chloro-3-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine (14.8 g, 28% yield) as a yellow solid.

[0762] 7-Bromo-5-chloro-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine: LC-MS (ESI): C 12 H 16 The calculated mass of BrClN4O3Si is 405.99; the measured m / z value is 407.0 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ8.35 (s, 1H), 6.16 (s, 2H), 3.71 (t, J = 7.8Hz, 2H), 0.93 (t, J = 7.8Hz, 2H), -0.00 (s, 9H).

[0763] 7-Bromo-5-chloro-3-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine: LC-MS (ESI): C12 H 16 The calculated mass of BrClN4O3Si is 405.99; the measured m / z value is 407.0 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ8.24 (s, 1H), 6.26 (s, 2H), 3.77 (dd, J = 16.7, 8.9Hz, 2H), 0.94 (t, J = 8.1Hz, 2H), -0.00 (s, 9H).

[0764] Step E: 7-Bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-3-amine

[0765] Iron powder (19.2 g, 343 mmol, 5.0 equivalent) was added to a solution of 7-bromo-5-chloro-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine (28.0 g, 68.7 mmol, 1.0 equivalent) and ammonium chloride (18.4 g, 343 mmol, 5.0 equivalent) in EtOH (400 mL), THF (400 mL), and water (200 mL) at room temperature. The mixture was stirred at 70 °C for 2 h. After cooling to room temperature, the mixture was filtered and the filter cake was washed with EA (200 mL x 3). The filtrate was concentrated under reduced pressure and the residue was diluted with EA (1200 mL). The organic layer was washed with water (500 mL) and brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 7-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-3-amine (26.0 g, 100% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI): C 12 H 18 The calculated quality of BrClN4OSi is 376.01; the measured m / z value is 377.2 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ7.96 (s, 1H), 6.02 (s, 2H), 5.78 (s, 2H), 3.64 (t, J = 7.8Hz, 2H), 0.89 (t, J = 7.8Hz, 2H), 0.00 (s, 9H).

[0766] Step F: 7-Bromo-5-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-3-amine

[0767] Acetic acid (5.23 g, 5.00 mL, 87.0 mmol, 6.57 equivalents) was added to a solution of 7-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-3-amine (5.00 g, 13.2 mmol, 1.0 equivalent) in acetone (150 mL) at room temperature, and the mixture was stirred at 50 °C for 4 h. Sodium cyanoborohydride (4.16 g, 66.2 mmol, 5.0 equivalents) was then added in portions to the mixture, and the reaction mixture was stirred at 50 °C overnight. After evaporation, the residue was diluted with EA (200 mL), washed with saturated NaHCO3 aqueous solution (200 mL x 3), water (200 mL), and brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography on silica gel (PE / EA = 15 / 1 to 10 / 1 v / v) to give 7-bromo-5-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-3-amine (3.20 g, 58% yield) as a yellow solid. LC-MS (ESI): C 15 H 24 The calculated quality of BrClN4OSi is 418.06; the measured m / z value is 419.0 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ7.98 (s, 1H), 6.32 (d, J = 7.6Hz, 1H), 5.83 (s, 2H), 4.02-3.98 (m, 1H), 3.67 (t, J = 7.6Hz, 2H), 1.35 (d, J = 6.0Hz, 6H), 0.90 (t, J = 7.64Hz, 2H), -0.00 (s, 9H).

[0768] Step G: 5-Chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-pyrazolo[4,3-b]pyridine-3-amine

[0769] Pd(dppf)Cl2 (401 mg, 548 μmol, 0.1 equivalent) was added to a solution of 7-bromo-5-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-3-amine (2.30 g, 5.48 mmol, 1.0 equivalent) and potassium vinyltrifluoroborate (1.10 g, 8.22 mmol, 1.5 equivalent) and tripotassium phosphate (3.49 g, 16.4 mmol, 3.0 equivalent) in 1,4-dioxane (50.00 mL) and water (5.00 mL) at room temperature. The reaction mixture was stirred at 85 °C for 2.5–3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EA (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography on silica gel (petroleum ether solution of ethyl acetate, 6% v / v) to provide a red oily substance, 5-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-pyrazolo[4,3-b]pyridine-3-amine (1.63 g, 81% yield). LC-MS (ESI): C 17 H 27 The calculated quality of ClN4OSi is 366.16; the measured m / z value is 367.2 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ7.66(s,1H),7.37(dd,J=17.4,11.2Hz,1H),6.32(d,J=17.4Hz,1H),6.09(d,J=8.0Hz,1H),5.83(d ,J=11.8Hz,1H),5.66(s,2H),4.05-3.96(m,1H),3.68-3.58(m,2H),1.35(d,J=6.4Hz,6H),0.96-0.84(m,2H),0.00(s,9H).

