IKZF2 degradation agent and application thereof

Abstract

Described herein are compounds of Formula I'and pharmaceutically acceptable salts, solvates or stereoisomers thereof, and uses thereof (e.g., as IKZF2 degrading agents).

Description

[0001] Related applications

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 446,105, filed February 16, 2023, and U.S. Provisional Application No. 63 / 323,792, filed March 25, 2022, the contents of which are incorporated herein by reference in their entirety. Background Art

[0003] IKAROS family zinc finger 2 (IKZF2), also known as Helios, described herein, is one of five members of the Ikaros family of transcription factors found in mammals. IKZF2 contains four zinc finger domains near its N-terminus, which are involved in DNA binding, and two zinc finger domains at its C-terminus, which are involved in protein dimerization. IKZF2 is approximately 50% identical to the Ikaros family members Ikaros (IKZF1), Aiolos (IKZF3), and Eos (IKZF4), with the highest homology (80%+ identity) in the zinc finger region. These four Ikaros family transcription factors bind to the same consensus DNA sites and can heterodimerize with each other when co-expressed in cells. The fifth Ikaros family protein, Pegasus (IKZF5), is only 25% identical to IKZF2, binds to different DNA sites than the other Ikaros family members, and does not readily heterodimerize with other Ikaros family proteins. IKZF2, IKZF1, and IKZF3 are primarily expressed in hematopoietic cells, whereas IKZF4 and IKZF5 are expressed in a variety of tissues.

[0004] IKZF2 is a key regulator of T cell activity and function. Genetic deletion of Helios results in increased anti-tumor immune responses. Notably, Helios is highly expressed in regulatory T cells (RTCs), a T cell subset that restricts effector T cell activity. Selective deletion of Helios in TRCs results in both loss of suppressive activity and gain of effector T cell function. Therefore, Helios is a key factor in limiting T cell effector function in Tregs. Currently, anti-CTLA4 antibodies are used clinically to target Tregs in tumors. However, targeting CTLA4 often leads to systemic activation of T effector cells, resulting in excessive toxicity and limiting therapeutic efficacy. Up to three-quarters of patients receiving combined anti-PD-1 and anti-CTLA4 therapy report experiencing grade 3 or higher adverse events. Therefore, there is a significant need for compounds that target Tregs in tumors without causing systemic activation of T effector cells. IKZF2-specific degraders have the potential to focus the enhanced immune response within or near the tumor, thereby providing potentially more tolerable and less toxic therapeutics for the treatment of cancer.

[0005] It has also been reported that Helios expression is upregulated in "exhausted" T cells in the presence of both chronic viral infection and dysfunctional chimeric antigen receptor (CAR) T cells. Overexpression or abnormal expression of Helios and various splicing isoforms has been reported in a variety of hematological malignancies, including T-cell leukemias and lymphomas. In addition, in a mixed lineage leukemia (MLL)-driven model, knockdown of Helios effectively inhibited proliferation and increased cell death. Based on these results, genomic analysis and chromatin accessibility analysis confirmed that IKZF2 deficiency leads to increased myeloid differentiation. These data suggest that myeloid leukemia cells have a differentiated requirement for IKZF2 compared with normal cells. Therefore, compared with normal hematopoietic stem cells, IKZF2 deficiency has a preferential effect on leukemia stem cells, providing a new strategy for targeting leukemia stem cells. Summary of the Invention

[0006] The present invention discloses a compound of formula (I'):

[0007]

[0008] Each variable in Formula I' is described, specified, and exemplified herein.

[0009] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0010] In certain aspects, the present disclosure further provides methods of degrading IKZF2 protein in a subject or a biological sample, comprising administering to the subject a compound disclosed herein, or contacting the biological sample with a compound disclosed herein.

[0011] In certain aspects, the present disclosure further provides a use of a compound disclosed herein for the preparation of a medicament for degrading IKZF2 protein in a subject or biological sample.

[0012] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading IKZF2 protein in a subject or a biological sample.

[0013] In certain aspects, the present disclosure provides methods of treating a disease or condition comprising administering to a subject in need thereof a compound disclosed herein.

[0014] In certain aspects, the present disclosure provides use of a compound disclosed herein in the preparation of a medicament for treating a disease or condition.

[0015] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating a disease or disorder.

[0016] In certain aspects, the present disclosure provides methods of (a) increasing IL-2 production; (b) inhibiting regulatory T cells; (c) enhancing effector T cells; (d) inhibiting tumor growth; and / or (e) enhancing tumor regression in a subject, comprising administering to a subject in need thereof a compound disclosed herein.

[0017] In certain aspects, the present disclosure provides the use of a compound disclosed herein in the preparation of a medicament for (a) increasing IL-2 production; (b) inhibiting regulatory T cells; (c) enhancing effector T cells; (d) inhibiting tumor growth; and / or (e) enhancing tumor regression in a subject. DETAILED DESCRIPTION

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

[0019] Compounds of the present disclosure

[0020] In certain aspects, the present disclosure provides compounds of formula (I'):

[0021]

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

[0023] X is -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)- or -S(=O)2-;

[0024] Y is -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)- or -S(=O)2-;

[0025] Each Z is independently -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)- or -S(=O)2-;

[0026] p is 0, 1, or 2;

[0027] Each R 3are independently deuterium, 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 Carbocyclyl, 3- to 12-membered heterocyclyl, -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, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally replaced by one or more R u replace;

[0028] Two geminal R 3 together to form an oxo group; or

[0029] Two geminal R 3 Together with the carbon atom to which it is attached, it forms C3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace;

[0030] Each R 4 are independently hydrogen or C 1-6 Alkyl, which is optionally replaced by one or more R u replace;

[0031] Ring A is C 3-12 carbocyclic ring or 3- to 12-membered heterocyclic ring;

[0032] R 1 is hydrogen or -MLQR 2 ;

[0033] M is absent, -(C=O)-, -S(=O)-, or -S(=O)2-;

[0034] L does not exist or [W] r ;

[0035] r is an integer from 1 to 3;

[0036] Each W is independently -C(R L )2-、C 3-4 carbocyclylene or 3 to 4 membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is optionally substituted by one or more R u replace;

[0037] Each R L are independently hydrogen, deuterium, 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 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace;

[0038] Two geminal R L Together with the carbon atom to which it is attached, it forms 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;

[0039] Q does not exist, -NR Q-, -O-, -C(=O)-, -S(=O)- or -S(=O)2-;

[0040] R Q is hydrogen or C 1-6 Alkyl, which is optionally replaced by one or more R u replace;

[0041] R 2 It is C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R 2a replace;

[0042] Each R 2a 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, -(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), -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 bC(=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, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally replaced by one or more R u replace; or

[0043] Two R's 2a Together with the atoms it is connected to form C 3-8 carbocyclyl or 3 to 8 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace;

[0044] R A 、R C and R E is independently at each occurrence 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 Carbocyclyl, 3- to 12-membered heterocyclyl, -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)NRc 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 groups are optionally replaced by one or more R u replace;

[0045] q is an integer from 0 to 2;

[0046] If valence permits, s is an integer from 0 to 12;

[0047] e is an integer selected from 0 to 5;

[0048] U is -CH2- or -C(=O)-;

[0049] R 5 For hydrogen, deuterium, C 1-6 Haloalkyl or C 1-6 alkyl; and

[0050] t is an integer from 0 to 2;

[0051] in:

[0052] 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, -(C 1-6 alkylene)-(C 6-10 Aryl), -(C 1-6 alkylene)-(5- to 10-membered heteroaryl), -(C1-6 alkylene)-(C 3-12 Carbocyclic), -(C 1-6 Alkylene)-(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, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic or heterocyclic radical 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 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl and 3- to 12-membered heterocyclyl; or

[0053] Two R's uTogether with one or more intervening atoms, they form C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 a carbocyclyl group or a 3- to 12-membered heterocyclyl group;

[0054] 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;

[0055] 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

[0056] 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

[0057] R c and R d Together with the nitrogen atom to which it is attached, it forms a 3- to 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more R z replace;

[0058] where R a 、R b 、R c and R d is independently and optionally replaced at each occurrence by one or more R z Replacement; and

[0059] Each R z 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 a carbocyclic group or a 3- to 6-membered heterocyclic group.

[0060] In certain embodiments, the compound is a compound of Formula (I'-1-i), (I'-1-ii), (I'-1-iii), (I'-1-iv), (I'-1-v), (I'-1-vi), (I'-1-vii), (I'-1-viii), (I'-1-ix), (I'-1-x), (I'-1-xi), (I'-1-xii), or (I'-1-xiii):

[0061]

[0062]

[0063] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0064] In certain embodiments, the compound is of Formula (I'-2-i), (I'-2-ii), (I'-2-iii), (I'-2-iv), (I'-2-v), (I'-2-vi), (I'-2-vii), (I'-2-viii), (I'-2-ix), (I'-2-x), (I'-2-xi), (I'-2-xii), or (I'-2-xiii):

[0065]

[0066]

[0067] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0068] In certain embodiments, when p is 0, then X and Y are not both -C(R 3 )2; and / or when p is 1, then not all of X, Y and Z are -C(R 3 )2.

[0069] In certain embodiments, Ring A is 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), cycloheptatrienyl (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 (C10 ) or spiro[4.5]decyl(C 10 )) or a 3- to 12-membered heterocyclyl (e.g., a heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

[0070] In certain embodiments, for wherein m and n are independently integers from 0 to 2.

[0071] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0072] In certain embodiments, m and n are each 1.

[0073] In certain embodiments, R 1 is hydrogen or -MLQR 2 .

[0074] In certain embodiments, M is absent, -(C=O)-, -S(=O)-, or -S(=O)2-.

[0075] In certain embodiments, L is absent or [W] r .

[0076] In certain embodiments, each W is independently -C(R L )2-、C 3-4 carbocyclylene (e.g., cyclopropylene (C3), cyclopropenylene (cyclopropenylene, C3), cyclobutylene (C4) or cyclobutenylene (cyclobutenylene, C4)) or 3 to 4 membered heterocyclylene (e.g., heterocyclylene comprising a 3 to 4 membered ring and a heteroatom selected from N, O and S), wherein the carbocyclylene or heterocyclylene is optionally substituted by one or more R u replace.

[0077] In certain embodiments, each R L are independently hydrogen, deuterium, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, 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)), C 1-6Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5), or hexyloxy (C6)), C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, methyl-n-butylamino, methylisobutylamino, methylsec-butylamino, methyltert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethylisopropylamino, ethyl-n-butylamino butylamino, ethyl sec-butylamino, ethyl isobutylamino, ethyl tert-butylamino, ethyl pentylamino, ethylhexylamino, propyl n-butylamino, propyl isobutylamino, propyl sec-butylamino, propyl tert-butylamino, propyl pentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 alkenyl (e.g., ethenyl (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), cycloheptatrienyl (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 (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10Aryl (e.g., phenyl or naphthyl) or 5- to 10-membered heteroaryl (e.g., a heteroaryl group 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, carbocyclyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted by one or more R u replace.

[0078] In certain embodiments, each R L are independently hydrogen, deuterium, 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, 3 to 6 membered heterocyclyl, C6 aryl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

[0079] In certain embodiments, each R L are independently hydrogen, deuterium, 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, 3 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0080] In certain embodiments, each R L are independently hydrogen, deuterium, 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0081] In certain embodiments, each R L are independently hydrogen, deuterium or C 1-6 alkyl.

[0082] In certain embodiments, L is -CH2-.

[0083] In certain embodiments, two geminal R L Together with the carbon atom to which it is attached, it forms C 3-6 Carbocyclic groups (e.g., ethenyl (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 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6)) or 3 to 6-membered heterocyclyl (e.g., a heterocyclyl comprising one or two 3 to 6-membered rings and 1-3 heteroatoms selected from N, O and S), wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0084] In certain embodiments, r is an integer from 1 to 3. In certain embodiments, r is 1. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is 3.

[0085] In certain embodiments, Q is absent, -NR Q -, -O-, -C(=O)-, -S(=O)- or -S(=O)2-.

[0086] In certain embodiments, R Q is hydrogen 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)), which is optionally substituted by one or more R u replace.

[0087] In certain embodiments, R 2 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), cycloheptatrienyl (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 (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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., a heteroaryl group comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl group is optionally substituted by one or more R 2a replace.

[0088] In certain embodiments, each R 2a are independently oxo, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, 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)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5), or hexyloxy (C6)), C 1-6Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, methyl-n-butylamino, methylisobutylamino, methylsec-butylamino, methyltert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethylisopropylamino, ethyl-n-butylamino butylamino, ethyl sec-butylamino, ethyl isobutylamino, ethyl tert-butylamino, ethyl pentylamino, ethylhexylamino, propyl n-butylamino, propyl isobutylamino, propyl sec-butylamino, propyl tert-butylamino, propyl pentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 alkenyl (e.g., ethenyl (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), cycloheptatrienyl (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 (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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 1-6alkylene)-(5- to 10-membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 Carbocyclic), -(C 1-6 Alkylene)-(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, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl radicals are optionally replaced by one or more R u replace.

[0089] In certain embodiments, each R 2a are independently oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkylamino, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, -(C 1-6alkylene)-(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)2NR c R d 、-NR c S(=O)2R a 、-NR b C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl radicals are optionally replaced by one or more R u replace.

[0090] In certain embodiments, both R 2a Together with the atoms it is connected to form C 3-8 carbocyclyl (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), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8)) or 3 to 8 membered heterocyclyl (e.g., a heterocyclyl comprising one or two 3 to 8 membered rings and 1-3 heteroatoms selected from N, O and S), wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0091] In certain embodiments, R A 、R C and R E is independently at each occurrence oxo, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, 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)), C 1-6Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5), or hexyloxy (C6)), C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, methyl-n-butylamino, methylisobutylamino, methylsec-butylamino, methyltert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethylisopropylamino, ethyl-n-butylamino butylamino, ethyl sec-butylamino, ethyl isobutylamino, ethyl tert-butylamino, ethyl pentylamino, ethylhexylamino, propyl n-butylamino, propyl isobutylamino, propyl sec-butylamino, propyl tert-butylamino, propyl pentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 alkenyl (e.g., ethenyl (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), cycloheptatrienyl (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 (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10Aryl (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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally replaced by one or more R u replace.

[0092] In certain embodiments, R A 、R C and R E is independently at each occurrence 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 3-6carbocyclyl, 3 to 6 membered heterocyclyl, C6 aryl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0093] In certain embodiments, R A 、R C and R E is independently at each occurrence 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, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0094] In certain embodiments, R A 、R C and R E is independently at each occurrence 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.

[0095] In certain embodiments, q is an integer from 0 to 2. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.

[0096] In certain embodiments, if valence permits, s is an integer from 0 to 12. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, if valence permits, s is 5. In certain embodiments, if valence permits, s is 6. In certain embodiments, if valence permits, s is 7. In certain embodiments, if valence permits, s is 8. In certain embodiments, if valence permits, s is 9. In certain embodiments, if valence permits, s is 10. In certain embodiments, if valence permits, s is 11. In certain embodiments, if valence permits, s is 12.

[0097] In certain embodiments, e is an integer selected from 0 to 5. In certain embodiments, e is 0. In certain embodiments, e is 1. In certain embodiments, e is 2. In certain embodiments, e is 3. In certain embodiments, e is 4. In certain embodiments, e is 5.

[0098] In certain embodiments, X is -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)- or -S(=O)2-.

[0099] In certain embodiments, Y is -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)- or -S(=O)2-.

[0100] In certain embodiments, each Z is independently -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)- or -S(=O)2-.

[0101] In certain embodiments, X is -O- and Y is -C(R 3 )2-. In certain embodiments, X is -C(R 3 )2- and Y is -O-. In certain embodiments, X is -NR 4 - and Y is -C(R 3 )2-.

[0102] In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2.

[0103] In certain embodiments, each R 3 are independently deuterium, hydrogen, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, 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)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5), or hexyloxy (C6)), C 1-6Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, methyl-n-butylamino, methylisobutylamino, methylsec-butylamino, methyltert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethylisopropylamino, ethyl-n-butylamino butylamino, ethyl sec-butylamino, ethyl isobutylamino, ethyl tert-butylamino, ethyl pentylamino, ethylhexylamino, propyl n-butylamino, propyl isobutylamino, propyl sec-butylamino, propyl tert-butylamino, propyl pentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 alkenyl (e.g., ethenyl (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), cycloheptatrienyl (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 (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl groups are optionally replaced by one or more R u replace.

[0104] In certain embodiments, each R 3 are independently hydrogen, deuterium, 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, 3 to 6 membered heterocyclyl, C6 aryl, or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

[0105] In certain embodiments, each R 3are independently hydrogen, deuterium, 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, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0106] In certain embodiments, each R 3 are independently hydrogen, deuterium, 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.

[0107] In certain embodiments, each R 3 are independently deuterium, hydrogen or C 1-6 alkyl.

[0108] In certain embodiments, two geminal R 3 Together they form an oxo group.

[0109] In certain embodiments, two geminal R 3 Together with the carbon atom to which it is attached, it forms C 3-6 Carbocyclic groups (e.g., ethenyl (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 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., a heterocyclyl comprising one or two 3- to 6-membered rings and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0110] In certain embodiments, each R 4 are independently hydrogen 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)), which is optionally substituted by one or more R u replace.

[0111] In certain embodiments, U is -CH2- or -C(=O)-.

[0112] In certain embodiments, R 5 For hydrogen, deuterium, C 1-6 Haloalkyl (e.g., C substituted with 1 to 8 halogen atoms selected from -F, -Cl, -Br, or -I) 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)).

[0113] In certain embodiments, t is an integer from 0 to 2. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2.

[0114] In certain embodiments, the compound is of formula (I'):

[0115]

[0116] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

[0117] R 1 is hydrogen or -LR 2 ;

[0118] L is -C(R L )2-;

[0119] Each R L are independently hydrogen, deuterium, 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, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more Ru replace;

[0120] R 2 C 6-10 Aryl or 5- to 10-membered heteroaryl, C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R 2a replace;

[0121] Each R 2a are independently oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkylamino, 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)2NR c R d 、-NR c S(=O)2R a 、-NR b C(=O)R a 、-C(=O)OR b , or -C(=O)NR c R d wherein the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl radicals are optionally replaced by one or more R u replace;

[0122] R A 、R C and R E is independently at each occurrence 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, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace;

[0123] X is -O- or -NR 4 -;

[0124] Each R 4 are independently hydrogen or C 1-6 alkyl;

[0125] Y is -CH2- or -O-; and

[0126] p is 0 or 1.

[0127] In certain aspects, the present disclosure provides compounds of formula (I):

[0128]

[0129] and pharmaceutically acceptable salts, solvates or stereoisomers thereof, wherein:

[0130] R 1 is hydrogen or -MLQR 2 ;

[0131] M is absent, -(C=O)-, -S(=O)-, or -S(=O)2-;

[0132] L is absent or [-C(R L )2-] r ;

[0133] Each R L 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 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace; or

[0134] Two R's L Together with the carbon atom to which it is attached, it forms C 3-12 a carbocyclyl group or a 3- to 12-membered heterocyclyl group;

[0135] r is an integer from 1 to 3;

[0136] Q does not exist, -NR Q -, -O-, -C(=O)-, -S(=O)- or -S(=O)2-;

[0137] R Q For hydrogen, C 1-6 Alkyl, wherein the alkyl group is optionally substituted by one or more R u replace;

[0138] R 2 It is C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R 2a replace;

[0139] Each R 2a 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, -(C 1-6 alkyl)-(C 6-10 Aryl), -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)-(C 3-12 Carbocyclic), -(C 1-6 alkyl)-(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, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally replaced by one or more R u replace; or

[0140] Two R's 2a Together they form oxygen;

[0141] R A and R C is independently at each occurrence 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 Carbocyclyl, 3- to 12-membered heterocyclyl, -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, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally replaced by one or more R u replace;

[0142] q is an integer from 0 to 2;

[0143] If valence permits, s is an integer from 0 to 12;

[0144] m and n are independently integers from 0 to 2;

[0145] X is -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)- or -S(=O)2-;

[0146] Y is -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)- or -S(=O)2-;

[0147] Each Z is independently -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)- or -S(=O)2-;

[0148] p is 0 or 1;

[0149] Each R 3 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 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2ORb 、-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, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally replaced by one or more R u replace;

[0150] Two geminal R 3 together to form an oxo group; or

[0151] Two geminal R 3 Together with the carbon atom to which it is attached, it forms C 3-12 a carbocyclyl group or a 3- to 12-membered heterocyclyl group;

[0152] Each R 4 are independently hydrogen or C 1-6 Alkyl, wherein the alkyl group is optionally substituted by one or more R u replace;

[0153] U is -CH2- or -C(=O)-;

[0154] R 5 For hydrogen, deuterium, C 1-6 Haloalkyl or C 1-6 alkyl; and

[0155] t is an integer from 0 to 2;

[0156] in:

[0157] 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, -(C 1-6 alkyl)-(C 6-10 Aryl), -(C 1-6 alkyl)-(5- to 10-membered heteroaryl), -(C 1-6 alkyl)-(C 3-12 Carbocyclic), -(C 1-6 alkyl)-(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)Ra 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic or heterocyclic radical 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 3-12 carbocyclyl and 3- to 12-membered heterocyclyl; or

[0158] Two R's u Together with one or more intervening atoms, they form C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 a carbocyclyl group or a 3- to 12-membered heterocyclyl group;

[0159] 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;

[0160] 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

[0161] 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

[0162] R c and R d Together with the nitrogen atom to which it is attached, it forms a 3- to 12-membered heterocyclic group;

[0163] where R a 、R b 、R c and R d is independently and optionally replaced at each occurrence by one or more Rz Replacement; and

[0164] 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 a carbocyclic group or a 3- to 6-membered heterocyclic group.

[0165] In certain embodiments, X is -C(R 3 )2-.

[0166] In certain embodiments, X is -NR 4 -.

[0167] In certain embodiments, X is -O-.

[0168] In certain embodiments, X is -S-.

[0169] In certain embodiments, X is -S(=O)-.

[0170] In certain embodiments, X is -S(=O)2-.

[0171] In certain embodiments, Y is -C(R 3 )2-.

[0172] In certain embodiments, Y is -NR 4 -.

[0173] In certain embodiments, Y is -O-.