[0770] Step H: 1-(5-chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)ethane-1,2-diol

[0771] NMO (3.89 g, 33.2 mmol, 2.0 equivalent) and potassium (VI) osmium tetroxide dihydrate (612 mg, 1.66 mmol, 0.1 equivalent) were added to a solution of 5-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-pyrazolo[4,3-b]pyridine-3-amine (6.10 g, 16.6 mmol, 1.0 equivalent) in acetone (120.00 mL) and water (60.0 mL). The reaction was stirred at 15 °C for 16 h. After filtration, the filtrate was evaporated under reduced pressure. The residue was diluted with EA (250 mL), washed with water (150 mL) and brine (150 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography on silica gel (ethyl acetate in petroleum ether solution, 36% v / v) to provide 1-(5-chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)ethane-1,2-diol (4.78 g, 72% yield) as a black oil. LC-MS (ESI): C 17 H 29 The calculated mass of ClN4O3Si is 400.17; the measured m / z value is 401.1 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ7.53(s,1H),6.01(d,J=8.0Hz,1H),5.93(d,J=5.0Hz,1H),5.77(d,J=11.8Hz,1H),5.59(d,J=11.8Hz,1H),5.23(q,J=5.6Hz,1H ),5.13(t,J=5.6Hz,1H),3.98(dq,J=13.0,6.4Hz,1H),3.72(t,J=5.6Hz,2H ),3.67-3.51(m,2H),1.32(d,J=6.4Hz,6H),0.95-0.82(m,2H),0.00(s,9H).

[0772] Step I: 5-Chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxaldehyde

[0773] NaIO4 (2.24 g, 10.5 mmol, 2.0 equivalent) was added to a solution of 1-(5-chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)ethane-1,2-diol (2.10 g, 5.24 mmol, 1.0 equivalent) in THF (20 mL) and water (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding saturated sodium thiosulfate aqueous solution (30 mL) and extracted with EA (40 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (ethyl acetate in petroleum ether solution, 15% v / v) to provide 5-chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxaldehyde (1.70 g, 88% yield) as a red solid. LC-MS (ESI): C 16 H 25 The calculated mass of ClN4O2Si is 368.14; the measured m / z value is 387.2 [M+18+H]. + . 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.08(s,1H),6.46(d,J=8.0Hz,1H),5.94(s,2H),4.12- 3.98(m,1H),3.59(t,J=8.0Hz,2H),1.39(d,J=6.4Hz,6H),0.88(t,J=8.0Hz,2H),0.00(s,9H).

[0774] Intermediate 26: 3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carboxaldehyde

[0775]

[0776] Step A: 7-Bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-amine

[0777] Iron powder (10.1 g, 181 mmol, 5.0 equivalent) was added to a solution of 7-bromo-5-chloro-3-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine (14.8 g, 36.3 mmol, 1.0 equivalent) and ammonium chloride (9.71 g, 181 mmol, 5.0 equivalent) in EtOH (200.0 mL), THF (200.0 mL), and water (100.0 mL) at room temperature. The mixture was stirred at 70 °C for 1 h. After cooling to room temperature, the mixture was filtered and the filter cake was washed with EA (150 mL x 3). The filtrate was concentrated under reduced pressure and the residue was diluted with EA (500 mL). The organic layer was washed with water (200 mL) and brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 13.7 g (100% yield) of a yellow solid, 7-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-amine, which was used directly in the next step without further purification. LC-MS (ESI): C 12 H 18 The calculated quality of BrClN4OSi is 376.01; the measured m / z value is 377.0 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ7.63 (s, 1H), 6.89 (s, 2H), 5.63 (s, 2H), 3.68 (t, J = 7.8Hz, 2H), 0.91 (t, J = 7.8Hz, 2H), -0.00 (s, 9H).

[0778] Step B: Methyl 3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carboxylate

[0779] Pd(dppf)Cl2 (969 mg, 1.32 mmol, 0.1 equivalent) was added to a solution of 7-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-amine (5.00 g, 13.2 mmol, 1.0 equivalent) and triethylamine (4.02 g, 5.52 mL, 39.7 mmol, 3.0 equivalent) in DMF (60.0 mL) and MeOH (60.0 mL). The mixture was stirred at 70 °C for 6 h under CO (balloon) conditions. After cooling to room temperature, MeOH was removed under reduced pressure and the solution was extracted with EA (100 mL x 3). The organic layer was washed with brine (80 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (EA / PE = 1 / 1 v / v) to give methyl 3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carboxylate (3.3 g, 72% yield) as a red solid. LC-MS (ESI): C 14 H 21 The calculated mass of ClN4O3Si is 356.11; the measured m / z value is 357.1 [M+H]. + .

[0780] 1 H NMR (400MHz, DMSO-d6) δ7.61 (s, 1H), 6.98 (s, 2H), 5.64 (s, 2H), 3.95 (s, 3H), 3.68 (t, J = 7.8Hz, 2H), 0.91 (t, J = 7.8Hz, 2H), -0.00 (s, 9H).

[0781] Step C: (3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-7-yl)methanol

[0782] Lithium aluminum hydride (213 mg, 5.60 mmol, 2.0 equivalent) was added to a solution of methyl 3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carboxylate (1.00 g, 2.80 mmol, 1.0 equivalent) in THF (40.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with Na₂SO₄·10H₂O and stirred for 30 min. After filtration, the filtrate was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid (3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-7-yl)methanol (600 mg, 65% yield), which was used directly in the next step without further purification. LC-MS (ESI): C 13 H 21 The calculated mass of ClN4O2Si is 328.11; the measured m / z value is 329.1 [M+H]. + . 1 H NMR(400MHz,DMSO-d6)δ7.15(s,1H),6.61(s,2H),5.59(s,2H),5.56(d,J=5.6H z,1H),4.88-4.76(m,2H),3.72-3.63(m,2H),0.95-0.87(m,2H),-0.01(s,9H).

[0783] Step D: 3-Amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carboxaldehyde

[0784] IBX (536 mg, 1.92 mmol, 2.0 equivalent) was added to a solution of (3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-7-yl)methanol (315 mg, 958 μmol, 1.0 equivalent) in DMSO (20.0 mL) at room temperature (10 °C). The reaction mixture was stirred at 27 °C for 1 h. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic extracts were washed with saturated aqueous Na₂S₂O₃ solution (40 mL x 2), saturated NaHCO₃ solution (40 mL), and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EA = 6 / 1) to provide 3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carboxaldehyde (50.0 mg, 16% yield) as a red solid. LC-MS (ESI): C 13 H 19 The calculated mass of ClN4O2Si is 326.10; the measured m / z value is 327.1 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,2H),7.70(s,1H),7.10(s,2H),5.65(s,2H),3.70-3.61(m,2H),0.94-0.85(m,2H),-0.00(s,9H).

[0785] Intermediate 27: 3-Amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxaldehyde

[0786]

[0787] Step A: Methyl 3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate

[0788] Pd(dppf)Cl2 (3.49 g, 4.77 mmol, 0.1 equivalent) and TEA (14.5 g, 19.9 mL, 143 mmol, 3.0 equivalent) were added to a stirred solution of 7-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (18.0 g, 47.7 mmol, 1.0 equivalent) in DMF (50.0 mL) and MeOH (50.0 mL). The reaction mixture was stirred at 70 °C for 16 h under a CO atmosphere (balloon). After cooling to room temperature, the mixture was filtered and the filtrate was diluted with EtOAc (600 mL). The organic layer was washed with brine (200 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EtOAc = 1 / 1 v / v) to give methyl 3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (14.0 g, yield 82%, purity 50%) as a brown oil. LC-MS (ESI): C 14 H 21 The calculated mass of ClN4O3Si is 356.11; the measured m / z value is 357.1 [M+H]. + .