[0174] In certain embodiments, Y is -S-.

[0175] In certain embodiments, Y is -S(=O)-.

[0176] In certain embodiments, Y is -S(=O)2-.

[0177] In certain embodiments, X is -O- and Y is -C(R 3 )2-. In some embodiments, X is -O- and Y is -CH2-. In certain embodiments, X is -C(R 3 )2- and Y is -O-. In certain embodiments, X is -NR 4 - and Y is -C(R 3 )2-. In certain embodiments, X is -C(R 3 )2- and Y is -NR 4 -.

[0178] In some embodiments, X is -O-, Y is -C(R 3 )2-, and p is 0.

[0179] In certain embodiments, Z is -C(R 3 )2-、-NR 4 - or -O-. In certain embodiments, Z is -C(R 3 )2- or -O-.

[0180] In certain embodiments, when p is 0, then X and Y are not both -C(R 3 )2; or when p is 1, then not all of X, Y, and Z are -C(R 3 )2.

[0181] In certain embodiments, p is 0. In certain embodiments, p is 1.

[0182] In certain embodiments, the compound is a compound of formula (I-1-i) to (I-1-xiii):

[0183]

[0184]

[0185]

[0186] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0187] In certain embodiments, R 1 In certain embodiments, R 1 -MLQR 2 .

[0188] In certain embodiments, M is absent. In certain embodiments, M is -(C=O)-, -S(=O)-, or -S(=O)2-.

[0189] In certain embodiments, L is -C(R L )2-. In certain embodiments, L is absent.

[0190] In certain embodiments, each R L 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 3-6carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0191] In certain embodiments, each R L are independently hydrogen or C 1-6 alkyl.

[0192] In certain embodiments, L is -CH2-.

[0193] In certain embodiments, both R L Together with the carbon atom to which it is attached, it forms C 3-12 a carbocyclic group or a 3- to 12-membered heterocyclic group.

[0194] In certain embodiments, Q is absent. In certain embodiments, Q is -NR Q -, -O-, -C(=O)-, -S(=O)-, or -S(=O)2-. In certain embodiments, Q is -NR Q -. In certain embodiments, Q is -O-. In certain embodiments, Q is -C(=O)-. In certain embodiments, Q is -S(=O)-. In certain embodiments, Q is -S(=O)2-.

[0195] In certain embodiments, R Q is hydrogen or C 1-6 In certain embodiments, R Q C 1-6 In certain embodiments, R Q For hydrogen.

[0196] In certain embodiments, R 2 C 6-10 Aryl, 5- to 10-membered heteroaryl, C 5-10 a carbocyclic group or a 5- to 10-membered heterocyclic group.

[0197] In certain embodiments, R 2 It is phenyl.

[0198] In certain embodiments, R 2 is a 5- to 10-membered heteroaryl group.

[0199] In certain embodiments, R 2 It is C 5-10 Carbocyclic group.

[0200] In certain embodiments, R 2 It is a 5- to 10-membered heterocyclic group.

[0201] In certain embodiments, each R2a are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0202] In certain embodiments, each R 2a are independently oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -S(=O)2R a 、-S(=O)2NR c R d 、-NR c S(=O)2R a 、-NR b 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 groups are optionally replaced by one or more R u replace.

[0203] In certain embodiments, both R 2a Together they form an oxo group.

[0204] In certain embodiments, each R 3 are independently H or C 1-6 In certain embodiments, each R 3 is H. In certain embodiments, the two geminal R 3 Together they form an oxo group.

[0205] In certain embodiments, each R 4 are independently hydrogen, C 1-6 Alkyl, C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the alkyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u In certain embodiments, each R 4 are independently H or C 1-6Alkyl, wherein the alkyl group is optionally substituted by one or more R u replace.

[0206] In certain embodiments, R A and R C is independently at each occurrence 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, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0207] In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6. In certain embodiments, s is 7. In certain embodiments, s is 8. In certain embodiments, s is 9. In certain embodiments, s is 10. In certain embodiments, s is 11. In certain embodiments, s is 12.

[0208] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.

[0209] In certain embodiments, m and n are independently 0 or 1. In certain embodiments, m and n are both 0. In certain embodiments, m and n are both 1. In certain embodiments, m is 0 and n is 1. In certain embodiments, m is 1 and n is 0.

[0210] In certain embodiments, U is -CH2-. In certain embodiments, U is -C(=O)-.

[0211] In certain embodiments, R 5 For hydrogen, deuterium, C 1-6 Haloalkyl or C 1-6 In certain embodiments, R 5 In certain embodiments, R 5 In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-6 alkyl.

[0212] In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2.

[0213] In certain embodiments, the compound is of formula (II):

[0214]

[0215] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

[0216] in:

[0217] R 1 is hydrogen or -LR 2 ;

[0218] L is -CH2-;

[0219] R 2 C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R 2a replace;

[0220] Each R 2a are independently oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -S(=O)2R a 、-S(=O)2NR c R d 、-NR c S(=O)2R a 、-NR b 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 groups are optionally replaced by one or more R u replace;

[0221] X is -O-;

[0222] Y is -CH2-; and

[0223] p is 0.

[0224] In certain embodiments, each R a Independently C 1-6Alkyl (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., ethenyl (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), cycloheptatrienyl (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 (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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., a heteroaryl group comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted by one or more R u replace.

[0225] In certain embodiments, each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl.

[0226] In certain embodiments, each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 a carbocyclic group or a 3- to 6-membered heterocyclic group.

[0227] In certain embodiments, each R a Independently C 1-6 Alkyl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0228] In certain embodiments, each R b are independently hydrogen, 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)), C 2-6 alkenyl (e.g., ethenyl (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), cycloheptatrienyl (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 (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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., a heteroaryl group comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted by one or more R u replace.

[0229] In certain embodiments, each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl.

[0230] In certain embodiments, each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 a carbocyclic group or a 3- to 6-membered heterocyclic group.

[0231] In certain embodiments, each R b are independently hydrogen, C 1-6 Alkyl, C 3-6 Carbocyclic or 3 to 6 membered heterocyclic or C 2-6 Alkynyl, wherein the alkyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0232] In certain embodiments, each R c and each R d are independently hydrogen, 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)), C 2-6 alkenyl (e.g., ethenyl (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), cycloheptatrienyl (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 (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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., a heteroaryl group comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted by one or more R u replace.

[0233] In certain embodiments, each R c and each R d are independently hydrogen, C 1-6 Alkyl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

[0234] In certain embodiments, R c and R d Together with the nitrogen atom to which it is attached, it forms a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclic group is optionally substituted by one or more R z replace.

[0235] In certain embodiments, R a 、R b 、R c and R d independently and optionally one or more R z replace.

[0236] In certain embodiments, R z 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 a carbocyclic group or a 3- to 6-membered heterocyclic group.

[0237] In certain embodiments, each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6Alkyl (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 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), n-butoxy (C4), isobutoxy (C4), sec-butoxy (C4), tert-butoxy (C4), pentyloxy (C5), or hexyloxy (C6)), C 1-6 Alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methylisopropylamino, methyl-n-butylamino, methylisobutylamino, methylsec-butylamino, methyltert-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethylisopropylamino, ethyl-n-butylamino butylamino, ethyl sec-butylamino, ethyl isobutylamino, ethyl tert-butylamino, ethyl pentylamino, ethylhexylamino, propyl n-butylamino, propyl isobutylamino, propyl sec-butylamino, propyl tert-butylamino, propyl pentylamino, propylhexylamino, n-butylpentylamino, isobutylpentylamino, sec-butylpentylamino, tert-butylpentylamino, n-butylhexylamino, isobutylhexylamino, sec-butylhexylamino, tert-butylhexylamino or pentylhexylamino), C 2-6 alkenyl (e.g., ethenyl (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), cycloheptatrienyl (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 (C 10) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl.

[0238] In certain embodiments, 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 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 with 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl.

[0239] In certain embodiments, 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 3-6 carbocyclyl, 3 to 6 membered heterocyclyl, C6 aryl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl.

[0240] In certain embodiments, 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 3-6carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl.

[0241] In certain embodiments, each R u 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 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl.

[0242] In certain embodiments, both R u Together with the carbon atom to which it is attached, it forms C 3-6 carbocyclyl (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 heterocyclyl (e.g., a heterocyclyl comprising a 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S).

[0243] In certain embodiments, two geminal R u Together with the carbon atom to which it is attached, it forms C 3-6 carbocyclyl (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 heterocyclyl (e.g., a heterocyclyl comprising a 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S).

[0244] The following describes embodiments of the variables in any of the chemical formulae described herein (e.g., Formulas I and I', as applicable). Any variable can be any moiety as described in the following embodiments. In addition, any combination of any moiety described for any variable with any moiety described for any other variable is also contemplated (as applicable).

[0245] Without wishing to be limited by this statement, although various selections of variables have been described herein, it should be understood that the present disclosure is intended to encompass operable embodiments having each combination of selections. The present disclosure can be interpreted as excluding inoperable embodiments resulting from certain combinations of selections. For example, although various selections of variables X, Y, and Z have been described herein, the present disclosure can be interpreted as excluding structures of compounds resulting from certain combinations of selections (e.g., when two adjacent members of X, Y, and Z are both nitrogen or both oxygen; or when one of two adjacent members of X, Y, and Z is nitrogen and the other is oxygen).

[0246] When a numerical range is listed, each discrete value and sub-range within the range is also contemplated. 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.

[0247] In certain embodiments, the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.

[0248] In certain embodiments, the compound is selected from the compounds in Table 1.

[0249] Table 1.

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[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] Table 2.

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311] Compared to known compounds (e.g., known IKZF2 degraders), the compounds of the present disclosure may have advantageous characteristics. For example, the compounds of the present disclosure may exhibit more potent estrogen receptor activity, more favorable pharmacokinetic properties (e.g., C max 、T max and / or AUC), and / or less interaction with other cellular targets (e.g., hepatocyte transporters such as OATP1B1) and corresponding improved safety (e.g., drug-drug interactions). These beneficial properties of the compounds of the present disclosure can be measured according to methods common in the art, such as those exemplified herein.

[0312] Due to the presence of double bonds, the compounds of the present disclosure may be in cis or trans, or Z or E configurations. It should be understood that while one configuration may be described in the structure of a compound or formula of the present disclosure, other configurations are also encompassed by the present disclosure. For example, a compound or formula of the present disclosure may be described in cis or trans, or Z or E configurations.

[0313] In one embodiment, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any individual compound) are pharmaceutically acceptable salts. In another embodiment, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any individual compound) are solvates. In another embodiment, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any individual compound) are hydrates.

[0314] The details of the present disclosure are shown in the accompanying description below. Although methods and materials similar or equivalent to the methods and materials described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects and advantages of the present application are apparent from the specification and claims. Unless the context clearly provides otherwise, in the specification and the appended claims, the singular also includes the plural. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by those of ordinary skill in the art to which this application belongs. All patents and publications cited in this specification are incorporated herein by reference in their entirety.

[0315] Forms of the compounds disclosed herein

[0316] Pharmaceutically acceptable salts

[0317] In some embodiments, the compounds disclosed herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts in the form of pharmaceutical compositions.

[0318] In some embodiments, the compounds described herein possess acidic or basic groups and, therefore, can react with any of 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 compound with a suitable acid or base, respectively, and isolating the salt thus formed.

[0319] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with minerals, organic acids, or inorganic bases, such salts including acetates, acrylates, adipates, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate , hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0320] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, such as, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; 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, benzenesulfonic acid, benzoic ... 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-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0321] In certain embodiments, the compounds described herein that contain free acid groups are reacted with a suitable base (e.g., a pharmaceutically acceptable hydroxide, carbonate, bicarbonate, or sulfate of a metal cation), with ammonia or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc.

[0322] Representative organic amines for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

[0323] Solvates

[0324] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." For example, complexes with water are referred to as "hydrates." Solvates are within the scope of the present invention.

[0325] Those skilled in the art of organic chemistry will also appreciate that many organic compounds can exist in more than one crystalline form. For example, the crystalline form can vary with solvates. Therefore, all crystalline forms or pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present invention.

[0326] In some embodiments, the compounds described herein exist in the form of solvates. The present disclosure provides methods for treating diseases by administering such solvates. The present disclosure further provides methods for treating diseases by administering such solvates in the form of pharmaceutical compositions.

[0327] Solvate contains stoichiometric or non-stoichiometric amount of solvent, such as water, ethanol etc. When the solvent is water, hydrate is formed, or when the solvent is alcohol, alcoholate is formed. The solvate of compound as herein described can be easily prepared or formed during the method described herein. In addition, the compound provided herein can exist in non-solvated form and solvated form. Generally speaking, for the purpose of the compound and method provided herein, solvated form is considered to be equivalent to non-solvated form.

[0328] Isomers / stereoisomers

[0329] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0330] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds disclosed herein include all cis, trans, cis, trans, entgegen (E) and zusammen (Z) isomers and their corresponding mixtures. All geometric forms of the compounds disclosed herein are considered, and they are within the scope of the present invention.

[0331] In some embodiments, the compounds disclosed herein have one or more chiral centers, and each center exists in the R configuration or the S configuration. The compounds disclosed herein include all diastereoisomers, enantiomers, and epimeric forms and their corresponding mixtures. All diastereoisomers, enantiomers, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the present invention.

[0332] In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or mutual conversion can be used for applications as described herein. In some embodiments, compounds as described herein are prepared in a separate stereoisomer form by reacting a racemic mixture of the compound with an optically active resolving agent to form a diastereomeric compound pair, separating the diastereomers and reclaiming the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by separation / resolving techniques based on solubility differences. In some embodiments, the optically pure enantiomers are then recovered together with the resolving agent.

[0333] Tautomers

[0334] In some embodiments, the compounds described herein exist as tautomers.The compounds described herein include all possible tautomers within the formulae described herein.

[0335] Tautomers are compounds that convert into each other through the migration of a hydrogen atom, accompanied by a conversion of a single bond and an adjacent double bond. In bond arrangements where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the present invention. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0336] Pharmaceutical composition

[0337] In certain embodiments, the compounds described herein are administered as neat chemicals. In some embodiments, the compounds described herein are 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, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, PA (2005)).

[0338] Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0339] In certain embodiments, the compound provided herein is substantially pure in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthesis by-products produced in one or more steps of the synthetic methods.

[0340] Pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage and suitable duration and frequency of administration will be determined by factors such as the following: the patient's condition, the type and severity of the patient's disease, the specific form of active ingredient and the method of administration. Generally speaking, the amount of the composition that appropriate dosage and treatment regimen provide is enough to provide treatment and / or prevention benefit, for example, improved clinical outcome (such as more frequent complete or partial remission or longer disease-free survival and / or total survival) or alleviate symptom severity. Optimal dose is usually determined using experimental models and / or clinical trials. Optimal dose depends on the patient's body mass, body weight or blood volume.

[0341] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and 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 application or ophthalmic application. In some embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0342] Isotope substances

[0343] In some aspects, the present disclosure provides a compound that is an isotopic derivative (eg, an isotopically labeled compound) of any of the compounds disclosed herein.

[0344] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0345] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 or Table 2.

[0346] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 or a pharmaceutically acceptable salt thereof.

[0347] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0348] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2 or a pharmaceutically acceptable salt thereof.

[0349] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2.

[0350] It should be understood that isotopic derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotopic derivatives can generally be prepared by implementing the procedures disclosed in the schemes and / or embodiments described herein, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0351] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0352] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any of the formulae disclosed herein.

[0353] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 or Table 2.

[0355] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 or a pharmaceutically acceptable salt thereof.

[0356] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1.

[0357] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 2.

[0359] It is understood that a deuterium-labeled compound comprises deuterium atoms having an abundance significantly greater than the natural deuterium abundance of 0.015%.

[0360] In some embodiments, the deuterium-labeled compound has a deuterium abundance factor of at least 3500 (52.5% deuterium added at each deuterium atom), at least 4000 (60% deuterium added), at least 4500 (67.5% deuterium added), at least 5000 (75% deuterium added), at least 5500 (82.5% deuterium added), at least 6000 (90% deuterium added), at least 6333.3 (95% deuterium added), at least 6466.7 (97% deuterium added), at least 6600 (99% deuterium added), or at least 6633.3 (99.5% deuterium added) per deuterium atom. As used herein, the term "deuterium abundance factor" refers to the ratio between the deuterium abundance and the natural deuterium abundance.

[0361] It should be understood that deuterium-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by implementing the procedures disclosed in the schemes and / or examples described herein, substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[0362] Compounds of the present disclosure containing the aforementioned deuterium atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 2 H) substitutions may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0363] Preparation and characterization of compounds

[0364] Compound of the present disclosure can be prepared with many methods well known to those skilled in the art of organic synthesis.For example, compound of the present disclosure can be synthesized using the synthetic method known in the method described below and organic chemical synthesis field or its variation understood by those skilled in the art. Compound of the present disclosure (that is, compound of the application (for example, compound of any formula disclosed herein or any single compound)) can be synthesized by following the step (for example, described in the embodiment) of general synthesis scheme and example described herein, scheme, program and / or synthesis outlined below.

[0365] General synthetic scheme

[0366]

[0367] Those skilled in the art can distinguish whether there is a stereocenter in a disclosed compound (e.g., a compound of any formula disclosed herein or any single compound). Therefore, the present disclosure includes two possible stereoisomers (unless specified in the synthesis), and not only includes racemic compounds, but also includes single enantiomers and / or diastereomers. When the desired compound is a single enantiomer or diastereomer, the compound can be obtained by stereospecific synthesis or by splitting the final product or any convenient intermediate. The splitting of the final product, intermediate or starting material may be affected by any suitable method known in the art. See, for example, " Stereochemistry of Organic Compounds " (Wiley-Interscience, 1994) by E.L. Eliel, S.H. Wilen and L.N. Mander.

[0368] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. “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), 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).

[0369] Suitable reference books and treatises that describe in detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide references to articles describing such preparations, include, for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; SR Sandler et al., “Organic Functional Group Preparations,” 2nd ed., Academic Press, New York, 1983; H.O. House, “Modern Synthetic Reactions,” 2nd ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; T.L. 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. Additional suitable reference books and treatises that describe in detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide references to articles describing such preparations, include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", 2nd revised edition (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 edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4th edition (1992) John 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) John Wiley & Sons, ISBN: 3-527-29645-X, a total of 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, a total of more than 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, a total of 73 volumes.

[0370] Specific and similar reactants are optionally identified by indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, which are available in most public and university libraries and online. Chemicals known but not listed in commercial catalogs are optionally prepared by conventional chemical synthesis facilities, wherein many standard chemical supply companies (e.g., those listed above) provide conventional synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P.H. Stahl and C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0371] Analytical methods, materials, and instruments

[0372] Unless otherwise noted, reagents and solvents are used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra are obtained at 400 MHz on Bruker or Varian spectrometers. Spectra are given in ppm (δ), and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) is used as internal standard. Liquid chromatography-mass spectrometry (LC / MS) is collected using SHIMADZU LCMS-2020EV or Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data are measured using an Agilent 1260-6125B LCMS system (with a diode array detector and an Agilent G6125BA mass spectrometer) or using a Waters Acquity UPLC system (with a diode array detector and a Waters 3100 mass spectrometer). Purity is characterized by UV wavelengths of 214 nm, 220 nm, 254 nm, and ESI. Column: Poroshell 120EC-C18 2.7 μm 4.6 × 100 mm; flow rate 0.8 mL / min; solvent A (100 / 0.1 water / formic acid), solvent B (100 acetonitrile); gradient: hold 5% B for 0.3 min, 5%-95% B from 0.3 to 2 min, hold 95% B for 4.8 min, 95%-5% B from 4.8 to 5.4 min, then hold 5% B for 6.5 min. Alternatively, column: Acquity UPLC BEH C18 1.7 μm 2.1 × 50 mm; flow rate 0.5 mL / min; solvent A (0.1% formic acid in water), solvent B (acetonitrile); gradient: hold 5% B for 0.2 min, 5%-95% B from 0.2 to 2.0 min, hold 95% B for 3.1 min, then hold 5% B for 3.5 min.

[0373] Exemplary Bioassays

[0374] The biological activity of the compounds of the present disclosure can be assessed using methods and assays known in the art.

[0375] Exemplary Cereblon Binding Assay

[0376] Binding to cerebon (CRBN) was measured using the Cereblon Binding Kit (Cisbio, #64BDCRBNPEG) according to the manufacturer's instructions. Briefly, serial dilutions of the compound were incubated with GST-tagged wild-type human CRBN protein, XL665-tagged thalidomide, and Europium Cryptate-tagged GST antibody. Time-resolved fluorescence resonance energy transfer (TR-FRET) measurements were obtained using, for example, MARS data analysis software (BMG Labtech). Readings were normalized to a control (0.5%) and IC was calculated using, for example, GraphPad Prism 8 software by nonlinear regression (four-parameter sigmoid fit with variable slope). 50 .

[0377] Example immunoblotting

[0378] Cells were cultured in appropriate culture medium containing 10% FBS at 37°C in a 5% CO2 atmosphere.

[0379] The cells were lysed, separated by SDS-PAGE, and transferred to a PVDF membrane (Millipore). The membrane was blocked using, for example, Odyssey TBS Blocker Buffer (LI-COR). Secondary antibodies labeled with, for example, IRDye 680RD and 800CW Dye were used. The washed membrane was scanned using, for example, an Odyssey CLx imager (LI-COR). The intensity of the Western blot signal was quantified using Odyssey software. Primary antibodies used included: Helios (D8W4X) Rabbit mAb (Cell Signaling Technology, #42427) and GAPDH mouse monoclonal antibody (Santa Cruz Biotechnology, sc-47724).

[0380] Exemplary IKZF2 HiBiT assay

[0381] The degradation of IKZF2 protein was determined by IKZF2 HiBiT assay using Jurkat-IKZF2-HiBiT (Promega) cell line. Briefly, cells were seeded in culture medium. Compounds were serially diluted in culture medium, and a certain volume of diluted compound was added to the appropriate wells of the plate. After the compound was added, the cells were incubated. At the end of the treatment, Nano-Glo HiBiT Lytic Detection Reagent (Promega) was added to each well, and the plate was then incubated at room temperature for a certain period of time. The luminescent signal was measured using a CALRIOstar plate reader (BMG Labtech). The readings were standardized based on the wells treated with DMSO, and the IC was calculated by nonlinear regression (four-parameter sigmoid fitting variable slope, least squares fitting and unconstrained) analysis using GraphPad Prism 8 software. 50 .

[0382] How to use

[0383] In certain aspects, the present disclosure provides methods of degrading IKZF2 protein in a subject, comprising administering to the subject a compound disclosed herein.

[0384] In certain aspects, the present disclosure provides use of a compound disclosed herein in the preparation of a medicament for degrading IKZF2 protein in a subject.

[0385] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading IKZF2 protein in a subject.

[0386] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (eg, in a therapeutically effective amount).

[0387] In certain aspects, the present disclosure provides methods of treating a disease or condition in a subject in need thereof, comprising administering to the subject a compound disclosed herein (eg, in a therapeutically effective amount).

[0388] In certain aspects, the present disclosure provides use of a compound disclosed herein in the preparation of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0389] In certain aspects, the present disclosure provides use of a compound disclosed herein in the preparation of a medicament for treating a disease or condition in a subject in need thereof.

[0390] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.

[0391] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating a disease or disorder in a subject in need thereof.

[0392] In certain embodiments, the disease or condition is an IKZF2-mediated disease or condition.

[0393] In certain embodiments, the disease or disorder is cancer.

[0394] In certain embodiments, the cancer includes, but is not limited to, one or more of the cancers listed in Table A.

[0395] Table A

[0396]

[0397]

[0398]

[0399]

[0400] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a hematological cancer. Exemplary hematological cancers include, but are not limited to, those listed in Table B. In certain embodiments, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.

[0401] Table B

[0402]

[0403]

[0404] In certain embodiments, the disease or disorder is T-cell leukemia or T-cell lymphoma, Hodgkin's lymphoma or non-Hodgkin's 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).

[0405] In certain embodiments, the subject is a mammal.

[0406] In certain embodiments, the subject is a human.

[0407] definition

[0408] As used in the specification and appended claims, unless otherwise indicated, the following terms have the meanings indicated below.

[0409] Chemical definition

[0410] The definitions of specific functional groups and chemical terms will be described in more detail below. Chemical elements are identified according to the periodic table of the elements (CAS version) on the inside 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 and specific functional moieties and reactivities are described in the following literature: 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.

[0411] The compounds described herein may contain one or more asymmetric centers and may therefore exist in various 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 in one or more stereoisomers). Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., 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 (E.F. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0412] The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0413] When a range of values ​​is listed, it is intended that every value and subrange within that range be included. 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.

[0414] The following terms are intended to have the meaning presented below, and are helpful for understanding the description and intended scope of the present invention. In the invention that may include a compound, a pharmaceutical composition containing such a compound, and a method using such a compound and a composition, unless otherwise stated, the following terms (if present) have the following meanings. It should also be understood that when described in this article, any part defined below can be substituted by a variety of substituents, and each definition is intended to include these substituted parts within the scope described below. Unless otherwise stated, the term "substituted" should be defined as set forth below. It should be further understood that the terms "group (group)" and "base (radical)" can be considered to be interchangeable when used in this article. The article "one / a kind" can be used in this article to refer to one / a kind or more than one / a kind (for example, at least one / a kind) grammatical object. For example, "an analogue" means an analogue or more than one analogue.

[0415] As used herein, "alkyl" refers to a group of straight-chain or branched saturated hydrocarbon groups having 1 to 20 carbon atoms ("C 1-20 In certain embodiments, an alkyl group has from 1 to 12 carbon atoms ("C 1-12 In certain embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In certain embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In certain embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In certain embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In certain embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In certain embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In certain embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In certain embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In certain embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In certain embodiments, an alkyl group has 1 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). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each example of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, an alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 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).

[0416] As used herein, "alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent group. When a range or number of carbons is provided for a particular "alkylene," it is understood that the range or number refers to the range or number of carbons in a linear carbon divalent chain. "Alkylene" may be substituted with one or more substituents as described herein or may be unsubstituted. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted divalent alkylene groups (e.g., substituted with one or more alkyl(methyl) groups) include, but are not limited to, substituted methylene groups (—CH(CH3)—, (—C(CH3)2—), substituted ethylene groups (—CH(CH3)CH2—, —CH2CH(CH3)—, —C(CH3)2CH2—, —CH2C(CH3)2—), substituted propylene groups (—CH(CH3)CH2CH2—, —CH2CH(CH3)CH2—, —CH2CH2CH(CH3)—, —C(CH3)2CH2CH2—, —CH2C(CH3)2CH2—), and the like.

[0417] As used herein, "alkenyl" refers to a straight or branched chain hydrocarbon group ("C 2-20 In certain embodiments, an alkenyl group does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In certain embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In certain embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In certain embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In certain embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In certain embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In certain embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In certain embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In certain embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 In some embodiments, alkenyl is an unsubstituted C 1-4, C 1-6, C 1-8, C 1-17, C 1-19, C 2-30, C 3-41, C 3-6, C 3-7, C 4-8, C 5-10, C 5-11, C 2-24, C 2-36, C 3-37, C 3-38, C 3-40, C 3-50, C 3-60, C 3-7, C 3-8, C 3-9, C 4-10, C 4-11, C 4-12, C 4-13, C 4-14, C 4-15, C 4-16, C 4-17, C 4-18, C 4-19, C 4-20, C 4-21, C 4-22, C 4-23, C 4-24, C 4-25, C 4-26, C 4-27, C 4-28, C 4-29, C 4-30, C 4-31, C 4-32, C 4-33, C 4-34, C 4-35, C 4-36, C 4-37, C 4-38, C 4-39, C 4-44, C 4-45, C 4-46, C 4-47, C 4-48, C 4-49, C 4-50, C 4-51, C 4-52, C 4-53, C 4-54, C 4-6 2-10 In certain embodiments, alkenyl is a substituted C 2-10 Alkenyl.

[0418] As used herein, "alkenylene" refers to an alkenyl group in which two hydrogen atoms are removed to provide a divalent group. When a range or number of carbon atoms is provided for a particular "alkenylene," it is understood that the range or number refers to the range or number of carbon atoms in a linear carbon divalent chain. "Alkenylene" may be substituted with one or more substituents as described herein or may be unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted divalent alkenylene 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)-), 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, and the like.

[0419] As used herein, "alkynyl" refers to a straight or branched chain hydrocarbon radical ("C 2-20 In certain embodiments, an alkynyl group does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2-10 In certain embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In certain embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In certain embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In certain embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In certain embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In certain embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In certain embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In certain embodiments, an alkynyl group has two carbon atoms (a "C2 alkynyl"). The carbon-carbon triple bond(s) can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). C 2-4Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl and pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, each example of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0420] As used herein, "alkynylene" refers to an alkynyl group in which two hydrogen atoms are removed to provide a divalent group. When a range or number of carbon atoms is provided for a particular "alkynylene," it is understood that the range or number refers to the range or number of carbon atoms in a linear carbon divalent chain. "Alkynylene" may be substituted with one or more substituents as described herein or may be unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0421] 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 a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkyl refers to a saturated group ("heteroalkyl") having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms. 1-10 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-9 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-8 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-7 In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC 1-6 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC 1-5In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms (“heteroC 1-4 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC 1-3 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC 1-2 In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC1 alkyl"). 2-6 Unless otherwise specified, each instance of heteroalkyl is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, heteroalkyl is an unsubstituted heteroC 1-10 In certain embodiments, heteroalkyl is a substituted heteroC 1-10 alkyl.

[0422] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein that contains 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 the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkenyl refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl"). 2-10 In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-9 In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-8 In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-7 In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC 2-6 In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-5 In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-4In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC 2-3 In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-10 In certain embodiments, heteroalkenyl is a substituted heteroC 2-10 Alkenyl.

[0423] As used herein, the term "heteroalkynyl" refers to an alkynyl group, as defined herein, containing 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 the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkynyl refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkynyl"). 2-10 In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-9 In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-8 In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-7 In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC 2-6 In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2-5 In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2-4 In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC 2-3 In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2-6Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroalkynyl group. 2-10 In certain embodiments, heteroalkynyl is a substituted heteroC 2-10 Alkynyl.

[0424] Similar to the definitions of "alkylene," "alkenylene," and "alkynylene" as described above, "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" as used herein refer to divalent radicals of heteroalkyl, heteroalkenyl, and heteroalkynyl groups, respectively. When a range or number of carbon atoms is provided for a particular "heteroalkylene," "heteroalkenylene," and "heteroalkynylene," it is understood that the range or number refers to the range or number of carbon atoms in the linear divalent chain. "Heteroalkylene," "heteroalkenylene," and "heteroalkynylene" may be substituted with one or more substituents as described herein or may be unsubstituted.

[0425] "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 the cyclic array) having 6-14 ring carbon atoms and zero heteroatoms ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "aryl"; for example, anthracenyl).

[0426] Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, , coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-dicyclopentadienylacene, s-dicyclopentadienylacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentacene, perylene, phenalene, phenanthren, phenanthren, septalene, pyrene, pyranthrenthren, rubicene, triphenylene, and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, aryl is a substituted C 6-14 Aryl.

[0427] As used herein, "arylene" refers to an aryl group in which two hydrogen atoms are removed to provide a divalent radical. When a range or number of carbon atoms is provided for a particular "arylene group," it is understood that the range or number refers to the range or number of carbon atoms in the aryl group. "Arylene" groups may be substituted with one or more substituents as described herein or may be unsubstituted.

[0428] "Heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in the cyclic array) provided with ring carbon atoms and 1-8 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

[0429] "Heteroaryl" also includes ring systems in which a heteroaryl as defined above is fused to one or more aryl groups, wherein the point of attachment is on the heteroaryl group or the 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 indicated, substitution may occur on the heteroaryl group or the one or more aryl groups. For bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment may be on either ring, i.e., the ring carrying the heteroatom (e.g., 2-indolyl) or the ring containing no heteroatoms (e.g., 5-indolyl).

[0430] In certain embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In certain embodiments, 5 to 6 membered heteroaryls have 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, 5 to 6 membered heteroaryls have 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, 5 to 6 membered heteroaryls have 1 ring heteroatom selected from nitrogen, oxygen and sulfur. In certain embodiments, 5 to 6 membered heteroaryls have 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, each example of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In certain embodiments, heteroaryl is unsubstituted 5 to 14 membered heteroaryl. In certain embodiments, heteroaryl is substituted 5 to 14 membered heteroaryl.

[0431] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. 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 tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, aza Azepinyl, oxa Oxepinyl and thia Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0432] As used herein, "heteroarylene" refers to a heteroaryl group in which two hydrogen atoms are removed to provide a divalent radical. When a range or number of ring members is provided for a particular "heteroarylene," it is understood that the range or number refers to the number of ring members in the heteroaryl group. "Heteroarylene" may be substituted with one or more substituents as described herein or may be unsubstituted.

[0433] "Carbocyclyl" refers to a non-aromatic ring system having 3 to 12 ring carbon atoms ("C 3-12 In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms ("C 5-12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5-8 In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms ("C 5-6 Carbocyclyl”). Exemplary C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-8 Carbocyclic groups include but are not limited to the above C 3-6 Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include but are not limited to the above C 3-8Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 )wait.

[0434] In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("C 3-12 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("C 3-10 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("C 3-8 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("C 3-6 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("C 5-12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5-8 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("C 5-6 carbocyclyl”). C 5-6 Examples of carbocyclic groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of the carbocyclic group include the above-mentioned C 5-6 Carbocyclic groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of the carbocyclic group include the above-mentioned C 3-6 carbocyclyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a carbocyclyl is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, a carbocyclyl is an unsubstituted C 3-12 In certain embodiments, a carbocyclyl group is a substituted C 3-12 Carbocyclic group.

[0435] As shown in the foregoing examples, in certain embodiments, carbocyclyl is a monocyclic ring ("monocyclic carbocyclyl") or a polycyclic ring ("polycyclic carbocyclyl") containing a fused, bridged, or spirocyclic ring system, and may be saturated or partially unsaturated. Unless otherwise indicated, each example of a carbocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents. In certain embodiments, a carbocyclyl is an unsubstituted C 3-12 In certain embodiments, a carbocyclyl group is a substituted C 3-12 Carbocyclic group.

[0436] "Fused carbocyclyl" or "fused carbocycle" refers to a ring system in which a carbocyclyl as defined above is fused to one or more carbocyclyls as defined above, i.e., sharing two common atoms (and therefore, a common bond), with the point of attachment being on either fused ring. In such cases, the number of carbons refers to the total number of carbons in the fused ring system. When substitution is indicated, unless otherwise indicated, the substitution may occur on either fused ring.

[0437] "Spirocarbocyclyl" or "spirocarbocycle" refers to a ring system in which a carbocyclyl as defined above forms a spiro structure with one or more carbocyclyls as defined above, i.e., shares a common atom with the point of attachment being on the carbocyclyl ring embedded with the spiro structure. In such cases, the number of carbons represents the total number of carbons in the carbocyclyl ring embedded with the spiro structure. When substitution is indicated, unless otherwise stated, substitution may occur on the carbocyclyl ring embedded with the spiro structure.

[0438] "Bridged carbocyclyl" or "bridged carbocycle" refers to a ring system in which a carbocyclyl as defined above forms a bridged structure with one or more carbocyclyls as defined above, i.e., sharing more than two atoms (and therefore, more than one bond), wherein the point of attachment is on any one of the carbocyclyl rings embedded in the bridged structure. In such cases, the number of carbons represents the total number of carbons in the carbocyclyl ring embedded in the bridged structure. When substitution is indicated, unless otherwise indicated, substitution may occur on any carbocyclyl ring embedded in the bridged structure.

[0439] As used herein, "carbocyclyl" refers to a carbocyclyl group in which two hydrogen atoms are removed to provide a divalent group. The divalent group can be present on different atoms or the same atom of the carbocyclyl group. When a range or number of carbon atoms is provided for a specific "carbocyclyl", it is understood that this range or number refers to the range or number of carbon atoms in the carbocyclyl group. A "carbocyclyl" group can be substituted with one or more substituents as described herein or can be unsubstituted.

[0440] "Heterocyclyl" refers to a group of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 12-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom when valence permits. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thienetanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiofuranyl, dithiofuranyl, 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 thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0441] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In certain embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0442] As shown in the above examples, in certain embodiments, the heterocyclic group can be a monocycle ("monocyclic heterocyclic group") or a polycycle ("polycyclic heterocyclic group") containing a fused, bridged or spirocyclic system, and can be saturated or can be partially unsaturated. The heterocyclic polycyclic system can include one or more heteroatoms in one or two rings. "Heterocyclic group" also includes a ring system in which the heterocyclic group as defined above is fused to one or more carbocyclic groups, wherein the point of attachment is on the carbocyclic group or heterocyclic group ring, and in such a case, the number of ring members represents the total number of ring members in the entire ring system. When substitution is indicated in such a case, unless otherwise stated, substitution can occur on the heterocyclic group or one or more carbocyclic groups. Unless otherwise stated, each example of the heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclic group") or substituted ("substituted heterocyclic group") by one or more substituents. In certain embodiments, the heterocyclic group is an unsubstituted 3 to 12 membered heterocyclic group. In certain embodiments, the heterocyclyl group is a substituted 3- to 12-membered heterocyclyl group.

[0443] "Fused heterocyclyl" or "fused heterocycle" refers to a ring system in which a heterocyclyl as defined above is fused to one or more heterocyclyl or carbocyclyl groups as defined above, i.e., sharing two common atoms (and therefore, a common bond), wherein the point of attachment is on either fused ring. In such cases, the number of ring members refers to the total number of ring members in the fused ring system. When substitution is indicated, unless otherwise indicated, the substitution may occur on either fused ring.

[0444] "Spiroheterocyclyl" or "spiroheterocycle" refers to a ring system in which a heterocyclyl as defined above forms a spiro structure with one or more heterocyclyls or carbocyclyls as defined above, i.e., shares a common atom with the point of attachment being on the heterocyclyl or carbocyclyl ring embedded in the spiro structure. In such cases, the number of ring members represents the total number of ring members of the heterocyclyl or carbocyclyl ring embedded in the spiro structure. When substitution is indicated, unless otherwise indicated, substitution may occur on any one of the heterocyclyl or carbocyclyl rings embedded in the spiro structure.

[0445] "Bridged heterocyclyl" or "bridged heterocycle" refers to a ring system in which a heterocyclyl as defined above forms a bridged structure with one or more heterocyclyls or carbocyclyls as defined above, i.e., sharing more than two atoms (and therefore, more than one bond), wherein the point of attachment is on the heterocyclyl or carbocyclyl ring embedded in the bridged structure. In such cases, the number of ring members refers to the total number of ring members of the heterocyclyl or carbocyclyl ring embedded in the bridged structure. When substitution is indicated, unless otherwise indicated, substitution may occur on either heterocyclyl or carbocyclyl ring embedded in the bridged structure.

[0446] As used herein, "heterocyclylene" refers to a heterocyclyl group in which two hydrogen atoms are removed to provide a divalent group. The divalent groups may be present on different atoms or on the same atom in the heterocyclylene group. When a range or number of ring members is provided for a particular "heterocyclylene," it is understood that the range or number refers to the number of ring members in the heterocyclylene group. "Heterocyclylene" may be substituted with one or more substituents as described herein or may be unsubstituted.

[0447] As used herein, "alkoxy" refers to the group -OR, where R is alkyl as defined herein. 1-6 Alkoxy refers to a group -OR, wherein each R is C as defined herein. 1-6 Alkyl. Exemplary C 1-6 The alkyl group is as described above.

[0448] As used herein, "alkylamino" refers to the group -NHR or -NR2, wherein each R is independently an alkyl group as defined herein. 1-6 Alkylamino refers to a group -NHR or -NR2, wherein each R is independently C as defined herein. 1-6 Alkyl. Exemplary C 1-6 The alkyl group is as described above.

[0449] "Oxo" refers to =0. When a group or atom other than aryl and heteroaryl is substituted with oxo, it is intended to indicate that two geminal groups on the group or atom form a double bond with the oxygen radical. When a heteroaryl is substituted with oxo, it is intended to indicate that the resonance structure / tautomer involving the heteroatom provides a carbon atom capable of forming two geminal groups, which form a double bond with the oxygen radical.

[0450] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In certain embodiments, halogen is fluorine or chlorine.

[0451] As used herein, "protecting group" is well-known 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 obtain 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 that require protection include, but are not limited to, hydroxyl, amino, thiol, and carboxylic acid. Therefore, protecting groups are referred to as hydroxyl protecting groups, amino protecting groups, thiol protecting groups, and carboxylic acid protecting groups, respectively.

[0452] Common types of hydroxy protecting groups include, but are not limited to, ethers (e.g., methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p-methoxyphenyl (PMP), tert-butyl, trityl (Trityl), allyl, and benzyl (Bn) ethers), silyl ethers (e.g., tert-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), triisopropylsilyloxymethyl (TOM), and tert-butyldimethylsilyl (TBDMS) ether), and esters (e.g., pivalate (Piv) and benzoate (Bz)).

[0453] Common types of amino protecting groups include, but are not limited to, carbamates (e.g., tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzylcarbonyl (Moz or MeOZ), 2,2,2-trichloroethoxycarbonyl (Troc), and benzylcarbamate (Cbz)), esters (e.g., acetyl (Ac), benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g., benzyl (Bn), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), and trityl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkylnitrobenzenesulfonamides (nitrobenzenesulfonyl (Nosyl)), and 2-nitrobenzenesulfonyl (Nps)).

[0454] Common types of thiol protecting groups include, but are not limited to, sulfides (eg, p-methylbenzyl (Meb), tert-butyl, acetamidomethyl (Acm), and trityl (Trityl)).

[0455] Common types of carboxylic acid protecting groups include, but are not limited to, esters (eg, methyl esters, trityl esters, tert-butyl esters, benzyl esters (Bn), S-tert-butyl esters, silyl esters, and orthoesters) and oxazolines.

[0456] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims.It is not intended that the present invention be limited in any manner by the above exemplary list of substituents.

[0457] Other definitions

[0458] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or corresponding agency in a country outside the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0459] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. 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 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) The present invention also provides a salt of a compound having a basic functional group, wherein the salt is an acid addition salt formed with a hydroxy-naphthoic acid, a hydroxy-naphthoic acid, a hydroxy-salt-1-ol, a hydroxy-2-hydroxy-1-ol, a hydroxy-3-hydroxy-2-hydroxy-1-ol, a hydroxy-4-hydroxy-2-hydroxy-1-ol, a hydroxy-5-hydroxy-3-hydroxy-2-hydroxy-1-ol, a hydroxy-6-hydroxy-7-hydroxy-1-ol, a hydroxy-7-hydroxy-2-hydroxy-1-ol, a hydroxy-8-hydroxy-3-hydroxy-1-ol, a hydroxy-9-hydroxy-2-hydroxy-1-ol, a hydroxy-10-hydroxy-2-hydroxy-1-ol, a hydroxy-11-hydroxy-2-hydroxy-1-ol, a hydroxy-12-hydroxy-2-hydroxy-1-ol, a hydroxy-13-hydroxy-2-hydroxy-1-ol, a hydroxy-14-hydroxy-2-hydroxy-1-ol, a hydroxy-15-hydroxy-2-ol, a hydroxy-16-hydroxy-2-ol, a hydroxy-17-hydroxy-2-ol, a hydroxy-18-hydroxy-2-ol, a hydroxy-29-hydroxy-2-ol, a hydroxy-21-hydroxy-22-ol, a hydroxy-23-hydroxy-23-ol, a hydroxy-24-hydroxy-24-ol, a hydroxy-25-hydroxy-26-ol, a hydroxy-27-hydroxy-27-ol, a hydroxy-28-hydroxy-29-ol, a hydroxy-29-hydroxy-28-ol, a hydroxy-29-hydroxy-2-ol, a hydroxy-3-hydroxy-2-ol, a hydroxy-3-hydroxy-2-ol, a hydroxy-3-hydroxy-2-ol, a hydroxy-4-hydroxy-2-ol, a hydroxy-4-hydroxy-2-ol, a hydroxy-5

[0460] "Solvate" refers to a form of a compound that is associated with a solvent or water (also referred to as a "hydrate"), typically by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the present invention can be prepared, for example, in crystalline form, and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both solution phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0461] A "subject" intended for administration includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0462] "Effective amount" means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment or prevention. "Effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. "Therapeutically effective amount" means an amount effective for therapeutic treatment. "Prophylactically effective amount" means an amount effective for preventative treatment.