[0789] Step B: (3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)methanol

[0790] LiAlH4 (638 mg, 16.8 mmol, 1.5 equivalent) was added fractionally to a solution of methyl 3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl carboxylate (4.00 g, 11.2 mmol, 1.0 equivalent) in THF (20.0 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched with sodium sulfate decahydrate and filtered. The filtrate was concentrated under reduced pressure and purified by rapid column chromatography on silica gel (PE / EtOAc = 1 / 1 v / v) to give (3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)methanol (1.40 g, 38% yield) as a pale yellow solid. LC-MS (ESI): C 13 H 21 The calculated mass of ClN4O2Si is 328.11; the measured m / z value is 329.1 [M+H]. + . 1H NMR (400MHz, CDCl3) δ7.35(s,1H),5.62(s,2H),5.07(s,2H),4.69(s,2H),4.63-4.44(m,1H),3.60-3.52(m,2H),0.94-0.84(m,2H),-0.00(s,9H).

[0791] Step C: 3-Amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxaldehyde

[0792] IBX (1.79 g, 6.39 mmol, 1.5 equivalent) was added to a stirred mixture of (3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)methanol (1.40 g, 4.26 mmol, 1.0 equivalent) in DMSO (20.0 mL). The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated aqueous Na₂SO₃ solution (30 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL x 4), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (ethyl acetate in petroleum ether solution, 10% v / v) to give 3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxaldehyde (900 mg, 64% yield) as a red solid. LC-MS (ESI): C 13 H 19 The calculated mass of ClN4O2Si is 326.10; the measured m / z value is 327.1 [M+H]. + .

[0793] Intermediate 28: 3-(3-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0794]

[0795] Step A: Methyl 4-bromo-2-ethylbenzoate

[0796] Potassium carbonate (6.03 g, 43.7 mmol, 2.0 equivalent) and methyl iodoform (4.65 g, 2.04 mL, 32.7 mmol, 1.5 equivalent) were added to a solution of 4-bromo-2-ethylbenzoic acid (5.0 g, 21.8 mmol, 1.0 equivalent) in DMF (25.0 mL). The mixture was stirred at room temperature for 16 h. After filtration, the filter cake was washed with EA (50 mL). The filtrate was diluted with EA (200 mL), washed with brine (100 mL x 4), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give methyl 4-bromo-2-ethylbenzoate (4.4 g, 83% yield) as a yellow solid. LC-MS (ESI): C 10 H 11 The calculated mass of BrO2 is 241.99; the measured m / z value is massless [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ7.71(d,J=8.4Hz,1H),7.59(s,1H),7.53(d,J=8.4Hz,1H),3.84(s,3H),2.89(q,J=7.4Hz,2H),1.15(t,J=7.4Hz,3H)

[0797] Step B: Methyl 4-bromo-2-(1-bromoethyl)benzoate

[0798] BPO (857 mg, 3.54 mmol, 0.2 equivalent) and NBS (3.46 g, 19.5 mmol, 1.1 equivalent) were added to a stirred mixture of methyl 4-bromo-2-ethylbenzoate (4.3 g, 17.7 mmol, 1.0 equivalent) in CCl4 (40 mL). The resulting mixture was stirred at 80 °C for 3 h under N2. After evaporation, the residue was diluted with EA (200 mL), washed with saturated Na2SO3 aqueous solution (100 mL x 2), saturated NaHCO3 aqueous solution (100 mL x 2), and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (PE / EtOAc = 5 / 1 v / v) to give methyl 4-bromo-2-(1-bromoethyl)benzoate (4.2 g, 74% yield) as a yellow oil. LC-MS (ESI): C 10 H 10 The calculated mass of Br2O2 is 319.90; the measured m / z value is massless [M+H]. + .

[0799] Step C: 3-(5-bromo-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0800] DIPEA (2.41 g, 3.3 mL, 18.6 mmol, 3.0 equivalence) was added to a solution of methyl 4-bromo-2-(1-bromoethyl)benzoate (2.0 g, 6.21 mmol, 10 equivalence) and 3-aminopiperidine-2,6-dione hydrochloride (1.53 g, 9.32 mmol, 1.5 equivalence) in MeCN (20 mL). The mixture was stirred at 85°C for 16 h under N2. After evaporation, the residue was purified by rapid column chromatography on a silica gel column (100% ethyl acetate) to give 3-(5-bromo-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 48% yield) as a gray solid. LC-MS (ESI): C 14 H 13 The calculated mass of BrN₂O₃ is 336.01; the measured m / z value is 337.0 [M+H]. + . 1 H NMR(400MHz,DMSO-d6)δ11.00-10.66(m,1H),7.98-7.83(m,1H),7.74-7.56(m,2H),4.96- 4.50(m,2H),2.89-2.69(m,1H),2.68-2.52(m,2H),2.03-1.98(m,1H),1.58-1.39(m,3H).