[0463] "Preventing," "prevention," or "prophylactic treatment" refers to reducing the risk of acquiring or developing a disease or disorder (i.e., causing at least one clinical symptom of the disease not to occur in a subject who has not been exposed to the disease-causing agent or in a subject who is susceptible to the disease before the onset of the disease).

[0464] The term "prophylaxis" is related to "prevention" and refers to measures or procedures whose purpose is to prevent rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include: administering vaccines; administering low molecular weight heparin to hospitalized patients at risk for thrombosis (e.g., due to immobility); and administering antimalarial agents (such as chloroquine) before visiting geographic areas where malaria is endemic or the risk of contracting malaria is high.

[0465] In one embodiment, "treating" or "treatment" or "therapeutic treatment" of any disease or disorder refers to ameliorating the disease or disorder (i.e., curbing the disease or lessening the manifestation, extent, or severity of at least one clinical symptom thereof). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In another embodiment, "treating" or "treatment" refers to modulating the disease or disorder physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In additional embodiments, "treating" or "treatment" involves slowing the progression of a disease.

[0466] It will also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0467] Stereoisomers that are not mirror images of each other are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and designated as right- or left-handed (i.e., (+)- or (-)-isomers, respectively). A chiral compound can exist as a single enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture."

[0468] "Tautomers" refer to compounds that have interchangeable forms of a particular compound structure and that vary in hydrogen atom and electron shift. Thus, the two structures can maintain equilibrium through the movement of electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert by treatment with an acid or base. Another example of tautomerism is the acid form and nitro form of phenylnitromethane, which are similarly formed by treatment with an acid or base. Tautomeric forms may be relevant to the optimal chemical reactivity and acquisition of biological activity for the compound of interest.

[0469] The term "enantiomerically pure" or "pure enantiomer" means that the compound contains greater than 95% by weight, greater than 96% by weight, greater than 97% by weight, greater than 98% by weight, greater than 98.5% by weight, greater than 99% by weight, greater than 99.2% by weight, greater than 99.5% by weight, greater than 99.6% by weight, greater than 99.7% by weight, greater than 99.8% by weight, or greater than 99.9% by weight of the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0470] As used herein and unless otherwise indicated, the term "enantiomerically pure (R)-compound" refers to at least about 95% by weight of the (R)-compound and up to about 5% by weight of the (S)-compound, at least about 99% by weight of the (R)-compound and up to about 1% by weight of the (S)-compound, or at least about 99.9% by weight of the (R)-compound and up to about 0.1% by weight of the (S)-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0471] As used herein, and unless otherwise indicated, the term "enantiomerically pure (S)-compound" or "(S)-compound" refers to at least about 95% by weight of the (S)-compound and up to about 5% by weight of the (R)-compound, at least about 99% by weight of the (S)-compound and up to about 1% by weight of the (R)-compound, or at least about 99.9% by weight of the (S)-compound and up to about 0.1% by weight of the (R)-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0472] In the compositions provided herein, the enantiomerically pure compound or its pharmaceutically acceptable salt, solvate, hydrate or prodrug can be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure (R)-compound can comprise, for example, about 90% of an excipient and about 10% of the enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such a composition can, for example, comprise, by weight, at least about 95% of the (R)-compound and by weight up to about 5% of the (S)-compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure (S)-compound can comprise, for example, about 90% of an excipient and about 10% of the enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such a composition can, for example, comprise, by weight, at least about 95% of the (S)-compound and by weight up to about 5% of the (R)-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with minimal or no excipients or carriers.

[0473] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures (racemic or otherwise) thereof.Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0474] When referring to a numerical value or a numerical range, the term "about" means that the numerical value or numerical range mentioned is an approximate value within the experimental variability (or within the statistical experimental error), so in some cases, the numerical value or numerical range will vary between 1% and 15% of the stated numerical value or numerical range. In certain embodiments, the numerical value or numerical range varies by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% of the amount or numerical range.

[0475] The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, e.g., embodiments of any composition of matter, composition, method or process, etc. described herein "consisting of" or "consisting essentially of" the recited features.

[0476] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "either or both" of the elements so combined, i.e., elements present in combination in some cases and uncombined in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "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 language such as "comprising"), a reference to "A and / or B" may refer to only A (optionally including elements other than B) in one embodiment; to only B (optionally including elements other than A) in another embodiment; to both A and B (optionally including other elements) in yet another embodiment; and so on.

[0477] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, that is, including the number of elements or the list and optionally at least one of the items not listed in addition, also including more than one. Only terms that clearly indicate the opposite, such as "only one of..." or "exactly one of...", or when used in the claims, "consisting of..." will refer to including exactly one element in the number of elements or the list. In general, the term "or" as used herein should only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not two") when used before an exclusive term (such as "any one," "one of...", "only one of...", or "exactly one of..."). When used in the claims, "consisting essentially of..." should have its ordinary meaning used in the field of patent law.

[0478] As used herein in the specification and claims, the phrase "at least one" when referring 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 each 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 that elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether or not 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") may, in one embodiment, refer to at least one (optionally including more than one) A, without B (and optionally including elements other than B); in another embodiment, refer to at least one (optionally including more than one) B, without A (and optionally including elements other than A); and in yet another embodiment, refer 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).

[0479] Although the present teaching has been described in conjunction with various embodiments and examples, it is not intended that the present teaching be limited to such embodiments or examples. On the contrary, as will be appreciated by those skilled in the art, the present teaching encompasses various alternatives, modifications, and equivalents.

[0480] Although various invention 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 changes and / or modifications is considered to be within the scope of the invention 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 that actual parameters, dimensions, materials, and / or configurations will depend on one or more specific applications in which the present invention is used. Those skilled in the art will recognize many equivalents to the specific invention embodiments described herein. Therefore, it should be understood that the above embodiments are presented only by way of example, and within the scope of the appended claims and their equivalents, the invention embodiments may be practiced in other ways than those specifically described and required. The invention embodiments of the present disclosure are directed to each individual feature, system, article, material, set, and / or method described herein. In addition, if such features, systems, articles, materials, sets, and / or methods are not mutually inconsistent, any combination of two or more such features, systems, articles, materials, sets, and / or methods is included within the scope of the invention disclosed herein.

[0481] Unless described to that effect, the claims should not be read as limited to the described order or elements. It should be understood that various changes in form and details may be made by one 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.

[0482] Example

[0483] In order to enable a more complete understanding of the invention described herein, the following examples are set forth.The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed in any way as limiting the scope thereof.

[0484] I. Synthetic Routes and Procedures

[0485] 3-(6-Oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (C-1)

[0486]

[0487] Step 1-2:

[0488] To a solution of pyridin-4-ylmethanol (WP08-1, 100 g, 916 mmol, 1.0 equiv) in DMF (400 mL) was added BnBr (172 g, 1.0 mol, 1.1 equiv). The mixture was heated to 100°C and stirred for 3 hours. TLC showed no starting material remaining and the formation of new spots. The residue was dissolved in EtOH (1500 mL), and 45 g of sodium borohydride (1.19 mol, 1.3 equiv) was added portionwise at 0°C. The mixture was stirred at 0°C for 1 hour, then refluxed for 2 hours. The solvent was evaporated under reduced pressure, after which water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (DCM:MeOH = 100:0-30:1) to give 107 g of the product WP08-3 (viscous oil, 2 steps, 80% yield).

[0489] LC / MS (ESI) m / z: 204.14; 1 H NMR(400MHz, CDCl3):7.25-7.41(m,5H),5.59-5.66(m,1H),4.01(s,2H),3.60(s, 2H),2.95-3.02(m,2H),2.61(t,J=5.8Hz,2H),2.36(s,br,1H),2.10-2.21(m,2H).

[0490] Step 3:

[0491] At 0 ° C, NIS (125 g, 1.2 eq) was added portionwise to a solution of 5-bromo-3H-isobenzofuran-1-one (1) (100 g, 1 eq) in trifluoromethanesulfonic acid (1000 g, 10 eq). The mixture was allowed to warm to room temperature and stirred overnight. TLC showed that no starting material remained and two new spots were formed. The reaction mixture was poured into ice water to precipitate a yellow solid. The mixture was filtered and the filter cake was washed with ice-cold water. The filter cake was dried and a mixture of product 2 (top spot on TLC) and product 2b (bottom spot on TLC, which was not further reacted in the next step) was obtained as a yellow solid (100 g, yield 62%).

[0492] LC / MS (ESI) m / z: 337.84; 1 H NMR (400MHz, CDCl3): 7.83 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 5.10 (s, 2H).

[0493] Step 4:

[0494] To a mixture of compound 2 (100 g, 1 equivalent), an aqueous solution of sodium hydroxide (57.5 g, 5 equivalents) (1000 mL, 1.5 M) and N,N-dimethylacetamide (600 mL) was added copper oxide (8.5 g, 0.2 equivalents). The reaction mixture was heated to 80 ° C and stirred for 12 hours. TLC showed that compound 2 (top spot on TLC) was completely consumed. The reaction mixture was poured into water (1000 mL) and treated with solid K2CO3 until pH 8-9 and extracted with EA. The aqueous layer was neutralized with 1N hydrochloric acid solution and extracted with ethyl acetate, washed with brine, then dried over sodium sulfate and evaporated. The crude product was purified by silica gel column chromatography to obtain compound WP08-4 (42 g, 39% yield) as a yellow solid.

[0495] LC / MS (ESI) m / z: 228.94; 1 H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.35 (s, 2H).

[0496] Step 5:

[0497] To a solution of compound WP08-4 (20 g, 1.0 eq) in 200 mL of THF was added compound WP08-3 (23.1 g, 1.3 eq) and PPh (34.4 g, 1.55 eq). The reaction mixture was cooled to 0°C, and DIAD (27.1 mL, 1.55 eq) was added dropwise. The resulting mixture was then stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography using 0-100% EtOAc / hexane. The desired product, WP08-5 (17.7 g, 49% yield), was obtained as a yellow foam.

[0498] LC / MS(ESI)m / z:414.0.

[0499] Step 6:

[0500] To a solution of WP08-5 (14.8 g, 35.7 mmol, 1.0 equiv) in toluene (150 mL) were added n-BuSnH (41.6 g, 142.9 mmol, 4.0 equiv) and AIBN (0.6 g, 3.57 mmol, 0.1 equiv). The mixture was heated to reflux and stirred overnight. TLC (PE:EA = 1:1) showed no residual starting material and the formation of a new spot. The reaction mixture was poured into saturated aqueous KF (100 mL) and stirred overnight. The reaction mixture was then extracted with ethyl acetate, washed with brine, and then dried over sodium sulfate. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give compound WP08-6 (7.1 g, 60% yield) as a white solid.

[0501] LC / MS(ESI)m / z:336.15.

[0502] Steps 7-8:

[0503] To a solution of WP08-6 (10 g, 29.8 mmol, 1.0 equiv) in DCE (100 mL) at 0°C was added chloroethyl α-chloroformate (ACE-Cl, 1.0 equiv), and the mixture was refluxed for 1 hour. The intermediate ACE-piperidine was formed, typically by evaporating the reaction mixture in vacuo and then heating the residue in MeOH for direct de-acetylation to WP08-7. The residue was dissolved in THF (100 mL), followed by the addition of 4.5 g of triethylamine (44.7 mmol, 1.5 equiv) and BoC₂O (38.7 mmol, 1.3 equiv). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, followed by the addition of water and extraction with EA. The combined organic phases were dried over Na₂SO₄ and evaporated. The residue was purified by flash chromatography to yield 6.0 g of the product, WP08-8 (2 steps, 60% yield).

[0504] LC / MS(ESI)m / z:346.16.

[0505] Step 9:

[0506] To a solution of compound WP08-8 (15 g, 1 equivalent) in tetrahydrofuran (100 mL) and water (100 mL) was added sodium hydroxide (8.7 g, 5 equivalents). The mixture was stirred at 20 ° C for 16 hours. TLC (ethyl acetate: hexane = 1: 1) showed that the reaction was complete. The mixture was adjusted to pH = 5-6 using aqueous hydrochloric acid (1 M) and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude product was not further purified and was used as a crude product in the next step.

[0507] LC / MS(ESI)m / z:364.17.

[0508] Step 10:

[0509] To a solution of compound WP08-9 (15 g, crude product, 1 equivalent) in dichloromethane (300 mL) was added manganese dioxide (20 equivalents). The mixture was stirred at 20°C for approximately 1 hour. TLC indicated the reaction was complete. The mixture was diluted with dichloromethane and filtered through a pad of celite. The filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1). The desired compound WP08-10 (8 g, 2 steps, 60%) was obtained as a yellow solid.

[0510] LC / MS(ESI)m / z:362.15.

[0511] Step 11:

[0512] To a mixture of methanol (20 mL) and dichloromethane (20 mL) of compound WP08-10 (3 g, 1.0 equivalent) were added 3-aminopiperidine-2,6-dione (4.0 g, 3 equivalents, TFA salt), AcONa (3.08 g, 6.0 equivalents) and AcOH (5.1 mL, 10.0 equivalents). The mixture was stirred at 25 ° C for 2 hours, after which sodium cyanoborohydride (1.57 g, 3.0 equivalents) was added and the mixture was further stirred for 30 minutes. LCMS showed that the reaction was complete. The reaction mixture was then quenched with water and concentrated under reduced pressure to give a residue, which was redissolved in acetonitrile and water (1:1, 30 mL). The solution was thoroughly mixed at the beginning. After standing at 0-5°C overnight, the mixture was filtered, and the filter cake was washed with acetonitrile and water (1:1), and dried in vacuo to give the crude product WP08-11 (900 mg, 60% yield) as a solid.

[0513] LC / MS(ESI)m / z:474.22.

[0514] Step 12:

[0515] To a solution of compound WP08-11 (900 mg, 1.0 equiv) in DMF (15 mL) were added HATU (795 mg, 1.1 equiv) and DIPEA (0.72 mL, 3.0 equiv), and the reaction was stirred at room temperature for 30 minutes. UPLC-MS indicated the formation of a new major peak with the desired MS. The reaction was then quenched with water, and the mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The target compound WP08-12 (675 mg, 75% yield) was obtained as a brown solid.

[0516] LC / MS (ESI) m / z: 456.21.1 H NMR (400MHz, chloroform-d) δ8.00 (s, 1H), 7.50 (d, J = 7.7Hz, 1H), 7.28 (s, 1H), 5.23 (d d,J=13.3,5.1Hz,1H),4.55(d,J=1.4Hz,2H),4.46(d,J=16.0Hz,1H),4.32(d ,J=16.0Hz,1H),4.15(s,2H),3.01–2.77(m,4H),2.38(dd,J=13.1,5.0Hz,1H ),2.29–2.17(m,1H),1.92(t,J=12.5Hz,2H),1.83–1.72(m,2H),1.52(s,9H).

[0517] Step 13:

[0518] Compound WP08-12 was treated with TFA in DCM at room temperature to deprotect the N-Boc group to provide the cereblon ligand C-1.

[0519] LC / MS(ESI)m / z:355.1.

[0520] 3-(7'-Oxo-2',3',7',9'-tetrahydro-8'H-spiro[piperidin-4,4'-pyrrolo[2,3-e]isoindol]-8'-yl)piperidine-2,6-dione (C-2):

[0521]

[0522] Step 1-2:

[0523] To a solution of 2-(pyridin-4-yl)ethan-1-ol (WP09-1, 10 g, 91.6 mmol, 1.0 equiv) in DMF (40 mL) was added BnBr (15.3 g, 108 mmol, 1.1 equiv). The mixture was heated to 100°C and stirred for 3 hours. TLC showed no residual starting material and the formation of new spots. The residue was dissolved in EtOH (150 mL), followed by the addition of 4.0 g of sodium borohydride (119.1 mmol, 1.3 equiv) in portions at 0°C. The mixture was stirred at 0°C for 1 hour and then refluxed for 2 hours. The solvent was evaporated under reduced pressure, followed by the addition of water and the mixture was extracted with EA. The combined organic phases were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (DCM:MeOH = 100:0 to 30:1) to afford 10 g of the product WP09-3 (viscous oil, 2 steps, 56% yield).

[0524] LC-MS: 218[M+H] + .

[0525] Step 3:

[0526] To a solution of compound WP09-3 (10 g, 1 eq) in DCM (200.0 mL) at 0°C was added DMAP (0.1 eq) and TEA (2 eq). EsCl (1.5 eq) was then slowly added, and the mixture was stirred at room temperature for 1 hour. The reaction was partitioned between EtOAc and water. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography to afford compound WP09-4 (10 g, 70% yield) as a yellow solid.

[0527] LC-MS: 310[M+H] + .

[0528] Step 4:

[0529] At 0 ° C, NIS (12.5 g, 1.2 eq) was added in batches to a solution of 5-bromo-3H-isobenzofuran-1-one (1) (10 g, 1 eq) in trifluoromethanesulfonic acid (100 g, 10 V). The mixture was returned to room temperature and stirred overnight. TLC showed that no starting material remained and two new spots were formed. The reaction mixture was poured into ice water and a yellow solid was precipitated. The mixture was filtered and the filter cake was washed with ice-cold water. The filter cake was dried and a yellow solid (10 g, 62% yield) was obtained, which was a mixture of product 2 (top spot on TLC) and product 2b (bottom spot on TLC, which was not further reacted in the next step).

[0530] Step 5:

[0531] To compound 2 (10g, 1 equivalent), sodium hydroxide (5.75g, 5 equivalents) in a mixture of water (100mL, 1.5M) and N, N-dimethylacetamide (60mL), copper oxide (0.85g, 0.2 equivalent) was added. The reaction mixture was heated to 80 ° C and stirred for 12 hours. TLC showed that compound 2 (top point of TLC) was completely consumed. The reaction mixture was poured into water (100mL) and treated with solid K2CO3 until pH 8-9 and extracted with EA. It was neutralized using 1N hydrochloric acid solution and the aqueous layer was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and evaporated. The crude product was purified by silica gel column chromatography to obtain compound WP08-4 (4.2g, 39% yield) as a yellow solid.

[0532] LC-MS: 229 / 231[M+H] + Step 6:

[0533] To a solution of compound WP08-4 (10 g, 1.0 eq) in 100 mL of DMF was added compound WP09-4 (16.2 g, 1.2 eq) and KCO (1.6 eq). The reaction mixture was heated to 70°C and stirred overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate, washed with brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography using 0-100% EtOAc / hexane. The desired product, WP09-5 (11 g, 60% yield), was obtained as a yellow foam.

[0534] LC-MS:428 / 430[M+H] + .

[0535] Step 7:

[0536] To a solution of WP09-5 (5 g, 1.0 equiv) in toluene (50 mL) was added n-Bu3SnH (13.6 g, 4.0 equiv) and AIBN (0.4 g, 0.1 equiv). The mixture was heated to reflux and stirred overnight. TLC (PE:EA=1:1) showed no residual starting material and the formation of new spots. The reaction mixture was poured into a saturated aqueous KF solution (100 mL) and stirred overnight. Afterwards, the reaction mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The residue was purified by silica gel column chromatography (DCM:MeOH=50:1) to give compound WP09-6 (2 g, 50% yield) as a white solid.

[0537] LC-MS: 350[M+H] + .

[0538] Steps 8-9:

[0539] To a solution of WP09-6 (3.0 g, 1.0 equiv) in DCE (100 mL) at 0°C was added chloroethyl α-chloroformate (ACE-Cl, 1.2 equiv), and the mixture was refluxed for 15 hours. The intermediate ACE-piperidine was formed, which was typically deacetated directly to WP09-7 by evaporating the reaction mixture in vacuo and then heating the residue in MeOH. The residue was dissolved in THF (100 mL), followed by the addition of trimethylamine (3.0 equiv) and Boc2O (1.3 equiv). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, followed by the addition of water and the mixture was extracted with EA. The combined organic phases were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography to afford WP09-8 (1.5 g, 2 steps, 50% yield).

[0540] LC-MS: 360[M+H] + . 1H NMR (600MHz, chloroform-d) δ7.47(d,J=7.6Hz,1H),7.08(d,J=7.6Hz,1H),5.24(s,2H),4.16(t,J=6.7H z,2H),3.88(m,2H),3.51(m,2H),2.52(t,J=6.8Hz,2H),2.13(m,2H),1.61(m,2H),1.46(s,9H).

[0541] Step 10:

[0542] To a solution of compound WP09-8 (2 g, 1 equivalent) in tetrahydrofuran (10 mL) and water (10 mL) was added sodium hydroxide (1.2 g, 5 equivalents). The mixture was stirred at 20 ° C for 16 hours. TLC (ethyl acetate: hexane = 1: 1) showed that the reaction was complete. The mixture was adjusted to pH = 5-6 using aqueous hydrochloric acid (1 M) and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude product was not further purified and used as a crude product in the next step.

[0543] Step 11:

[0544] To a solution of compound WP09-9 (2 g, crude product, 1 equivalent) in dichloromethane (30 mL) was added manganese dioxide (20 equivalents). The mixture was stirred at 20° C. for approximately 1 hour. TLC indicated that the reaction was complete. The mixture was diluted with dichloromethane and filtered through a pad of celite. The filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH=10:1). The desired compound WP09-10 (1.2 g, 2 steps, 60%) was obtained as a yellow solid.

[0545] LC-MS: 376[M+H] + .

[0546] Step 12:

[0547] To a mixture of compound WP09-10 (532 mg, 1.0 equiv) in methanol (5 mL) and dichloromethane (5 mL) was added 3-aminopiperidine-2,6-dione (698 mg, 3 equiv, HCl salt), AcONa (698 mg, 6.0 equiv) and AcOH (0.85 mL, 10.0 equiv). The mixture was stirred at 25 ° C for 1 hour, after which sodium cyanoborohydride (268 mg, 3.0 equiv) was added and the mixture was further stirred for 30 minutes. LCMS showed that the reaction was complete. Next, the reaction mixture was quenched with water and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (20% to 50% ACN, neutral). After lyophilization, the desired product WP09-11 (415 mg, 60% yield) was obtained as a solid.