[0801] Step D: 3-(3-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindolin-2-yl)piperidin-2,6-dione

[0802] Pd(dppf)Cl2 (239 mg, 326 μmol, 0.1 equivalent) was added to a solution of 3-(5-bromo-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.1 g, 3.26 mmol, 1.0 equivalent), anhydrous potassium acetate (961 mg, 9.79 mmol, 3.0 equivalent), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentaborane) (1.24 g, 4.89 mmol, 1.5 equivalent) in anhydrous dioxane (10 mL). The reaction mixture was stirred at 100 °C for 16 h under N2. After evaporation, the residue was washed with water (50 mL) and EA (10 mL), and dried to give 900 mg (72%) of 3-(3-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindololin-2-yl)piperidine-2,6-dione as a gray solid. LC-MS (ESI): C 20 H 25The calculated quality of BN2O5 is 384.19; the measured m / z value is 385.0 [M+H]. + . 1 H NMR(400MHz,DMSO-d6)δ10.93(d,J=12.4Hz,1H),7.93-7.87(m,1H),7.83-7.75(m,1H),7.71-7.63(m,1H),4 .86-4.59(m,2H),2.82-2.75(m,1H),2.62-2.56(m,2H),2.03-1.99(m,1H),1.46-1.42(m,3H),1.32(s,12H).

[0803] Intermediate 29: 6-chloro-1-(oxetane-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxaldehyde

[0804]

[0805] Step A: Methyl 6-chloro-1-(oxetane-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate

[0806] Cs₂CO₃ (5.10 g, 15.7 mmol, 3.0 equivalent) and 3-iodooxetane (2.40 g, 13.1 mmol, 2.5 equivalent) were added to a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (1.10 g, 5.22 mmol, 1.0 equivalent) in DMF (30 mL), and the reaction mixture was stirred at 80 °C for 16 h under N₂. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was washed with EA (100 mL x 2). The combined filtrates were washed with brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (petroleum ether solution of ethyl acetate, from 0% to 20% v / v) to provide methyl 6-chloro-1-(oxetane-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate as a yellow solid (650 mg, 47% yield). LC-MS (ESI): C 12 H 11 The calculated mass of ClN₂O₃ is 266.05; the measured m / z value is 267.0 [M+H]. + . 1 H NMR (DMSO-d6) δ8.26 (d, J = 3.6 Hz, 1H), 7.62 (s, 1H), 7.01 (d, J = 3.6 Hz, 1H), 6.01-5.88 (m, 1H), 5.05-4.94 (m, 4H), 3.97 (s, 3H).

[0807] Step B: (6-chloro-1-(oxetane-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol

[0808] LiAlH4 (427 mg, 11.2 mmol, 1.5 equivalent) was added fractionally to a solution of methyl 6-chloro-1-(oxetane-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-carboxylate (2.00 g, 7.50 mmol, 1.0 equivalent) in THF (40.0 mL) at 0°C and the reaction was stirred at 0°C for 1 h. The reaction was diluted with THF (50 mL), quenched with sodium sulfate decahydrate, and stirred for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide (6-chloro-1-(oxetane-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (1.80 g, 98% yield) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 11 H 11 The calculated mass of ClN2O2 is 238.05; the measured m / z value is 239.0 [M+H]. + .

[0809] Step C: 6-Chloro-1-(oxetane-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxaldehyde

[0810] IBX (8.19 g, 50% wt, 14.6 mmol, 2.0 equivalent) was added in portions to a solution of (6-chloro-1-(oxecyclobutan-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (1.80 g, 7.32 mmol, 1.0 equivalent) in DMSO (20.0 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate (150 mL), washed with saturated aqueous Na₂S₂O₃ solution (100 mL x 2), saturated aqueous sodium bicarbonate solution (100 mL), and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (10% to 20% petroleum ether solution of ethyl acetate) to give 6-chloro-1-(oxetane-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxaldehyde (500 mg, 29% yield) as a yellow solid. LC-MS (ESI): C 11 The calculated mass of H9ClN2O2 is 236.04; the measured m / z value is 237.1 [M+H]. + . 1H NMR (400MHz, DMSO-d6) δ10.31 (s, 1H), 8.30 (d, J = 3.6Hz, 1H), 7.78 (s, 1H), 7.14 ( d, J=3.6Hz, 1H), 6.00-5.93 (m, 1H), 5.04 (t, J=7.4Hz, 2H), 4.97 (t, J=7.4Hz, 2H).

[0811] Intermediate 30: 6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-4-carboxaldehyde

[0812]

[0813] Step A: Methyl 6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate

[0814] To a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (1.50 g, 7.12 mmol, 1.0 equivalent) in DCM (20.0 mL) and DMF (5 mL), copper acetate monohydrate (2.84 g, 14.2 mmol, 2.0 equivalent), cyclopropylboronic acid (3.06 g, 35.6 mmol, 5.0 equivalent), and TEA (7.21 g, 9.93 mL, 71.2 mmol, 10.0 equivalent) were added. The reaction mixture was stirred at 40 °C for 16 h under N2 (containing O2). After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with DCM (150 mL). The filtrate was washed with brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (petroleum ether solution of ethyl acetate, from 0% to 30% v / v) to provide methyl 6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate as a white solid (700 mg, 39% yield). LC-MS (ESI): C 12 H 11 The calculated mass of ClN2O2 is 250.05; the measured m / z value is 251.1 [M+H]. + .

[0815] Step B: (6-chloro-1-(oxetane-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol

[0816] Lithium aluminum(III) hydride (117 mg, 3.07 mmol, 1.1 equivalent) was added fractionally to a solution of methyl 6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-carboxylate (700 mg, 2.79 mmol, 1.0 equivalent) in THF (10.0 mL) at 0 °C, and the mixture was stirred at 0 °C for 10 min. The reaction mixture was quenched with saturated aqueous NH4Cl solution (15 mL) at 0 °C and extracted with EA (15 mL x 3). The organic layer was washed with H2O (15 mL x 3) and brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentr...

Claims

1. A compound of formula II: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: W is -N(R 1 ) 2, 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted by one or more R 1b replace; Two R's 1 Together with the nitrogen atom to which they are attached, they form a 3- to 12-membered heterocyclic group or a 5- to 10-membered heteroaryl group, wherein the heterocyclic group or heteroaryl group is optionally substituted by one or more R 1b replace; Each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3- to 12-membered heterocyclic group, -SR b 、-S(=O)R a , -S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-NR c S(=O)2R a 、 -NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR c R d 、 -NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、 -OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、 -OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; or Two adjacent R 1b Together with the inserted atoms, it forms C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more R u replace; or Each R 1 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclic group, 3 to 12 membered heterocyclic group, -(C 1-6 Alkylene)-(C 6-10 Aryl), -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), -(C 1-6 Alkylene)-(C 3-12 Carbocyclic), -(C 1-6 Alkylene)-(3 to 12 membered heterocyclic group), -S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 1a replace; Each R 1a are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3- to 12-membered heterocyclic group, -SR b 、-S(=O)R a , -S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-NR c S(=O)2R a 、 -NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR c R d 、 -NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、 -OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、 -OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; X is -[C(R 2 )2]- m , O or NR X ; when X is O or NR X When W is a 3- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted by one or more R 1b replace; Each R 2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3- to 12-membered heterocyclic group, -SR b 、-S(=O)R a , -S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-NR c S(=O)2R a 、 -NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR c R d 、 -NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、 -OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、 -OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; Two R 2 together to form an oxo group; or Two R 2 Together with the carbon atom to which they are attached, they form C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u Replacement; m is an integer from 0 to 5; R X It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, -S(=O)2R a 、-S(=O)2OR b , -S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; Ring A is a 9- or 10-membered bicyclic fused ring system containing at least one 5- or 6-membered heteroaryl group; each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3- to 12-membered heterocyclic group, -SR b 、-S(=O)R a , -S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-NR c S(=O)2R a 、 -NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR c R d 、 -NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、 -OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、 -OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; When valence permits, n is an integer from 0 to 10; or Two adjacent R A Together with the inserted atoms, it forms C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace; Each R B are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3- to 12-membered heterocyclic group, -SR b 、-S(=O)R a , -S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-NR c S(=O)2R a 、 -NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR c R d 、 -NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、 -OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、 -OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; p is an integer from 0 to 3; U is -C(R 4 )2- or -C(=O)-; Each R 4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace; or Two R's 4 Together with the carbon atom to which they are attached, they form C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace; Each R D are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; d is an integer selected from 0 to 4; R 3 It is hydrogen, deuterium, C 1-6 Haloalkyl or C 1-6 Alkyl; and q is an integer from 0 to 2; in: Each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3- to 12-membered heterocyclic group, -SR b 、-S(=O)R a , -S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-NR c S(=O)2R a 、 -NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR c R d 、 -NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、 -OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、 -OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- to 6-membered heteroaryl; or Two R's u Together with one or more intervening atoms, it forms C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group or 3 to 12 membered heterocyclic group; Each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 Aryl or 5- to 10-membered heteroaryl; Each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; and Each R c and R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; or R c and R d Together with the nitrogen atom to which they are attached, they form a 3- to 12-membered heterocyclic group or a 5- to 10-membered heteroaryl group, wherein the heterocyclic group or heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclic group and 3 to 6 membered heterocyclic group; wherein R a , R b , R c and R d Each independently and optionally represented by one or more R z Replace; each R z are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclic group, 3- to 6-membered heterocyclic group, C6 aryl group or 5- to 6-membered heteroaryl group, The conditions are: i) When ring A is hour, Then m is not 0; ii) When each R 1 are independently hydrogen, C 1-6 Alkyl, C 3-12 Carbocyclic or -C(=O)(C 1-6 alkyl), then 1) m is not 0; and 2) two geminal R 2 do not form an oxo group together; and iii) the compound is not 2. The compound according to claim 1, wherein the compound is a compound of formula II-1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