[0548] Step 13:

[0549] To a solution of compound WP09-11 (415 mg, 1.0 eq) in DMF (5 mL) was added HATU (421 mg, 1.3 eq) and DIPEA (0.47 mL, 3.0 eq), and the reaction was stirred at room temperature for 30 minutes. UPLC-MS indicated the formation of a new major peak with the desired MS, after which the reaction was quenched with water and the mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The desired compound WP09-12 was obtained as a brown solid (300 mg, 75% yield).

[0550] LC-MS: 470[M+H] + .

[0551] Step 14:

[0552] Compound WP09-12 was treated with TFA in DCM at room temperature to deprotect the N-Boc group to provide the cereblon ligand C-2.

[0553] LC / MS(ESI)m / z:369.2.

[0554] (S)-3-(6'-oxo-1',2',6',8'-tetrahydro-7'H-spiro[piperidin-4,3'-pyrrolo[3,4-g]indol]-7'-yl)piperidine-2,6-dione (C-3); and

[0555] (S)-3-(1'-methyl-6'-oxo-1',2',6',8'-tetrahydro-7'H-spiro[piperidin-4,3'-pyrrolo[3,4-g]indol]-7'-yl)piperidin-2,6-dione (C-5)

[0556]

[0557] Step 1:

[0558] To a solution of 5-bromo-3H-isobenzofuran-1-one (1) (10 g, 1 eq) in trifluoromethanesulfonic acid (100 g, 10 V) was added NIS (12.5 g, 1.2 eq) in portions at 0°C. The mixture was returned to room temperature and stirred overnight. TLC showed no residual starting material and two new spots were formed. The reaction mixture was poured into ice water to precipitate a yellow solid. The mixture was filtered and the filter cake was washed with ice-cold water. The filter cake was dried to give a yellow solid (10 g, 62% yield), which was a mixture of product 2 (top spot on TLC) and product 2b (bottom spot on TLC, which was not further reacted in the next step).

[0559] Step 2:

[0560] Compound 3 was prepared according to the reported procedure (Bioorg. Med. Chem. Lett. 2016, 26, 228–234). To a flask containing compound 2 (500 mg, 1.0 equiv), compound 3 (377 mg, 1.2 equiv), Pd2(dba)3 (136 mg, 0.1 equiv), Xantphos (257 mg, 0.3 equiv) and Cs2CO3 (1447 mg, 3.0 equiv) was added toluene (15 mL). The reaction was evacuated and backfilled with N2 three times. The reaction was stirred at 80°C for 6 hours, after which it was allowed to cool to room temperature and filtered. The filtrate was evaporated and the residue was purified by silica gel chromatography (0-25% ethyl acetate in hexane) to give 316 mg (yield = 51%) of product 4 as a light yellow powder.

[0561] LC-MS:323.14[M+H]+.1H NMR (400MHz, chloroform-d) δ7.61(d,J=8.0Hz,1H),7.17(d,J=7.9Hz,1H),5.64–5.53(m,1H),5 .36(s,2H),3.93–3.79(m,4H),3.53(t,J=5.7Hz,2H),2.17–2.05(m,2H),1.46(s,9H).

[0562] Step 3 and Step 4:

[0563] To a solution of compound 4 (300 mg, 1.0 equiv) and AIBN (35 mg, 0.3 equiv) in toluene (10 mL) was added Bu SnH (954 μL, 5.0 equiv). The reaction was stirred at 110 ° C in a sealed tube for 24 hours. Afterwards, it was refrigerated to room temperature and quenched with saturated KF aqueous solution (20 mL), and the mixture was stirred overnight. The resulting mixture was extracted with ethyl acetate (3 times). The combined organic layer was washed with brine (3 times), dried over Na SO, filtered, and concentrated under reduced pressure to give a crude mixture. The mixture was purified by silica gel chromatography (0-30% ethyl acetate / hexane) to give the crude product 5 (90 mg) as a light yellow oil.

[0564] LC-MS: 343.37[M+H] + .

[0565] To a solution of compound 5 (90 mg) in MeOH (5 mL) was added Pd / C (90 mg). The reaction was evacuated and backfilled with H2 and stirred at room temperature under H2 for 6 hours. The filtrate was then filtered through celite and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0-50% ethyl acetate in hexanes) to give compound 6 (50 mg, 20% yield for steps 3 and 4) as a white solid.

[0566] LC-MS: 345.22[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.37 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 5.20 (s, 2H), 4.19–4.04 (m, 2H), 3.67 (s, 2H), 3.00–2.77 (m, 2H), 1.91–1.68 (m, 4H), 1.48 (s, 9H). 13 C NMR (101MHz, CDCl3) δ171.42,154.87,143.02,142.81,128.22,126.10,123.66,117.49,79.98,67.97,56.18,44.96,40.85,35.64,28.54.

[0567] Step 5:

[0568] To a THF / MeOH / HO (2mL / 2mL / 1mL) solution of compound 6 (48mg, 1.0 equivalent) was added NaOH (111mg, 20 equivalents). The reaction was stirred at room temperature overnight and then concentrated to remove most of the THF / MeOH. The residue was diluted with 1mL water, then neutralized to pH 4-6 with a 2N HCl aqueous solution, and then extracted with EA (5mL, 6 times). The combined organic layer was washed with salt water, filtered, dried over NaSO, and concentrated under reduced pressure to obtain 50mg of the crude product 7 as a light yellow oil, which was used directly in the next step.

[0569] LC-MS: 363.28[M+H] + .

[0570] Step 6:

[0571] To a solution of compound 7 (40 mg, 1.0 eq) in DCM (5 mL) was added NaHCO (28 mg, 3.0 eq) followed by portionwise addition of DMP (47 mg, 1.0 eq). After 10 minutes, the reaction mixture was diluted with DCM and washed with brine, dried over NaSO, filtered and concentrated to give 40 mg of the crude product 8 as a yellow oil, which was used directly in the next step.

[0572] LC-MS: 361.27 [M+H] + .

[0573] Step 7:

[0574] To a solution of 9 (73 mg, 4.0 equivalents) and NaOAc (28 mg, 4 equivalents) in MeOH (4 mL) was added 8 (40 mg, 1.0 equivalents) and AcOH (317 μL, 50 equivalents). After 15 minutes, NaBHCN (34.5 mg, 5.0 equivalents) was added and the resulting mixture was stirred at 40 ° C for 3 hours. The reaction mixture was concentrated to remove some MeOH, and the mixture was purified by preparative HPLC to give Boc-protected C-3, which was further treated with TFA and concentrated to remove TFA. 10 mg of the final compound C-3 was obtained as a white solid.

[0575] LC-MS:423.16[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.28–7.17 (m, 2H), 5.14 (dd, J=13.3, 5.2 Hz, 1H), 4.39–4.23 (m, 2H), 3.67 (s, 2H), 3.51–3.39 (m, 2H), 3.25–3.12 (m, 2H), 2.98–2.84 (m, 1H), 2.84–2.72 (m, 1H), 2.56–2.39 (m, 1H), 2.23–1.96 (m, 5H).

[0576] Step 8:

[0577] To a solution of 9 (18 mg, 4.0 equiv) and NaOAc (6.9 mg, 4 equiv) in MeOH (3 mL) was added 8 (40 mg, 1.0 equiv) and AcOH (0.5 mL). After 15 minutes, NaBHCN (34.5 mg, 20 equiv) was added portionwise, and the resulting mixture was stirred at 40 ° C overnight. The reaction mixture was concentrated to remove some MeOH, and the mixture was purified by preparative HPLC to give Boc-protected C-5, which was further treated with TFA and concentrated to remove TFA. 4.7 mg of the final compound C-5 was obtained as a gray solid.

[0578] LC-MS:469.26[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.21 (s, 2H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.72–4.55 (m, 2H), 3.51–3.39 (m, 4H), 3.24–3.13 (m, 2H), 2.99 (s, 3H), 2.96–2.83 (m, 1H), 2.83–2.74 (m, 1H), 2.60–2.46 (m, 1H), 2.22–2.03 (m, 3H), 2.03–1.94 (m, 2H). 3-(6-Oxo-6,8-dihydrospiro[furo[3,4-e]isoindole-3,4'-piperidinyl]-7(1H)-yl)piperidine-2,6-dione (C7)

[0579]

[0580] Step 1:

[0581] At 0 ° C, to a solution of 5-bromo-3H-isobenzofuran-1-one (C-7.1) (10 g, 1 equivalent) in trifluoromethanesulfonic acid (80 mL, 20 equivalents) was added NIS (12.5 g, 1.2 equivalents) in portions. The mixture was returned to room temperature and stirred overnight. TLC showed that no starting material remained and two new spots were formed. The reaction mixture was poured into ice water and a yellow solid was precipitated. The mixture was filtered and the filter cake was washed with ice-cold water. The filter cake was dissolved in DCM and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give a yellow solid. The crude product was purified by flash chromatography. A lower polarity product (top spot of TLC) C-7.2 (8 g, 50% yield) was obtained as a brown solid.

[0582] Step 2:

[0583] Compound C-7.2 (8 g, 1 equivalent), Pd(dppf)Cl2 (0.2 equivalent), K2CO3 (3 equivalents) and di In 40 DEG C of 40 DEG C of 80 DEG C, 1 ...

[0584] LC-MS: 239 / 241[M+H] +; 1 H NMR (600 MHz, CHLOROFORM-d) δ 7.70 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 6.92 (dd, J = 18.0, 11.6 Hz, 1H), 5.62 (d, J = 11.6 Hz, 1H), 5.42 (d, J = 18.0 Hz, 1H), 5.33 (s, 2H).

[0585] Step 3:

[0586] A solution of compound C-7.3 (5 g) in CH2Cl2 (100 mL) was cooled to -78°C and then bubbled with O3. The O3 was continued for 30 minutes until the color turned light blue, and then air was bubbled through the solution for 10 minutes to remove excess O3. After Me2S (2 mL) was added dropwise, the solution was stirred and allowed to warm to room temperature. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine and dried over MgSO4. The residue was quickly purified by chromatography to give compound C-7.4 (4 g).

[0587] Step 4:

[0588] To a solution of compound C-7.4 (4 g, 1.0 equiv) in MeOH (40 mL, 10 V) at 0°C was added NaBH4 (1.9 g, 3 equiv). TLC indicated complete consumption of compound 4, and LCMS indicated the presence of the desired product. The reaction mixture was quenched at 20°C by adding H2O, then concentrated under reduced pressure to remove MeOH. The mixture was then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to ethyl acetate) to give compound C-7.5 (3 g, 75% yield).

[0589] Step 5:

[0590] Compound C-7.5 (4 g, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.7 g, 1.5 eq), potassium carbonate (6.9 g, 3.0 eq), and Pd(dppf)Cl2 (2.4 g, 0.2 eq) were injected into a round-bottom flask equipped with a stirrer. The flask was evacuated and backfilled with nitrogen (x3). Two The mixture was stirred at 90°C for 10 hours. The cooled reaction mixture was diluted with EtOAc and washed with Celite TMThe insoluble material was removed by filtration. The filtrate was washed with water and saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel chromatography using a gradient elution of MeOH in DCM. The pure fractions were combined and concentrated to give compound C-7.6 (5 g, 89%).

[0591] Step 6:

[0592] To a mixture of compound C-7.6 (6 g, 1 eq) in MeCN (60 mL) was added NBS (3.7 g, 1.2 eq) in portions. The mixture was stirred at 20 ° C for 16 hours. The mixture was concentrated in vacuo and the crude product was purified by flash silica gel chromatography using a gradient elution of MeOH in DCM to give compound C-7.7 (6.6 g, 90% yield) as a white solid.

[0593] 1 H NMR (600MHz, chloroform-d) δ7.87(d,J=7.9Hz,1H),7.66(d,J=7.9Hz,1H),5.25(s,2H),5.16(d,J=13.0Hz,1H),5.05(d,J= 13.0Hz,1H),4.25(m,2H),4.08–3.81(m,2H),3.33(m,1H),2.68–2.56(m,1H),1.65(d,J=13.9Hz,1H),1.50(s,9H).

[0594] Step 7:

[0595] To a solution of compound C-7.7 (500 mg, 1.0 equivalent) in toluene (10 mL) and MeOH (1 mL) was added n-Bu3SnH (5.0 equivalents) and AIBN (0.1 equivalents). The mixture was heated to reflux and stirred overnight. After cooling, additional n-Bu3SnH (5.0 equivalents) was added to the above mixture and kept stirring for an additional 12 hours at 100 ° C. TLC showed that no starting material remained, and the reaction mixture was poured into a saturated KF aqueous solution (100 mL) and stirred for 1 hour. Afterwards, the reaction mixture was filtered and extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The crude product was purified by silica gel column chromatography (PE: EA = 4: 1) to obtain compound C-7.8 (60% yield) as a white solid. LC-MS: 346 [M + H] + ; 1HNMR(600MHz,DMSO-d6)δ7.78(d,J=7.8Hz,1H),7.57(d,J=7.8Hz,1H),5.39(s,2H),5.09(s,2H),3.9 8(brs,2H),3.07(brs,2H),1.88(td,J=13.1,4.9Hz,2H),1.64(dd,J=13.8,2.4Hz,2H),1.43(s,9H).

[0596] Step 8:

[0597] To a solution of compound C-7.8 (1.25 g, 1 equivalent) in tetrahydrofuran (10 mL) and water (10 mL) was added sodium hydroxide (720 mg, 5 equivalents). The mixture was stirred at 20°C for 16 hours. TLC (ethyl acetate:hexane=1:1) indicated that the reaction was complete. The mixture was adjusted to pH=5-6 using aqueous hydrochloric acid (1 M) and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude product 9 was not further purified and was used crude in the next step.

[0598] Step 9:

[0599] To a solution of compound C-7.9 (1 g, crude product, 1 equivalent) in dichloromethane (50 mL) was added manganese dioxide (20 equivalents). The mixture was stirred at 20°C for approximately 1 hour. TLC indicated the reaction was complete. The mixture was diluted with dichloromethane and MeOH, then filtered through a pad of celite. The filtrate was concentrated in vacuo to yield the crude product C-7.10 (0.6 g, crude product), which was used directly in the next step.

[0600] Step 10:

[0601] To a mixture of compound C-7.10 (300 mg, crude product, 1.0 equivalent) in methanol (5 mL) and dichloromethane (5 mL) was added 3-aminopiperidine-2,6-dione (162 mg, 1.5 equivalents, HCl salt), AcONa (204 mg, 3.0 equivalents) and AcOH (150 μL, 3.0 equivalents). The mixture was stirred at 20 ° C for 1 hour, after which sodium cyanoborohydride (104 mg, 2.0 equivalents) was added and the mixture was further stirred for 30 minutes. LCMS showed that the reaction was complete. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (20% to 50% ACN, neutral). After lyophilization, 120 mg of the desired product C-7.11 was obtained as a white solid.

[0602] Step 11:

[0603] To a solution of compound C-7.11 (180 mg, 1.0 eq) in DMF (3 mL) at 0°C was added HATU (216 mg, 1.5 eq) and DIPEA (0.2 mL, 3.0 eq), and the reaction was stirred at room temperature for 30 minutes. UPLC-MS indicated the formation of a new major peak with the desired MS, after which the reaction was quenched with water, and the mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The target compound C-7.12 (100 mg, 60% yield) was obtained as a brown solid.

[0604] LC-MS: 456[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),7.66(d,J=7.7Hz,1H),7.47(d,J=7.7Hz,1H),5.16–5.11(m,1H),5.08(m,2H),4.44(d,J=17.4Hz,1H),4.29(d, J=17.4Hz,1H),3.98(m,2H),3.04(m,3H),2.60(d,J=17.0Hz,1H),2.42–2. 31(m,1H),2.04–1.93(m,1H),1.92–1.80(m,2H),1.64(m,2H),1.43(s,9H).

[0605] Step 12:

[0606] Compound C-7.12 is treated with TFA in DCM at room temperature to deprotect the N-Boc group to provide the cereblon ligand C-7.

[0607] LC / MS(ESI)m / z:355.1.

[0608] Synthetic procedure for preparing IKZF2 degrader 3-362

[0609]

[0610] To a solution of A (0.02 mmol) in MeOH (4 mL) was added NaOAc (0.06 mmol) and then B (0.06 mmol). After stirring at room temperature for 30 minutes, 5 equivalents of NaBH CN (0.10 mmol) were added. After 12 hours, an additional 5 equivalents of NaBH CN (0.1 mmol) were added. The resulting reaction mixture was kept stirring for another 12 hours. The solvent was then removed under reduced pressure and the resulting residue was purified by preparative HPLC to obtain title compound 3-362.

[0611] II. Characterization of Compounds

[0612] Characterization data of the compounds are shown in Table E2.

[0613] Table E1. Characterization Data

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640] For compounds B-1 to B-58

[0641] Intermediate B1: tert-Butyl 4-(chloromethyl)-3,6-dihydro-2H-pyridine-1-carboxylate

[0642]

[0643] Step A: tert-Butyl 3-hydroxy-4-methylenepiperidine-1-carboxylate

[0644] A suspension of SeO2 (61.8 g, 558 mmol, 0.55 eq) in DCM (3000 mL) was cooled to -10°C, followed by the dropwise addition of an aqueous solution of 2-peroxy-2-methyl-propane (274 g, 291 mL, 2.10 eq, 70% purity), and the resulting mixture was stirred at -10°C for 30 minutes. The reaction mixture was further cooled to -30°C, followed by the dropwise addition of a solution of compound 5-1 (200 g, 1.01 mol, 1 eq) in DCM (1000 mL), and the resulting mixture was stirred at -30°C for 1 hour. The reaction mixture was heated to 20°C and stirred for a further 18 hours, after which the mixture was cooled to 0°C, and borneol and water (1.0 L) were added. The resulting mixture was stirred at 0°C for 30 minutes. The organic phase was separated and the aqueous phase was extracted with DCM (500 mL). 10% w / v NaHSO solution (1000 mL) was then added portionwise to the combined organic phases at 0 ° C. During this time, the temperature was kept below 10 ° C. and the mixture was stirred for an additional 5 minutes after the addition. The organic phase was separated and the aqueous phase was extracted with DCM (500 mL). The combined organic phases were washed with brine (1000 mL), dried over anhydrous Na SO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). 3-hydroxy-4-methylenepiperidine-1-carboxylic acid tert-butyl ester (370 g) was obtained as a white solid with a typical yield of 34.2%. 1H NMR(400MHz,DMSO-d6)δ=5.22(br d,J=3.9Hz,1H),4.98(s,1H),4.79(s,1H),3.93-3.76(m,2H),3.71(td,J=4.3,12.6Hz,1H),2.9 2-2.77(m,1H),2.76-2.53(m,1H),2.30(td,J=3.5,13.4Hz,1H),2.10-1.95(m,1H),1.40(s,9H).

[0645] Step B: tert-Butyl 4-(chloromethyl)-3,6-dihydro-2H-pyridine-1-carboxylate

[0646] At 15 ° C, to a solution of tert-butyl 3-hydroxy-4-methylenepiperidine-1-carboxylate (100g, 469mmol, 1.00 equivalent) in toluene (2000mL), 2,6-lutidine (55.2g, 60.0mL, 516mmol, 1.10 equivalent) was added. The mixture was cooled to 0 ° C, and then SOCl2 (66.9g, 40.8mL, 563mmol, 1.20 equivalent) was added dropwise to the mixture under N2 atmosphere, during which the temperature was maintained below 10 ° C. The mixture was stirred at 110 ° C for 3 hours and then cooled to 20 ° C. Brine (2x600mL) was added and the resulting mixture was stirred at 20 ° C for 30 minutes. The organic phase was separated and saturated NaHCO3 solution (600mL) was added portionwise at 15 ° C. The organic phase was separated, washed with brine (1000mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Tert-butyl 4-(chloromethyl)-3,6-dihydro-2H-pyridine-1-carboxylate (200 g) was obtained as a red oil in a typical yield of 49.0%. 1 HNMR (400MHz, CDCl3-d) δ = 5.72 (br s, 1H), 3.98 (s, 2H), 3.88 (br s, 2H), 3.49 (br t, J = 5.6Hz, 2H), 2.17 (br s, 2H), 1.43 (s, 9H).

[0647] Intermediate B2: (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0648]

[0649] Step A: Methyl 4-bromo-2-formyl-3-hydroxybenzoate

[0650] At 20 ℃, to 4-bromo-3-hydroxybenzoic acid methyl ester (200g, 865mmol, 1.00 equivalent) in TFA (2.0L), HMTA (485g, 3.46mol, 4.00 equivalent) was added, and the resulting mixture was stirred at 125 ℃ for 12 hours. The mixture was cooled to 20 ℃, quenched with 2N HCl solution (5V), and a yellow precipitate was observed. The mixture was stirred for 10 minutes, and then additional H2O (5V) was added, and the reaction mixture was stirred for another 1 hour. The mixture was filtered, and the filter cake was dissolved in DCM (2.0L), filtered through diatomaceous earth, dried over anhydrous Na2SO4 and concentrated in vacuo. 4-bromo-2-formyl-3-hydroxybenzoic acid methyl ester (144g) was obtained as a gray solid with a typical yield of 64.2%. 1 HNMR (400MHz, DMSO-d6) δ = 12.06 (br s, 1H), 10.38 (s, 1H), 8.00 (d, J = 8.2Hz, 1H), 7.30 (d, J = 8.2Hz, 1H), 3.87 (s, 3H).

[0651] Step B: (S)-tert-Butyl 5-amino-4-(5-bromo-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate

[0652] To a suspension of methyl 4-bromo-2-formyl-3-hydroxybenzoate (17.3 g, 72.4 mmol, 1.05 equiv, HCl salt) in MeOH (300 mL) was added DIPEA (9.37 g, 72.4 mmol, 12.6 mL, 1.05 equiv), compound 2 (17.8 g, 69.0 mmol, 1.00 equiv) and AcOH (6.22 g, 103 mmol, 5.92 mL, 1.50 equiv) at 20° C. and stirred for 1.5 hours, after which NaBH3CN (8.67 g, 138 mmol, 2.00 equiv) was added portionwise at 20° C., and the resulting mixture was stirred for 3 hours at 20° C. The mixture was quenched by H2O (200 mL) at 20° C. and concentrated under reduced pressure. The solvent residue was then extracted with EtOAc (3x150 mL), and the combined organic layers were washed with brine (2x200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 100% ethyl acetate). (S)-tert-butyl 5-amino-4-(5-bromo-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (23.0 g) was obtained as a yellow solid in a typical yield of 78.4%. 1H NMR (400MHz, DMSO-d6) δ = 10.44 (s, 1H), 7.67-7.55 (m, 2H), 7.20 (s, 1H), 7.11 (d, J = 7.9Hz, 1H), 4.76-4.67 ( m,1H),4.58(d,J=17.9Hz,1H),4.39(d,J=17.9Hz,1H),2.23-2.07(m,3H),2.03-1.91(m,1H),1.32(s,9H).

[0653] Step C: 4-(((2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-1-oxoisoindolin-4-yl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylic acid (S)-tert-butyl ester

[0654] To a solution of tert-butyl 4-(chloromethyl)-3,6-dihydro-2H-pyridine-1-carboxylate (150 g, 363 mmol, 1.00 equiv) in MeCN (2000 mL) at 20° C. was added KCO (150.49 g, 1.09 mmol, 3.00 equiv), NaI (5.44 g, 0.36 mmol, 0.10 equiv) and (S)-tert-butyl 5-amino-4-(5-bromo-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (136 g, 472 mmol, 1.30 equiv, 80% purity). The reaction mixture was stirred at 60° C. for 12 hours before being cooled again to 20° C. The resulting mixture was filtered and the filter cake was washed with DCM (2×500 mL). The filtrate was concentrated in vacuo and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). (S)-tert-butyl 4-(((2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-1-oxoisoindolin-4-yl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate was obtained as a red solid in a typical yield of 72.4%. 1 H NMR (400MHz, CDCl3-d) δ = 7.67 (d, J = 8.0Hz, 1H), 7.44 (d, J = 8.0Hz, 1H), 6.33 (br s, 1H), 5.86 (br s,1H),5.48(brs,1H),4.90(dd,J=6.3,8.6Hz,1H),4.66-4.59(m,1H),4.53(s,1H),4.50(br s,2H),3.98(br s,2H),3.60(br t,J=5.5Hz,2H),2.43-2.10(m,7H),1.49(s,9H),1.41(s,9H).

[0655] Step D: tert-Butyl 7-[(1S)-4-tert-Butoxy-1-carbamoyl-4-oxo-butyl]-6-oxo-spiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate

[0656] To a solution of (S)-tert-butyl 4-(((2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-1-oxoisoindolin-4-yl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (125 g, 205 mmol, 1.00 equiv) in toluene (1500 mL) at 20° C. was added AIBN (5.06 g, 0.03 mmol, 0.15 equiv) and Bu SnH (270 mL, 1.02 mmol, 4.98 equiv). The reaction mixture was stirred at 110° C. for 12 hours before being cooled to 20° C. Saturated KF solution (1000 mL) was added and the resulting mixture was stirred at 20° C. for an additional 2 hours. The mixture was filtered and the filter cake was washed with EtOAc (2×500 mL). The organic phase is separated, and the aqueous phase is extracted with ethyl acetate (3x500mL). The combined organic phase is washed with brine (500mL), over anhydrous Na2SO4, dried, filtered and concentrated in vacuo. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate=100 / 1 to 1 / 1). 7- [(1S) -4- tert-butoxy -1- carbamoyl -4- oxo-butyl] -6- oxo- spiral [2,8- dihydrofuran [2,3-e] isoindole -3,4'- piperidine] -1'- carboxylic acid tert-butyl ester (160g) is obtained as a white solid, and typical yield is 56.6%. 1 H NMR (400MHz, CDCl3-d) δ = 7.40 (d, J = 7.6Hz, 1H), 7.20 (d, J = 7.6Hz, 1H), 6.41 (br s, 1H), 5.61 (br s,1H),4.92-4.85(m,1H),4.55-4.49(m,2H),4.12(q,J=7.1Hz,3H),2.88(br t,J=12.0Hz,2H),2.40-2.09(m,5H),1.94-1.82(m,2H),1.77-1.68(m,2H),1.50-1.47(m,9H),1.42-1.40(m,9H).

[0657] Step E: (3S)-3-(6-oxospiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dionebenzenesulfonate

[0658] A solution of anhydrous benzenesulfonic acid (19.6 g, 124 mmol, 2.00 equivalents) in MeCN (400 mL) was heated to 100 ° C, after which a solution of 7- [(1S) -4- tert-butoxy -1- carbamoyl -4- oxo - butyl] -6- oxo - spiro [2, 8- dihydrofuran [2, 3-e] isoindole -3, 4 '- piperidine] -1 '- carboxylic acid tert-butyl ester (47.0 g, 62.1 mmol, 1.00 equivalents, 70% purity) in MeCN (100 mL) was added dropwise to the mixture. The mixture was stirred at 100 ° C for 12 hours and then cooled to 20 ° C. The mixture was filtered and the filter cake was dried under reduced pressure. The title compound (37.0 g) was obtained as a white solid with a typical yield of 92.8%. 1 HNMR (400MHz, D2O-d2) δ = 7.75 (br d, J = 7.4Hz, 2H), 7.55-7.36 (m, 5H), 5.11 (br dd, J = 5.2, 13.4Hz, 1H), 4.64 (s, 2H), 4.53-4.35 (m, 2H), 3.49 (br d,J=13.2Hz,2H),3.20-3.06(m,2H),2.99-2.78(m,2H),2.48(dq,J=5.3,13.1Hz,1H),2.25-2.08(m,3H),2.05-1.93(m,5H).

[0659] Step F: (3S)-3-(6-oxospiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione hydrochloride

[0660] (3S)-3-(6-oxospiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidin-2,6-dionebenzenesulfonate (37 g) was dissolved in HCl / dihydrofuro[2,3-e]isoindole-3,4'-piperidin]-7-yl A solution of 4-nitropropane (4M, 370 mL) was stirred at 20° C. for 12 h, after which the mixture was filtered and the filter cake washed with MeCN (2×200 mL). The filter cake was dried under reduced pressure to obtain the title compound (24.0 g) as a red solid in a typical yield of 80.7%. 1H NMR(400MHz,D2O-d2)δ=7.48-7.36(m,2H),5.12(dd,J=5.3,13.3Hz,1H),4.69-4.61(m,2H),4.53-4.37(m,2H),3.51(br dd,J=3.4,13.3Hz,2H),3.22-3.06(m,2H),2.98-2.80(m,2H),2.56-2.43(m,1H),2.29-2.08(m,3H),2.05-1.90(m,2H). Intermediate B3: (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl-2,2-d2)piperidine-2,6-dione

[0661]

[0662] Step A: 1-tert-Butyl 4-methyl 3,6-dihydropyridine-1,4(2H)-dicarboxylate

[0663] To a solution of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (10.0 g, 30.2 mmol, 1.0 equiv) in MeOH (150.0 mL) was added DIPEA (39.0 g, 52.6 mL, 302 mmol, 10.0 equiv) and Pd(dppf)Cl2 (2.21 g, 3.02 mmol, 0.1 equiv). The resulting mixture was stirred under CO (1 atm) at 70°C for 1 hour. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with H2O (30.0 mL) and extracted with EA (60 mL×3). The organic layer was washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate in petroleum ether, from 0% to 19%) to give 1-tert-butyl 4-methyl 3,6-dihydropyridine-1,4(2H)-dicarboxylate (5.80 g, 79% yield) as a yellow oil. LC-MS (ESI): C 12 H 19 Calculated molecular weight of NO4, 241.29; observed m / z, 186.7 [M-55] + . 1 H NMR (400MHz, DMSO-d6) δ6.86 (s, 1H), 4.00 (d, J = 2.4Hz, 2H), 3.68 (s, 3H), 3.42 (t, J = 5.6Hz, 2H), 2.28-2.25 (m, 2H), 1.41 (s, 9H).

[0664] Step B: tert-Butyl 4-(hydroxymethyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate

[0665] At 0 ° C, to a solution of 1-tert-butyl 4-methyl 3,6-dihydropyridine-1,4 (2H)-dicarboxylate (2.10 g, 8.70 mmol, 1.0 equivalent) in anhydrous THF (50.0 mL), LiAlD4 (402 mg, 9.57 mmol, 1.1 equivalents) was added portionwise. The reaction mixture was stirred at 0 ° C for 1 hour. Na2SO4.10H2O (5 g) was slowly added to the above solution, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether solution of ethyl acetate, 0% to 70%) to obtain tert-butyl 4-(hydroxymethyl-d2)-3,6-dihydropyridine-1 (2H)-carboxylate (700 mg, 37% yield) as a yellow oil. LC-MS (ESI): C 11 H 17 The calculated molecular weight of D2NO3 is 215.29; the experimental m / z value is no MS signal. 1 H NMR (400MHz, DMSO-d6) δ5.56 (s, 1H), 4.71 (s, 1H), 3.80 (s, 2H), 3.39 (t, J = 5.6Hz, 2H), 2.02-1.92 (m, 2H), 1.39 (s, 9H).

[0666] Step C: tert-Butyl 4-(bromomethyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate

[0667] Under N2, to a DCM (50.00mL) solution of tert-butyl 4- (hydroxymethyl -d2) -3,6- dihydropyridine -1 (2H) -carboxylate (1.90g, 8.83mmol, 1.0 equivalent) and triphenylphosphine (3.47g, 13.2mmol, 1.5 equivalents), CBr4 (4.39g, 13.2mmol, 1.5 equivalents) was added portionwise. The reaction mixture was stirred at 0 ° C for 5 hours. After evaporation, the residue was purified by flash column chromatography (petroleum ether solution of ethyl acetate, 0% to 19%) to give tert-butyl 4- (bromomethyl -d2) -3,6- dihydropyridine -1 (2H) -carboxylate (1.60g, 65% yield) as a yellow oil. LC-MS (ESI): C 11 H 16 Calculated molecular weight of D2BrNO2, 278.19; observed m / z, 224.0 [M-55] + .

[0668] Step D: tert-Butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate

[0669] A mixture of tert-butyl 4-(bromomethyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate (2.00 g, 7.19 mmol, 1.0 equiv), 5-bromo-4-hydroxyisobenzofuran-1(3H)-one (1.65 g, 7.19 mmol, 1.0 equiv), and K2CO3 (1.99 g, 14.4 mmol, 2.0 equiv) in DMF (30.0 mL) was stirred at 50° C. for 2 hours. After cooling to room temperature, the mixture was dissolved in EA (100 mL), washed with brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate in petroleum ether, 0% to 40%) to give tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate (2.30 g, 75% yield) as a yellow oil. LC-MS (ESI): C 19 H 20 Calculated molecular weight of D2BrNO5, 426.30; observed m / z, 450.1 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ7.89(d,J=8.0Hz,1H),7.51(d,J=8.0Hz,1H),5.95(s,1H),5 .72(s,2H),3.93(s,2H),3.53(t,J=5.6Hz,2H),2.28(d,J=1.8Hz,2H),1.47(s,9H).

[0670] Step E: tert-Butyl 6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate-2,2-d2

[0671] To a solution of tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate (2.20 g, 5.16 mmol, 1.0 equiv) and AIBN (254 mg, 1.55 mmol, 0.3 equiv) in toluene (30.0 mL) was added tributyltin hydride (9.01 g, 8.38 mL, 31.0 mmol, 6.0 equiv). The reaction mixture was stirred in a sealed tube at 120 ° C for 16 hours. After cooling to room temperature, the mixture was quenched by KF aqueous solution (30 mL) and stirred for 2 hours. After filtration, the filtrate was extracted with EA (50 mL × 3). The organic phase was washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate in petroleum ether, 0% to 33%) to give tert-butyl 6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate-2,2-d2 (1.50 g, 83% yield) as a white solid. LC-MS (ESI): C 19 H 21 Calculated molecular weight of D2NO5, 347.41; observed m / z, 292.2 [M-55] + . 1 H NMR (400MHz, DMSO-d6) δ7.52(d,J=7.6Hz,1H),7.38(d,J=7.6Hz,1H),5.36(s,2H),3.95( d,J=12.2Hz,2H),2.91-2.87(s,2H),1.85-1.77(m,2H),1.71-1.67(m,2H),1.42(s,9H).

[0672] Step F: 1'-(tert-Butoxycarbonyl)-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid-2,2-d2

[0673] To a solution of tert-butyl 6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate-2,2-d2 (600 mg, 1.73 mmol, 1.0 equiv) in THF (12.0 mL), MeOH (12.0 mL), and H2O (4.00 mL) was added NaOH (138 mg, 3.45 mmol, 2.0 equiv). The reaction mixture was stirred at 40°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EA (40 mL), adjusted to pH 4-5 with aqueous HCl (3N), and extracted with EA (50 mL x 4). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1'-(tert-butoxycarbonyl)-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid-2,2-d2 acid (600 mg, 95% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 23 The calculated molecular weight of D2NO6 is 365.42; the observed m / z is 364.3 [MH] - .

[0674] Step G: tert-Butyl 8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate-2,2-d2

[0675] At 25 ° C, to a DCM (20.0 mL) solution of 1'-(tert-butoxycarbonyl)-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid-2,2-d2 acid (1.50 g, 4.10 mmol, 1.0 equivalent), active manganese dioxide (7.14 g, 82.1 mmol, 20.0 equivalents) was added. The reaction mixture was stirred at 25 ° C for 4 hours. After filtering through a short silica gel column, the filtrate was collected and concentrated under reduced pressure to give tert-butyl 8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate-2,2-d2 (760 mg, 52% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 21 Calculated molecular weight of D2NO6, 363.41; observed m / z, 364.3 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ8.09(s,1H),7.55(d,J=7.6Hz,1H),7.33(d,J=7.6Hz,1H),6.65(s, 1H), 3.95 (d, J = 12.2Hz, 2H), 2.89 (s, 2H), 1.83-1.78 (m, 2H), 1.70-1.67 (m, 2H), 1.43 (s, 9H).

[0676] Step H: Tert-butyl (S)-7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate-2,2-d2

[0677] To a solution of tert-butyl 8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate-2,2-d2 (350 mg, 963 μmol, 1.0 equiv) and (S)-tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride (460 mg, 1.93 mmol, 2.0 equiv) in DMF (10.0 mL) was added acetic acid (578 mg, 554 μL, 9.63 mmol, 10.0 equiv). The reaction mixture was stirred at 40°C for 2 hours, followed by the addition of sodium triacetoxyborohydride (4.08 g, 19.3 mmol, 20.0 equiv). The mixture was stirred at 40°C for 16 hours. After cooling to room temperature, the mixture was dissolved in EA (40 mL), washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (ethyl acetate in petroleum ether, from 0% to 90%) to obtain tert-butyl (S) -7- (1-amino-5- (tert-butoxy) -1,5-dioxopentan-2-yl) -6-oxo-7,8-dihydro -2H, 6H-spiro [furo [2,3-e] isoindole -3,4'-piperidine] -1'-carboxylate -2,2-d2 (300 mg, 58% yield) as a white solid. LC-MS (ESI): C 28 H 37 Calculated molecular weight of D2N3O7, 531.65; observed m / z, 532.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.60(s,1H),7.45(d,J=7.6Hz,1H),7.30(d,J=7.6H z,1H),7.23(s,1H),4.77-4.73(m,1H),4.56(d,J=17.2Hz,1H),4.45(d,J=1 7.2Hz,1H),4.00(d,J=12.8Hz,2H),2.96(s,2H),2.23-2.20(m,3H),2.09-2 .02(m,1H),1.97-1.84(m,2H),1.82-1.74(m,2H),1.49(s,9H),1.38(s,9H).

[0678] Step I: (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl-2,2-d2)piperidine-2,6-dionebenzenesulfonate

[0679] To a solution of tert-butyl (S)-7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate-2,2-d2 (350 mg, 660 μmol, 1.0 equiv) in MeCN (10.0 mL) was added anhydrous benzenesulfonic acid (313 mg, 1.98 mmol, 3.0 equiv) and the reaction mixture was stirred at 90 °C for 7 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was slurried with acetonitrile (10 mL) to give (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl-2,2-d2)piperidine-2,6-dionebenzenesulfonate (300 mg, 88% yield) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 25 H 25 Calculated molecular weight of D2N3O7S, 515.58; observed m / z, 358.3 [M+H] + .

[0680] Intermediate B4: (S)-tert-Butyl 5-amino-4-(5-fluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidinyl]-7-yl)-5-oxopentanoate

[0681]

[0682] Step A: 4-Bromo-2-fluoro-5-hydroxybenzoic acid

[0683] To a solution of 2-fluoro-5-hydroxybenzoic acid (10.0 g, 1.0 eq) in MeCN (100 mL) at room temperature was added TsOH (10.1 g, 1.0 eq). The mixture was stirred for 10 minutes and then added dropwise to a solution of NBS (11.4 g, 1.1 eq) in MeCN (50 mL) over 20 minutes. The reaction mixture was stirred at room temperature overnight and concentrated to give the crude title compound (15.0 g), which was used in the next step without further purification.

[0684] Step B: Methyl 4-bromo-2-fluoro-5-hydroxybenzoate

[0685] To a solution of 4-bromo-2-fluoro-5-hydroxybenzoic acid (crude product, 15.0 g, 1.0 equivalent) in MeOH (100 mL) was added 2,2-dimethoxypropane (18.3 g, 3.0 equivalents) at room temperature. The reaction mixture was stirred at 60 ° C overnight. It was then cooled to room temperature and concentrated. The residue was purified by flash column chromatography (PE / EA) to give the title compound (600 mg).

[0686] Step C: Methyl 4-bromo-6-fluoro-2-formyl-3-hydroxybenzoate

[0687] At 20 DEG C, to 4-bromo-2-fluoro-5-hydroxybenzoic acid methyl ester (249mg, 1mmol, 1 equivalent) in TFA (5mL), HMTA (560mg, 4mmol, 4 equivalents) was added. The mixture was stirred at 125 DEG C for 12 hours. TLC (petroleum ether / ethyl acetate=5 / 1) indicated that the starting material was completely consumed, and the desired product appeared. The mixture was quenched with 2N HCl (5V) to form a yellow solid. The mixture was stirred for 10 minutes, then additional water (5V) was added and stirred for 1 hour. The mixture was filtered. The filter cake was dissolved in DCM, filtered on diatomaceous earth, dried, and most of the solvent was removed in vacuo. The title compound (110mg, 0.4mmol, 40% yield) was obtained as a gray solid.

[0688] 1 H NMR (400 MHz, chloroform-d) δ 12.28 (s, 1H), 10.08 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 4.01 (s, 3H). LC-MS (m / z): [MH] + =274.99.

[0689] Step D: (S)-tert-Butyl 5-amino-4-(5-bromo-7-fluoro-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate

[0690] At 20 DEG C, add (S) -4,5- diamino -5- oxopentanoic acid tert-butyl ester (212mg, 1.05mmol, 1.05 equivalents, HCl) in MeOH (5mL).Afterwards at the same temperature, DIEA (1.05mmol, 1.05 equivalents), 4- bromo -6- fluoro -2- formyl -3- hydroxybenzoic acid methyl esters (277mg, 1mmol, 1 equivalent) and AcOH (1.5mmol, 1.5 equivalents) are added in the mixture. After 1.5 hours, by NaBH cN (2mmol, 2 equivalents) is added in the mixture portionwise, and the mixture is stirred at 20 DEG C for 3 hours. After the reaction is complete, by adding H at 20 DEG C o quenching reaction mixture, then concentrating under reduced pressure to remove MeOH. Afterwards, extract the mixture with EtOAc. Wash the organic layer merged with salt solution (200mLx2), through Na sO drying, filtration and under reduced pressure concentration, to obtain residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 1 to ethyl acetate) to obtain the title compound (293 mg, 0.68 mmol, 65% yield) as a yellow solid.

[0691] Step E: (S)-benzyl 4-(((2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0692] At 20 ° C, (S) -5-amino-4- (5-bromo-7-fluoro-4-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoic acid tert-butyl ester (202 mg, 0.47 mmol, 1 equivalent), 4- (chloromethyl) -3,6-dihydropyridine -1 (2H) -carboxylic acid benzyl ester (280 mg, 0.49 mmol, 1.05 equivalents) and K2CO3 (194 mg, 1.41 mmol, 3 equivalents) were added to DMF (5 mL). The mixture was then stirred at 60 ° C for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a residue, to which water (20 mL) was added. The product was extracted with DCM (20 mL × 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to give the title compound (194 mg, 60% yield) as a yellow solid.

[0693] Step F: (S)-7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-fluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylic acid benzyl ester

[0694] (S)-4-(((2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (330 mg, 0.5 mmol, 1 eq), BuSnH (614 mg, 2 mmol) and AIBN (8.2 mg, 0.05 mmol, 0.1 eq) were added to toluene (5 mL) at 20 ° C, and the mixture was stirred at 110 ° C for 12 hours. After the reaction was complete, the mixture was quenched by adding saturated potassium fluoride solution and stirred for 1 hour. The product was extracted with EA. The organic layer was dried over NaSO and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography to give the title compound (84 mg, 29% yield) as a yellow solid.

[0695] 1 H NMR (400MHz, CDCl3) δ7.38-7.31(m,5H),6.84(d,J=8.4Hz,1H),6.40(s,1H),5.35(s,1H),5.16(s,2H),4.85(dd,J=8.9,6.1Hz,1H),4.52(s,2H), 4.48(d,J=17.2Hz,1H),4.36(d,J=17.2Hz,1H),4.20(brs,2H),4.12(q, J=7.1Hz,1H),2.94(m,2H),2.37-2.16(m,6H),1.76(m,2H),1.42(s,9H).

[0696] Step G: (S)-tert-Butyl 5-amino-4-(5-fluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)-5-oxopentanoate

[0697] To a 100 mL flask equipped with a magnetic stirrer was added (S) -7- (1- amino -5- (tert-butoxy) -1,5- dioxopentan -2- yl) -5- fluoro -6- oxo -7,8- dihydro -2H, 6H- spiro [furo [2,3-e] isoindole -3,4'- piperidine] -1'- carboxylic acid benzyl ester (200 mg), MeOH (10 mL), followed by 10% Pd / C (20 mg). After flushing the flask with hydrogen, a hydrogen balloon was connected and the reaction mixture was stirred for 2 hours. When the starting material was completely consumed as monitored by TLC (DCM: MeOH = 10: 1), the reaction mixture was filtered through celite and washed with additional MeOH. The solvent was removed and the residual title compound (120 mg) as a white solid was used directly in the next step.