3. The compound according to claim 1 or 2, wherein X is -[C(R 2 )2]- m .

4. A compound according to any one of claims 1 to 3, wherein W is -N(R 1 )2.

5. The compound according to claim 1, wherein the compound is a compound of formula II-2 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

6. The compound according to any one of claims 1 to 5, wherein Ring A is a 9-membered bicyclic heteroaryl group containing 1 to 4 nitrogen atoms.

7. The compound according to claim 6, wherein Ring A is imidazo[1,5-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, indolyl, benzo[d]imidazolyl, indazolyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[d]thiazolyl, benzo[b]thienyl or benzofuranyl.

8. A compound according to any one of claims 1 to 5, wherein yes in: R 3a It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, -(C 1-3 Alkylene)-(C 3-6 Carbocyclic), -(C 1-3 alkylene)-(3 to 6-membered heterocyclic group), -(C 1-3 Alkylene)-(C6 aryl), -(C 1-3 alkylene)-(5- to 6-membered heteroaryl), -S(=O)2R a 、-S(=O)2OR b , -S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

9. The compound according to claim 8, wherein yes 10. The compound according to claim 8 or 9, wherein R 3a It is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl or -(C 1-3 wherein the alkyl, alkylene, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

11. The compound according to any one of claims 1 to 5, wherein Ring A is a 10-membered bicyclic heteroaryl group containing 1 to 3 nitrogen atoms.

12. The compound according to claim 10, wherein yes 13. The compound according to any one of claims 1 to 5, wherein Ring A is a 9- or 10-membered bicyclic fused ring system comprising a 5- or 6-membered heteroaryl and a C 5-6 Carbocyclic group.

14. The compound according to claim 13, wherein yes 15. A compound according to any one of claims 1 to 14, wherein each R 1 are independently hydrogen, C 1-6 Alkyl, -(C 1-6 Alkylene)-(C 6-10 Aryl) or -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), wherein the alkyl, alkylene, aryl or heteroaryl is optionally substituted by one or more R 1a replace.

16. The compound according to claim 15, wherein each R 1a are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

17. The compound according to claim 15, wherein each R 1a are independently halogen, C 1-6 Alkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the alkyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

18. A compound according to any one of claims 1 to 14, wherein two R 1 Together with the nitrogen atom to which they are attached, they form a 1b A substituted 5- or 10-membered heterocyclic group.

19. A compound according to any one of claims 1 to 14, wherein two R 1 Together with the nitrogen atom to which they are attached, they form a 1b Substituted 5- to 10-membered heteroaryl.

20. The compound according to claim 18 or 19, wherein each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, or -S(=O)2R a wherein the alkyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

21. The compound according to claim 18 or 19, wherein each R 1b are independently oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C6 aryl, 5- to 6-membered heteroaryl or -S(=O)2R a wherein the alkyl, alkoxy, alkylamino, aryl or heteroaryl groups are optionally substituted by one or more R u replace.