[0698] Intermediate B5: (S)-3-(5-chloro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0699]

[0700] Step A: (S)-tert-Butyl 7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate

[0701] To a mixture of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (100 mg, 0.28 mmol, 1.0 equiv) and TEA (85 mg, 0.84 mmol, 3 equiv) in anhydrous DCM (10 mL) was slowly added di-tert-butyl dicarbonate (123 mg, 0.56 mmol, 2.0 equiv). The mixture was stirred at room temperature for 5 hours under an N2 atmosphere. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (15 mL×3). The organic layer was washed with brine (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50%) to afford tert-butyl (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate as a pale yellow solid (120 mg, 94% yield). LC-MS (ESI): Molecular weight calculated for C₂₄H₂₆N₃O₆: 455; m / z observed, 456.2 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ10.97(s,1H),7.42(d,J=7.6Hz,1H),7.27(d,J=7.6Hz,1H),5.11-5.06(m,1H),4 .65-4.50(m,2H),4.39(d,J=17.2Hz,1H),4.22(d,J=17.2Hz,1H),3.94(d,J=11.2Hz,2H),3.07-2.76(m,3H ), 2.62-2.56 (m, 1H), 2.42-2.33 (m, 1H), 2.05-1.91 (m, 1H), 1.88-1.76 (m, 2H), 1.70 (d, J = 10.6 Hz, 2H), 1.43 (s, 9H) Step B: (S)-5-chloro-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-1'-carboxylic acid tert-butyl ester

[0702] To a solution of (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (60 mg, 132 μmol, 1.0 equiv) in anhydrous ACN (5.0 mL) was added NCS (18 mg, 132 μmol, 1.0 equiv) and the mixture was stirred at room temperature under N2 atmosphere for 6 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (15 mL × 3). The organic layer was washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50%) to give (S)-tert-butyl 4-chloro-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate (60.0 mg, 93% yield) as a pale yellow solid. LC-MS (ESI): C 24 H 28 The calculated molecular weight of ClN3O6 is 489; the observed m / z is 490.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),7.62(s,1H),5.20-5.15(m,1H),4.80-4.67(m,1H),4.47(d,J=17.4Hz,1H),4.30(d,J=17.4Hz,1H),4.15 -4.05(m,2H),3.10-2.91(m,3H),2.65-2.611(m,1H),2.53-2.45(m,1H) ,2.11-2.06(m,1H),2.03-1.94(m,2H),1.86-1.75(m,2H),1.56(s,9H).

[0703] Step C: (S)-3-(5-chloro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0704] To a solution of (S)-tert-butyl 7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (50 mg, 110 μmol, 1.0 equiv) in EA (5.0 mL) was added HCl-dihydro-1,4-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate. alkane (4N) (0.25 mL, 1.00 mmol, 10.0 equiv) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give (S)-3-(4-chloro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione hydrochloride (40.0 mg, 93% yield) as a light yellow solid. LC-MS (ESI): C 19 H 20 The calculated molecular weight of ClN3O4 is 389; the observed m / z is 390.2 [M+H] + .

[0705] Intermediate B6: (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-5-carbonitrile

[0706]

[0707] Step A: 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-cyano-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylic acid (S)-tert-butyl ester

[0708] To a solution of (S)-7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (200 mg, 329 μmol, 1.0 equiv) in DMF (10.0 mL) at 25 ° C was added cuprous cyanide (88.3 mg, 986 μmol, 3.0 equiv). The reaction mixture was stirred at 140 ° C for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with DCM (30 mL × 3). The organic layer was washed with brine (30 mL × 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA=1 / 1) to give (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxolan-2-yl)-5-cyano-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate (160 mg, 88% yield) as a yellow solid. LC-MS (ESI): C 29 H 38 Calculated molecular weight of N4O7: 554.27; observed m / z: 555.3 [M+H] + .

[0709] Step B: (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-5-carbonitrile

[0710] To a solution of (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-cyano-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (160 mg, 288 μmol, 1.0 equiv) in MeCN (5.0 mL) was added anhydrous benzenesulfonic acid (151.4 mg, 288 μmol, 3.0 equiv) at 0° C. The reaction mixture was stirred at 80° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-5-carbonitrile (20.0 mg, 18% yield) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 20 H 20Calculated molecular weight of N4O4: 380.15; observed m / z: 381.2 [M+H] + .

[0711] Intermediate B7: (S)-3-(5-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0712]

[0713] Step A: (S)-tert-Butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate

[0714] To a solution of (S)-7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (200 mg, 378 μmol, 1.0 equiv) in MeCN (5.0 mL) at 25 ° C., NBS (67.2 mg, 378 μmol, 1.0 equiv) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL×3). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA=2 / 1) to give (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxolan-2-yl)-5-bromo-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate (180 mg, 78% yield) as a white solid. LC-MS (ESI): C 28 H 38 Calculated molecular weight of BrN3O7: 607.2; observed m / z: 608.2 [M+H] + .

[0715] Step B: (S)-tert-Butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate

[0716] To a 1,4-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylic acid tert-butyl ester (200 mg, 329 μmol, 1.0 equiv), potassium carbonate (136 mg, 986 μmol, 3.0 equiv) and Pd(dppf)Cl2 (48.1 mg, 65.7 μmol, 0.2 equiv) was added 1,4-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate at 25°C was added tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate (200 mg, 329 μmol, 1.0 equiv). The mixture was stirred at 25°C for 1 hr. 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane (82.5 mg, 657 μmol, 2.0 equiv) was added to a solution of oxane (5.0 mL) and water (0.5 mL). The reaction mixture was stirred at 80°C under N2 for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1 / 1) to give (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate (141 mg, 79% yield) as a yellow solid. LC-MS (ESI): C 29 H 41 Calculated molecular weight of N3O7: 543.3; observed m / z: 544.3 [M+H] + Step C: (S)-3-(5-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0717] To a solution of (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (141 mg, 259 μmol, 1.0 equiv) in MeCN (5.0 mL) was added benzenesulfonic acid (123 mg, 778 μmol, 3.0 equiv) at 25° C. The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give (S)-3-(5-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dionebenzenesulfonic acid (360 mg, 79% yield, 30% purity) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 20 H 23 Calculated molecular weight of N3O4: 369.2; observed m / z: 370.2 [M+H] + .

[0718] Intermediate B8: 3-(3'-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0719]

[0720] Step A: tert-Butyl 4-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate

[0721] At 0 ° C, to a solution of trimethyl (oxo) sulfoxide iodide (8.25g, 37.5mmol, 4.0 equivalents) in DMSO (10.0mL), NaH (60% suspension in oil) (1.5g, 37.5mmol, 4.0 equivalents) was added, and the mixture was stirred under N2 and room temperature for 1 hour. Afterwards, tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (2.00g, 9.38mmol, 1.0 equivalents) was added to the above mixture, and the resulting mixture was stirred under N2 and room temperature for 16 hours. The reaction mixture was quenched with ice water (50mL) and extracted with EA (100mL×3). The organic layer was washed with brine (100mL×4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 20% to 50%) to give tert-butyl 4-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (400 mg, 19% yield) as a pale yellow solid. LC-MS (ESI): C 12 H21 Calculated molecular weight of NO3, 227.30; observed m / z, 172.1 [M-55] + . 1 H NMR (400MHz, DMSO-d6) δ3.48-3.40(m,3H),3.14(s,1H),2.75(d,J=4.6Hz,1H),2.55( dd,J=12.0,8.6Hz,1H),1.73(s,1H),1.52(s,2H),1.41(s,9H),0.75(d,J=6.8Hz,3H).

[0722] Step B: tert-Butyl 4-(hydroxymethyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate

[0723] To a solution of tert-butyl 4-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.00 g, 4.40 mmol, 1.0 equivalent) in toluene (10.0 mL), aluminum isopropoxide (2.70 g, 2.60 mL, 13.2 mmol, 3.0 equivalents) was added. The mixture was stirred at N2 and 110 ° C for 16 hours. After the reaction mixture was cooled to room temperature, it was adjusted to pH = 4-5 with aqueous HCl solution (3N) and extracted with EA (50 mL × 3). The organic layer was washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (ethyl acetate in petroleum ether, 20% to 50%) to give tert-butyl 4-(hydroxymethyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate (850 mg, 85% yield) as a light yellow oil. LC-MS: No MS signal under normal conditions. LC-MS (ESI): C 12 H 21 The calculated molecular weight of NO3 is 227.30; the experimental m / z value is no MS signal.

[0724] Step C: tert-Butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate

[0725] To a solution of 5-bromo-4-hydroxyisobenzofuran-1(3H)-one (420 mg, 1.83 mmol, 1.0 equiv) in THF (20.0 mL) was added triphenylphosphine (721 mg, 2.75 mmol, 1.5 equiv) and tert-butyl 4-(hydroxymethyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate (417 mg, 1.83 mmol, 1.0 equiv). The mixture was stirred under N2 at 0°C for 20 minutes, after which DIAD (556 mg, 535 μL, 2.75 mmol, 1.5 equiv) was added dropwise to the mixture. The resulting mixture was stirred at room temperature overnight. After evaporation, the crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 20%) to afford tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate (180 mg, 22% product) as a yellow oil. LC-MS (ESI): C 20 H 24 Calculated molecular weight of BrNO5, 438.32; observed m / z, 342.0 [M-55] + .

[0726] Step D: tert-Butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate

[0727] To a solution of tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate (180 mg, 411 μmol, 1.0 equiv) and AIBN (13.5 mg, 82.1 μmol, 0.2 equiv) in toluene (20.0 mL) was added tributyltin hydride (478 mg, 444 μL, 1.64 mmol, 4.0 equiv). The reaction was stirred under N2 at 110°C for 16 hours. After cooling to room temperature, the mixture was quenched with saturated aqueous KF solution (30 mL) and stirred for 1 hour. The reaction mixture was extracted with EA (30 mL x 3). The organic phases were combined, washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The mixture was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 30%) to give tert-butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate as a white solid (120 mg, 81% yield). LC-MS (ESI): C 20 H 25Calculated molecular weight of NO5, 359.42; observed m / z, 304.0 [M-55] + . 1 H NMR (400MHz, DMSO-d6) δ7.47(d,J=7.6Hz,1H),7.40(d,J=7.6Hz,1H),5.36(d,J=2.4Hz,2H),4.79(d,J=9.8Hz,1H),4.48(d,J=9. 8Hz,1H),3.99-3.77(m,2H),3.04-2.66(m,2H),2.01(d,J=10.8Hz,3H),1.97-1.87(m,2H),1.77(d,J=13.2Hz,1H),1.43(s,9H).

[0728] Step E: tert-Butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate

[0729] To a solution of tert-butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (110 mg, 306 μmol, 1.0 equiv) in THF (9.00 mL), MeOH (9.00 mL) and H2O (3.00 mL) was added NaOH (24 mg, 612 μmol, 2.0 equiv). The reaction mixture was stirred at 40°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EA (20 mL), adjusted to pH 4-5 with aqueous HCl (3N), and extracted with EA (40 mL x 4). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (110 mg, 90% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 20 H 27 Calculated molecular weight of NO6, 377.44; experimental m / z, 376.4 [MH] - Step F: 1'-(tert-Butoxycarbonyl)-7-formyl-3'-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid

[0730] A mixture of 1'-(tert-butoxycarbonyl)-7-(hydroxymethyl)-3'-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (110 mg, 291 μmol, 1.0 equivalent) and active manganese dioxide (507 mg, 5.83 mmol, 20.0 equivalent) in DCM (20.0 mL) was stirred at room temperature for 16 hours. After filtering through a short column, the filtrate was collected and concentrated under reduced pressure to give 1'-(tert-butoxycarbonyl)-7-formyl-3'-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (100 mg, 91% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 20 H 25 Calculated molecular weight of NO6, 375.42; observed m / z, 376.1 [M+H] + .

[0731] Step G: tert-Butyl 7-(2,6-dioxopiperidin-3-yl)-3'-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate

[0732] To a solution of 1'-(tert-butoxycarbonyl)-7-formyl-3'-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (110 mg, 293 μmol, 1.0 equiv) and 3-aminopiperidine-2,6-dione hydrochloride (96.5 mg, 586 μmol, 2.0 equiv) in DMF (10.0 mL) was added acetic acid (0.52 g, 0.50 mL, 8.7 mmol, 30.0 equiv), and the reaction mixture was stirred at 40°C for 2 hours. Sodium triacetoxyborohydride (186 mg, 879 μmol, 3.0 equiv) was then added to the mixture, and the mixture was stirred at 40°C for 16 hours. After cooling to room temperature, the mixture was dissolved in EA (40 mL), washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3'-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (80.0 mg, 58% yield) as a gray solid. LC-MS (ESI): C 25 H 31 Calculated molecular weight of N3O6, 469.54; observed m / z, 470.2 [M+H] + .

[0733] Step H: 3-(3'-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0734] To a solution of tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3'-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (70.0 mg, 149 μmol, 1.0 equiv) in DCM (3 mL) was added HCl-dihydro-1'-carboxylate dropwise at room temperature. alkane (4N) (8.0mL, 32mmol, 10.4 equivalents). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3- (3'-methyl-6-oxo-6,8-dihydro-2H, 7H-spiro [furo [2,3-e] isoindole-3,4'-piperidin] -7-yl) piperidine-2,6-dione (30.0mg, 54% yield) as a gray solid. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 20 H 23 Calculated molecular weight of N3O4, 369.42; observed m / z, 370.1 [M+H] + .

[0735] Intermediate B9: 3-(3'-hydroxy-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0736]

[0737] Step A: 1'-(tert-Butoxycarbonyl)-3'-hydroxy-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid

[0738] To a mixture of tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (400 mg, 1.11 mmol, 1.0 eq) in THF (9.00 mL), MeOH (9.00 mL) and H2O (3.00 mL) was added NaOH (89 mg, 2.21 mmol, 2.0 eq), and the reaction mixture was stirred at 40°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EA (20 mL), adjusted to pH = 4-5 with aqueous HCl solution (3N), and extracted with EA (40 mL x 4). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1'-(tert-butoxycarbonyl)-3'-hydroxy-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (400 mg, 95% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 25 Calculated molecular weight of NO7, 379.41; experimental m / z, 378.3 [MH] - .

[0739] Step B: 1'-(tert-Butoxycarbonyl)-7-formyl-3'-hydroxy-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid

[0740] A mixture of 1'-(tert-butoxycarbonyl)-3'-hydroxy-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (420 mg, 1.11 mmol, 1.0 equivalent) and active manganese dioxide (1.92 g, 22.1 mmol, 20.0 equivalents) in DCM (40.0 mL) was stirred at room temperature for 16 hours. After filtering through a short column, the filtrate was collected and concentrated under reduced pressure to give 1'-(tert-butoxycarbonyl)-7-formyl-3'-hydroxy-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (260 mg, 62% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 21 Calculated molecular weight of F2NO6, 377.39; observed m / z, 378.1 [M+H] + .

[0741] Step C: tert-Butyl 7-(2,6-dioxopiperidin-3-yl)-3'-hydroxy-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate

[0742] To a solution of 1'-(tert-butoxycarbonyl)-7-formyl-3'-hydroxy-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (260 mg, 689 μmol, 1.0 eq) and 3-aminopiperidine-2,6-dione hydrochloride (227 mg, 1.38 mmol, 2.0 eq) in DMF (10.0 mL) was added acetic acid (1.0 mL), and the reaction mixture was stirred at 40 ° C for 2 hours. Sodium triacetoxyborohydride (438 mg, 2.07 mmol, 3.0 eq) was added to the above mixture, and the resulting mixture was stirred at 40 ° C for 16 hours. After cooling to room temperature, the mixture was dissolved in EA (40 mL), washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH in DCM, 10%) to give tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3'-hydroxy-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (260 mg, 80% yield) as a gray solid. LC-MS (ESI): C 24 H 29 Calculated molecular weight of N3O7, 471.51; observed m / z, 472.2 [M+H] + .

[0743] Step D: 3-(3'-Hydroxy-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0744] To 7- (2,6- dioxopiperidin-3-yl) -3'-hydroxy -6- oxo -7,8- dihydro -2H, 6H- spiral [furo [2,3-e] isoindole -3,4'- piperidine] -1'- carboxylic acid tert-butyl ester (260mg, 551 μmol, 1.0 equivalent) in DCM (5.0mL) solution, TFA (1.7mL, 22.1mmol, 40.0 equivalent) is added, and the reaction mixture is stirred at room temperature for 6 hours. The mixture is carefully concentrated under reduced pressure to give 3- (3'-hydroxy -6- oxo -6,8- dihydro -2H, 7H- spiral [furo [2,3-e] isoindole -3,4'- piperidine] -7-yl) piperidine -2,6- dione trifluoroacetate (100mg, 48% yield) as a yellow oil. The crude product is used directly in the next step without further purification. LC-MS(ESI):C 19 H 21 Calculated molecular weight of N3O5, 371.39; observed m / z, 372.2 [M+H] + .

[0745] Intermediate B10. 3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0746]

[0747] Step A: tert-Butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0748] To a solution of 5-bromo-4-hydroxyisobenzofuran-1(3H)-one (5.0 g, 21.80 mmol, 1.0 equiv) in THF (150 mL) were added tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (5.59 g, 26.2 mmol, 1.2 equiv) and triphenylphosphine (8.59 g, 32.7 mmol, 7.31 mL, 1.5 equiv). The mixture was stirred at 0°C under N2 for 20 minutes. DIAD (6.62 g, 32.7 mmol, 6.37 mL, 1.5 equiv) was then added dropwise to the mixture, and the mixture was stirred at room temperature overnight. After evaporation, the crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 20%) to give tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (9.0 g, 97% yield) as a yellow solid. LC-MS (ESI): C 19 H 22 Calculated molecular weight of BrNO5, 424.29; observed m / z, 369.9 [M+H-56] + . 1 H NMR (400MHz, DMSO-d6) δ7.83(d,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),5.89(s,1H),5.66( s,2H),4.66(s,2H),3.88(s,2H),3.48(dd,J=14.6,9.0Hz,2H),2.22(s,2H),1.41(s,9H).

[0749] Step B: tert-Butyl 6-oxo-2',3',6,8-tetrahydro-1'H,2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate

[0750] To a solution of tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (5.00 g, 7.90 mmol, 1.0 equiv) in DMF (30.0 mL) was added sodium formate (591 mg, 8.69 mmol, 1.1 equiv), palladium diacetate (177 mg, 790 μmol, 0.1 equiv), sodium acetate (1.62 g, 19.7 mmol, 2.5 equiv) and TEA (1.44 g, 8.69 mmol, 1.33 mL, 1.1 equiv). The mixture was stirred under N2 at 70°C for 16 hours. After cooling to room temperature, the mixture was filtered and the filter cake was washed with EA (100 mL). The filtrate was washed with brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 30%) to give tert-butyl 6-oxo-2',3',6,8-tetrahydro-1'H,2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate (1.70 g, 62.7% yield) as a colorless oil. LC-MS (ESI): C 19 H 21 Calculated molecular weight of NO5, 343.38; observed m / z, 344.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.41(d,J=7.6Hz,1H),7.34(d,J=7.6Hz,1H),7.03-6.98(m,1H),5.38(s,2H),4.88-4.82(m,1H),4.60(d ,J=9.2Hz,1H),4.39(d,J=9.2Hz,1H),3.81-3.75(m,1H),3.47-3.41(m,1H),2.02-1.98(m,1H),1.84-1.78(m,1H),1.47(s,9H).

[0751] Step C: tert-Butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate

[0752] To a solution of tert-butyl 6-oxo-2', 3', 6,8-tetrahydro-1'H, 2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate (4.70 g, 13.7 mmol, 1.0 equivalent) in THF (60.0 mL) at N2 and -78 ° C, BH3-THF (1N) (34.2 mL, 34.2 mmol, 2.5 equivalents) was added. The reaction was slowly heated to 0 ° C and stirred at 0 ° C for 5 hours. Water (5 mL) was added to the above mixture, followed by sodium perborate (5.60 g, 68.4 mmol, 5.0 equivalents). The resulting mixture was stirred overnight. The mixture was diluted with DCM (100 mL), washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 40%) to give tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate as a white powder (2.70 g, 54% yield). LC-MS (ESI): C 19 H 23 Calculated molecular weight of NO6, 361.39; observed m / z, 306.1 [M+H-56] + . 1 H NMR (400MHz, DMSO-d6) δ7.51(d,J=7.6Hz,1H),7.37(d,J=7.6Hz,1H),5.35(d,J=2.6Hz,2H),5.31(d,J=4.6Hz,1H),4.83(d,J=9. 0Hz, 1H), 4.53 (d, J = 9.0Hz, 1H), 4.01 (s, 1H), 3.87 (s, 1H), 3.76-3.73 (m, 1H), 2.83-2.56 (m, 2H), 1.88-1.74 (m, 2H), 1.43 (s, 9H).

[0753] Step D: tert-Butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate

[0754] To a solution of tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.80 g, 4.98 mmol, 1.0 equivalent) in DCM (30.0 mL) was added Dess-Martin periodinane (5.28 g, 12.5 mmol, 2.5 equivalents). The mixture was stirred at room temperature for 4 hours. The reaction was diluted with DCM (60 mL), washed with aqueous sodium thiosulfate (30 mL x 2) and washed with brine (40 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 40%) to give tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.3 g, 72.6% yield) as a colorless oil. LC-MS (ESI): C 19 H 21 Calculated molecular weight of NO6, 359.38; observed m / z, 360.1 [M+H] + .

[0755] Step E: tert-Butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate

[0756] To a solution of tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.20 g, 3.34 mmol, 1.0 equiv), triethylammonium fluoride (3.23 g, 3.27 mL, 20.0 mmol, 6.0 equiv) and N,N-diethyl-S,S-difluoro-sulfilimine tetrafluoroborate (3.44 g, 15.0 mmol, 4.5 equiv) in DCM (50.0 mL) at 25° C. was added TEA (845 mg, 1.16 mL, 8.35 mmol, 2.5 equiv) and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO solution (30 mL) and extracted with DCM (30 mL×3). The separated organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 30%) to give 3',3'-difluoro-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate tert-butyl ester (260 mg, 20% yield) as a yellow oil. LC-MS (ESI): C19 H 21 Calculated molecular weight of F2NO5, 381.38; observed m / z, 382.1 [M+H] + .