22. A compound according to any one of claims 1 to 21, wherein each R 2 are independently hydrogen or C 1-6 alkyl.

23. A compound according to any one of claims 1-21, wherein each R 2 It's hydrogen.

24. A compound according to any one of claims 1 to 21, wherein two R 2 Together they form an oxo group.

25. The compound according to any one of claims 1-24, wherein m is 1.

26. A compound according to any one of claims 1-25, wherein each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, C6 aryl group, 5 to 6 membered heteroaryl group or -NR c S(=O)R a wherein the alkyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

27. A compound according to any one of claims 1-25, wherein each R A are independently oxo, halogen, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkynyl, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, or -NR c S(=O)R a wherein the alkyl, alkoxy, alkylamino, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

28. The compound of any one of claims 1-27, wherein n is 0, 1 or 2.

29. A compound according to any one of claims 1-28, wherein each R B are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

30. A compound according to any one of claims 1-28, wherein each R B are independently halogen, C 1-6 Alkyl or C 1-6 Alkoxy.

31. The compound of any one of claims 1-30, wherein p is 0 or 1.

32. A compound according to any one of claims 1-31, wherein U is -C(R 4 )2-, and each R 4 are independently hydrogen or C 1-6 alkyl.

33. A compound according to any one of claims 1-32, wherein each R D are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

34. A compound according to any one of claims 1-33, wherein d is 0.

35. A compound according to any one of claims 1 to 34, wherein R 3 It's hydrogen.

36. A compound according to any one of claims 1-35, wherein q is 1.

37. The compound according to claim 1, wherein the compound is a compound of formula II-2 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Two R's 1 Together with the nitrogen atom to which they are attached, they form a 1b substituted 3- to 12-membered heterocyclyl; Each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3- to 12-membered heterocyclic group, -SR b 、-S(=O)R a , -S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-NR c S(=O)2R a 、 -NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR c R d 、 -NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、 -OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、 -OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; or Two adjacent R 1b Together with the intervening atoms, it forms a C6 aryl or 5- to 6-membered heteroaryl group, wherein The aryl or heteroaryl group is optionally substituted by one or more R u replace; Each R 2 It is hydrogen; m is 1; Ring A is a 5- or 6-membered heteroaryl group and a C 5-6 a 9- or 10-membered bicyclic fused heteroaryl or a 9- or 10-membered bicyclic fused ring system of a carbocyclyl group; Each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3- to 12-membered heterocyclic group, -SR b 、-S(=O)R a , -S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-NR c S(=O)2R a 、 -NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR c R d 、 -NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、 -OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、 -OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; n is an integer from 0 to 2; Each R B are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3- to 12-membered heterocyclic group, -SR b 、-S(=O)R a , -S(=O)2R a 、-S(=O)2OR b 、-S(=O)2NR c R d 、-NR c S(=O)2R a 、 -NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR c R d 、 -NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、 -OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、 -OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; p is an integer from 0 to 3; U is -CH2-; Each R D are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 A carbocyclic group or a 3- to 6-membered heterocyclic group, wherein The alkyl, alkoxy, alkylamino, carbocyclic or heterocyclic group is optionally substituted by one or more R u replace; d is an integer selected from 0 to 4; R 3 It is hydrogen, deuterium, C 1-6 Haloalkyl or C 1-6 Alkyl; and q is 1.

38. The compound of claim 1, wherein the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.

39. A pharmaceutical composition comprising a compound according to any one of claims 1-38 and a pharmaceutically acceptable excipient.

40. A method of degrading IKZF2 protein in a subject or a biological sample, comprising administering to the subject a compound according to any one of claims 1-38 or contacting the biological sample with a compound according to any one of claims 1-38.

41. Use of a compound according to any one of claims 1-38 in the preparation of a medicament for degrading IKZF2 protein in a subject or a biological sample.

42. A compound according to any one of claims 1-38 for use in degrading IKZF2 protein in a subject or biological sample.

43. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1-38.

44. Use of a compound according to any one of claims 1-38 in the preparation of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

45. A compound according to any one of claims 1-38 for use in treating or preventing a disease or disorder in a subject in need thereof.

46. ​​The method, use or compound for use according to any one of claims 43 to 45, wherein the disease or condition is an IKZF2-mediated disease or condition.

47. The method, use or compound of any one of claims 43-45, wherein the disease or condition is T-cell leukemia, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid or gastrointestinal stromal tumor (GIST).

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