[0757] Step F: 1'-(tert-Butoxycarbonyl)-3',3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid

[0758] To a solution of tert-butyl 3',3'-difluoro-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (280 mg, 734 μmol, 1.0 eq) in THF (9.00 mL), MeOH (9.00 mL), and H2O (3.00 mL) was added NaOH (44 mg, 1.10 mmol, 1.5 eq). The mixture was stirred at 40°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EA (20 mL), adjusted to pH 4-5 with HCl solution (3N), and extracted with EA (40 mL x 4). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to a colorless oil of 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (290 mg, 99% yield). The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 23 Calculated molecular weight of F2NO6, 399.39; observed m / z, 398.3 [MH] - .

[0759] Step G: 1'-(tert-Butoxycarbonyl)-3',3'-difluoro-7-formyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid

[0760] A solution of 1'-(tert-butoxycarbonyl)-3', 3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (260 mg, 651 μmol, 1.0 equivalent) and active manganese dioxide (1.13 g, 13.0 mmol, 20.0 equivalents) in DCM (20.0 mL) was stirred at room temperature for 16 hours. After filtering through a short column, the filtrate was collected and concentrated under reduced pressure to give 1'-(tert-butoxycarbonyl)-3', 3'-difluoro-7-formyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (250 mg, 96.6% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H21 Calculated molecular weight of F2NO6, 397.37; observed m / z, 398.1 [M+H] + .

[0761] Step H: tert-Butyl 7-(2,6-dioxopiperidin-3-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate

[0762] To a solution of 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-formyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (260 mg, 654 μmol, 1.0 equiv) and 3-aminopiperidine-2,6-dione hydrochloride (215 mg, 1.31 mmol, 2.0 equiv) in DMF (10.0 mL) was added acetic acid (0.52 g, 0.50 mL, 8.7 mmol, 13.0 equiv) and the reaction was stirred at 40°C for 2 hours. Sodium triacetoxyborohydride (416 mg, 1.96 mmol, 3.0 equiv) was added to the above mixture, and the resulting mixture was stirred at 40°C for 16 hours. After cooling to room temperature, the mixture was dissolved with EA (60 mL), washed with brine (30 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 90%) to give tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (220 mg, 68.4% yield) as a gray solid. LC-MS (ESI): C 24 H 27 Calculated molecular weight of F2N3O6, 491.49; observed m / z, 492.2 [M+H] + .

[0763] Step I: Obtain 3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0764] To a solution of tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (200 mg, 407 μmol, 1.0 equiv) in DCM (5.00 mL) was added trifluoroacetic acid (2.99 g, 2.00 mL, 26.3 mmol, 64.5 equiv) and the reaction was stirred at 25 °C for 1 hour. The mixture was concentrated and dried to give 3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione trifluoroacetate (150 mg, 94% yield) as a gray solid. LC-MS (ESI): C 19 H 19 Calculated molecular weight of F2N3O4, 391.37; observed m / z, 392.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.99 (d, J = 4.4Hz, 1H), 9.67 (s, 1H), 7.48-7.37 (m, 2H), 5. 16-4.96(m,2H),4.74-4.63(m,1H),4.44(t,J=17.0Hz,1H),4.27(t,J=16.6Hz,1H), 3.93-3.71(m,2H),3.03(t,J=12.0Hz,1H),2.97-2.83(m,1H),2.60(d,J=17.2Hz,1 H), 2.46-2.40 (m, 2H), 2.26-2.23 (m, 1H), 2.08 (d, J = 5.0Hz, 1H), 2.00-1.98 (m, 1H).

[0765] Intermediate B11: (3S)-3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0766]

[0767] Step A: tert-Butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0768] To a solution of 5-bromo-4-hydroxyisobenzofuran-1(3H)-one (10.0 g, 43.60 mmol, 1.0 equiv) in THF (300 mL) were added tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (11.18 g, 52.4 mmol, 1.2 equiv) and triphenylphosphine (17.18 g, 65.4 mmol, 14.62 mL, 1.5 equiv). The mixture was stirred at 0°C under N2 for 20 minutes. DIAD (13.24 g, 65.4 mmol, 12.74 mL, 1.5 equiv) was then added dropwise to the mixture, and the mixture was stirred at room temperature overnight. After evaporation, the crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 20%) to afford tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (18.0 g, 97% yield) as a yellow solid. LC-MS (ESI): C 19 H 22 Calculated molecular weight of BrNO5, 424.29; observed m / z, 369.9 [M+H-56] + . 1 H NMR (400MHz, DMSO-d6) δ7.83(d,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),5.89(s,1H),5.66( s,2H),4.66(s,2H),3.88(s,2H),3.48(dd,J=14.6,9.0Hz,2H),2.22(s,2H),1.41(s,9H).

[0769] Step B: tert-Butyl 6-oxo-2',3',6,8-tetrahydro-1'H,2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate

[0770] To a solution of tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (15.00 g, 23.70 mmol, 1.0 equiv) in DMF (90.0 mL) were added sodium formate (1.77 g, 26.07 mmol, 1.1 equiv), palladium diacetate (531 mg, 2.37 mmol, 0.1 equiv), sodium acetate (4.86 g, 59.1 mmol, 2.5 equiv) and TEA (4.32 g, 26.07 mmol, 3.99 mL, 1.1 equiv). The mixture was stirred at 70° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered and the filter cake was washed with EA (300 mL). The filtrate was washed with brine (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 30%) to give tert-butyl 6-oxo-2', 3', 6,8-tetrahydro-1'H, 2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate (5.10 g, 62.7% yield) as a colorless oil. LC-MS (ESI): C 19 H 21 Calculated molecular weight of NO5, 343.38; observed m / z, 344.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.41(d,J=7.6Hz,1H),7.34(d,J=7.6Hz,1H),7.03-6.98(m,1H),5.38(s,2H),4.88-4.82(m,1H),4.60(d ,J=9.2Hz,1H),4.39(d,J=9.2Hz,1H),3.81-3.75(m,1H),3.47-3.41(m,1H),2.02-1.98(m,1H),1.84-1.78(m,1H),1.47(s,9H).

[0771] Step C: tert-Butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate

[0772] To a solution of tert-butyl 6-oxo-2', 3', 6,8-tetrahydro-1'H, 2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate (5.10 g, 14.87 mmol, 1.0 equivalent) in THF (60.0 mL) under N2 and -78 ° C, BH3-THF (1N) (37.1 mL, 37.1 mmol, 2.5 equivalents) was added. The reaction was slowly heated to 0 ° C and stirred at 0 ° C for 5 hours. Water (10 mL) was added to the above mixture, followed by sodium perborate (6.07 g, 74.2 mmol, 5.0 equivalents). The resulting mixture was stirred overnight. The mixture was diluted with DCM (100 mL), washed with brine (50 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 40%) to give tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate as a white powder (2.93 g, 54% yield). LC-MS (ESI): C 19 H 23 Calculated molecular weight of NO6, 361.39; observed m / z, 306.1 [M+H-56] + . 1 H NMR (400MHz, DMSO-d6) δ7.51(d,J=7.6Hz,1H),7.37(d,J=7.6Hz,1H),5.35(d,J=2.6Hz,2H),5.31(d,J=4.6Hz,1H),4.83(d,J=9. 0Hz, 1H), 4.53 (d, J = 9.0Hz, 1H), 4.01 (s, 1H), 3.87 (s, 1H), 3.76-3.73 (m, 1H), 2.83-2.56 (m, 2H), 1.88-1.74 (m, 2H), 1.43 (s, 9H).

[0773] Step D: tert-Butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate

[0774] To a solution of tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (2.90 g, 8.10 mmol, 1.0 equiv) in DCM (60.0 mL) was added Dess-Martin periodinane (8.60 g, 20.35 mmol, 2.5 equiv). The mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with aqueous sodium thiosulfate (60 mL) and extracted with DCM (90 mL × 3). The organic layer was washed with saturated aqueous NaHCO3 (60 mL × 2), brine (40 mL × 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (2.12 g, 72.6% yield) as a colorless oil. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 19 H 21 Calculated molecular weight of NO6, 359.38; observed m / z, 360.1 [M+H] + .

[0775] Step E: tert-Butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate

[0776] To a solution of tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (2.0 g, 5.57 mmol, 1.0 equiv), triethylammonium fluoride (5.38 g, 5.44 mL, 33.4 mmol, 6.0 equiv) and N,N-diethyl-S,S-difluoro-sulfimidate tetrafluoroborate (XtalFluor-E) (5.73 g, 25.0 mmol, 4.5 equiv) in DCM (100.0 mL) at 0° C. was added TEA (1.41 g, 1.94 mL, 13.9 mmol, 2.5 equiv), and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO solution (60 mL) and extracted with DCM (100 mL×3). The separated organic phase was washed with brine (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 30%) to give tert-butyl 3',3'-difluoro-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.0 g, 47% yield) as a yellow oil. LC-MS (ESI): C 19 H 21 Calculated molecular weight of F2NO5, 381.38; observed m / z, 382.1 [M+H] + .

[0777] Step F: 1'-(tert-Butoxycarbonyl)-3',3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid

[0778] To a solution of tert-butyl 3',3'-difluoro-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (280 mg, 734 μmol, 1.0 eq) in THF (9.00 mL), MeOH (9.00 mL), and H2O (3.00 mL) was added NaOH (44 mg, 1.10 mmol, 1.5 eq). The mixture was stirred at 40°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EA (20 mL), adjusted to pH 4-5 with HCl solution (3N), and extracted with EA (40 mL x 4). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to a colorless oil of 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (290 mg, 99% yield). The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 23 Calculated molecular weight of F2NO6, 399.39; observed m / z, 398.3 [MH] - .

[0779] Step G: tert-Butyl 2,2-difluoro-8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate

[0780] 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (1.6g, 4.01mmol, 1.0 equivalent) and active manganese dioxide (6.97g, 80.1mmol, 20.0 equivalent) DCM (30.0mL) solution was stirred at room temperature for 16 hours. After providing short column filtration, the filtrate was collected and concentrated under reduced pressure to give 2,2-difluoro-8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (1.5g, yield 96.6%) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 21 Calculated molecular weight of F2NO6, 397.37; observed m / z, 398.1 [M+H] + .

[0781] Step H: tert-Butyl 7-((S)-1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate

[0782] To a solution of tert-butyl 3',3'-difluoro-8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.60 g, 4.03 mmol, 1.0 equiv) and tert-butyl (S)-4,5-diamino-5-oxopentanoate hydrochloride (1.92 g, 8.05 mmol, 2.0 equiv) in DMF (30.0 mL) was added acetic acid (2.42 g, 2.32 mL, 40.3 mmol, 10.0 equiv), and the reaction mixture was stirred at 40° C. for 2 hours. Sodium triacetoxyborohydride (2.56 g, 1.79 mL, 12.1 mmol, 3.0 equiv) was added to the above mixture, and the resulting mixture was stirred at 40° C. for 16 hours. After cooling to room temperature, the mixture was diluted with EA (100 mL), washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (ethyl acetate in petroleum ether, 0% to 90%) to give 7- ((S) -1- amino -5- (tert-butoxy) -1,5- dioxopentan-2-yl) -3', 3'- difluoro -6- oxo -7,8- dihydro -2H, 6H- spiro [furo [2,3-e] isoindole -3,4'- piperidine] -1'- carboxylic acid tert-butyl ester (1.80 g, 79% yield) as a white solid. LC-MS (ESI): C 28 H 37 Calculated molecular weight of F2N3O7, 565.61; observed m / z, 566.4 [M+H] + .

[0783] Step I: (3S)-3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindol-3,4'-piperidin]-7-yl)piperidine-2,6-dionebenzenesulfonate

[0784] To a solution of tert-butyl 7-((S)-1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (1.80 g, 3.18 mmol, 1.0 equiv) in MeCN (30.0 mL) was added anhydrous benzenesulfonic acid (1.51 g, 9.55 mmol, 3.0 equiv) and the reaction mixture was stirred at 90°C under N2 for 7 h. After cooling to room temperature, the mixture was concentrated and the residue was slurried with acetonitrile (30 mL) to give (3S)-3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindol-3,4'-piperidin]-7-yl)piperidine-2,6-dionebenzenesulfonate (1.20 g, 68% yield) as a white solid. LC-MS (ESI): C 19 H 19 Calculated molecular weight of F2N3O4, 391.37; observed m / z, 392.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.99(d,J=4.6Hz,1H),9.48(s,2H),7.64-7.59(m,2H),7.46(d,J=7 .6Hz,1H),7.39(d,J=7.7Hz,1H),7.35-7.29(m,3H),5.17-4.99(m,2H),4.74-4.66(m,1H),4 .43(t,J=17.2Hz,1H),4.27(t,J=17.2Hz,1H),3.98-3.72(m,2H),3.40(d,J=13.0Hz,1H),3. 06-2.88(m,2H),2.60-2.58(m,1H),2.46-2.38(m,2H),2.27-2.22(m,1H),2.01-1.98(m,1H).

[0785] Intermediate B12: 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde

[0786]

[0787] Step A: Ethyl (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate

[0788] A mixture of ethyl 4,4,4-trifluoro-3-oxobutanoate (1.00 g, 5.43 mmol, 1.0 equivalent) and acetic anhydride (1.66 g, 1.54 mL, 16.3 mmol, 3.0 equivalents) in triethyl orthoformate (8.00 mL) was stirred at 130 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure to give (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (1.20 g, 92% yield) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS: No ion signal was shown under normal conditions. LC-MS: No ion signal was shown under normal conditions. LC-MS (ESI): C9H 11 Calculated molecular weight of F3O4, 240.06; observed m / z, 241.1 [M+H] + .

[0789] Step B: Ethyl 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

[0790] At room temperature, to a solution of (Z) -2- (ethoxymethylene) -4,4,4- trifluoro -3- oxobutanoic acid ethyl ester (1.20 g, 5.00 mmol, 1.0 equivalent) in EtOH (30.0 mL) was added triethylamine (607 mg, 836 μL, 6.00 mmol, 1.2 equivalents) and (4- chlorophenyl) hydrazine hydrochloride (1.07 g, 6.00 mmol, 1.2 equivalents). The mixture was heated to 100 ° C for 5 hours. After evaporation, the residue was diluted with ethyl acetate (50 mL), washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified on silica gel by flash column chromatography (PE / EA = 50 / 1) to give 1- (4- chlorophenyl) -5- (trifluoromethyl) -1H- pyrazole -4- carboxylic acid ethyl ester (723 mg, 45% yield) as a yellow solid. LC-MS(ESI):C 11 Calculated molecular weight of H8D2F2N2O, 318.04; observed m / z, 319.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.32 (s, 1H), 7.69-7.66 (m, 2H), 7.63-7.60 (m, 2H), 4.32 (q, J = 7.2Hz, 2H), 1.31 (t, J = 7.2Hz, 3H).

[0791] Step C: (1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanol

[0792] To a solution of ethyl 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (350 mg, 1.10 mmol, 1.0 equiv) in THF (10.0 mL) at 0°C was added lithium aluminum hydride (83.4 mg, 2.20 mmol, 20 equiv). The reaction mixture was stirred at 0°C for 20 minutes. The reaction mixture was carefully quenched with Na2SO4.10H2O and stirred for 30 minutes. After filtration, the filtrate was diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3) on ice. The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give (1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (300 mg, 98% yield) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS(ESI):C 11 Calculated molecular weight of H8ClF3N2O, 276.03; observed m / z, 277.1 [M+H] + .

[0793] Step D: 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde

[0794] At room temperature, to a solution of 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (300 mg, 1.08 mmol, 1.0 equivalent) in DMSO (10.0 mL) was added IBX (759 mg, 2.71 mmol, 2.5 equivalents). The reaction mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with saturated Na2S2O3 solution (30 mL), saturated NaHCO3 solution (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Flash column chromatography was provided to purify the crude product on silica gel (PE / EA=20 / 1), providing 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxaldehyde (227 mg, 76% yield) as a yellow solid. LC-MS (ESI): C 11 Calculated molecular weight of H6ClF3N2O, 274.01; observed m / z, 275.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.07 (s, 1H), 8.44 (s, 1H), 7.70 (d, J = 8.8Hz, 2H), 7.64 (d, J = 8.8Hz, 2H).

[0795] Intermediate B13: 3-(4-chlorophenyl)iso Azole-5-carboxaldehyde

[0796]

[0797] Step A: (Z)-4-Chlorobenzaldehyde oxime

[0798] A mixture of 4-chlorobenzaldehyde (6.00 g, 42.7 mmol, 1.0 equiv), hydroxylammonium chloride (2.97 g, 42.7 mmol, 1.0 equiv) and Cs2CO3 (2.26 g, 21.3 mmol, 0.5 equiv) in MeOH (36.0 mL) and H2O (18.00 mL) was stirred at 30 ° C for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (100 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (ethyl acetate in petroleum ether, from 0 to 20%) to give (Z)-4-chlorobenzaldehyde oxime (5 g, 75% yield) as a white solid. LC-MS (ESI): Molecular weight calculated: C7H6ClNO 155.01; m / z observed value, 156.0 [M+H] + .

[0799] Step B: (E)-4-Chloro-N-hydroxybenzoyl chloride

[0800] To a solution of (Z)-4-chlorobenzaldehyde oxime (1.00 g, 6.43 mmol, 1 equivalent) in DMF (20 mL) was added NCS (171.6 mg, 1.286 mmol, 0.2 equivalent). NCS (686.4 mg, 5.144 mmol, 0.8 equivalent) was then added in small portions, and the resulting mixture was stirred at 30 ° C for 24 hours. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine (50 mL × 4), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (ethyl acetate in petroleum ether, 0 to 20%) to give (E)-4-chloro-N-hydroxybenzoyl chloride (0.8 g, 66% yield) as a white solid. LC-MS (ESI): calculated molecular weight: C7H5Cl2NO 188.97; m / z observed value, 190.0 [M+H] + .

[0801] Step C: (3-(4-chlorophenyl)iso oxazol-5-yl)methanol

[0802] To a solution of (E)-4-chloro-N-hydroxybenzoyl chloride (0.6 g, 3.2 mmol, 1.0 equiv) and propargyl alcohol (0.19 g, 3.5 mmol, 1.1 equiv) in t-BuOH (5.0 mL) and H₂O (5.0 mL) were added sodium ascorbate (63.0 mg, 0.32 mmol, 0.1 equiv) and copper(II) sulfate pentahydrate (24 mg, 95.0 μmol, 0.03 equiv). The mixture was stirred for 30 minutes. KOCO₃ (961 mg, 9.6 mmol, 3.0 equiv) was then added to the mixture, and the resulting mixture was stirred at 30°C for 1.5 hours. The reaction mixture was quenched with water (30 mL) 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 residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether, from 0 to 35%) to give (3-(4-chlorophenyl)isothiazolinone as a white solid. oxazol-5-yl)methanol (0.38 g, yield 57%). LC-MS (ESI): C 10 Calculated molecular weight of H8ClNO2: 209.02; observed m / z: 210.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.88 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 6.96 (s, 1H), 5.73 (t, J = 6.0 Hz, 1H), 4.61 (d, J = 6.0 Hz, 2H).

[0803] Step D: 3-(4-chlorophenyl)isothiazolinone Azole-5-carboxaldehyde

[0804] To (3-(4-chlorophenyl) iso To a solution of oxazol-5-yl)methanol (120 mg, 572 μmol, 1.0 equiv) in DCM (5.0 mL) was added Dess-Martin periodinane (267 mg, 630 μmol, 1.1 equiv). The mixture was stirred at room temperature for 2 hours. The reaction was diluted with EA (60 mL), washed with saturated NaS2O3 aqueous solution (30 mL), saturated NaHCO3 aqueous solution (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE=1 / 10) to give 3-(4-chlorophenyl)isothiazolinone as a yellow solid. Azole-5-carboxaldehyde (100 mg, yield 84%). LC-MS (ESI): C 10The calculated molecular weight of H6ClNO2 is 207.01; the experimental m / z value shows no MS signal.

[0805] Intermediate B14: 3-(4-chlorophenyl)isothiazole-5-carboxaldehyde

[0806]

[0807] Step A: 3-(4-chlorophenyl)isothiazole

[0808] 3-Bromoisothiazole (100 mg, 610 μmol, 1.0 equiv), (4-chlorophenyl)boronic acid (143 mg, 915 μmol, 1.5 equiv), tetrakis(triphenylphosphine)palladium(o) (70.5 mg, 61.0 μmol, 0.1 equiv) and potassium carbonate (169 mg, 1.2 mmol, 2.0 equiv) were dissolved in 1,4-dichloroisothiazole. A solution of oxane (6.0 mL) and H2O (1.0 mL) was stirred at 80°C under N2 for 4 hours. After cooling to room temperature, the mixture was diluted with DCM (50 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (EA / PE = 1 / 10) to give 3-(4-chlorophenyl)isothiazole (82.0 mg, 68% yield) as a yellow oil. LC-MS (ESI): calculated molecular weight for C9H6ClNS, 195.0; observed m / z, 196.1 (M+H) + . 1 HNMR (400MHz, DMSO-d6) δ9.18 (d, J = 0.6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 0.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H).

[0809] Step B: 3-(4-chlorophenyl)isothiazole-5-carbaldehyde

[0810] To a mixture of 3-(4-chlorophenyl)isothiazole (50.0 mg, 256 μmol, 1.0 equivalent) in anhydrous THF (5.0 mL) was added n-butyl lithium (2.5 M in n-hexane) (0.16 mL, 384 μmol, 1.5 equivalents) under N2 and -78 ° C, and the mixture was stirred at this temperature for 30 minutes. Anhydrous DMF (93.4 mg, 1.3 mmol, 5.0 equivalents) was then added to the above mixture, and the resulting mixture was stirred under N2 and -78 ° C for 30 minutes. The mixture was quenched by adding saturated NH4Cl aqueous solution (20 mL), stirred for 15 minutes, and extracted with EA (20 mLx4). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE=1 / 10) to give 3-(4-chlorophenyl)isothiazole-5-carbaldehyde (28.0 mg, 49% yield) as a yellow solid. LC-MS (ESI): C 10 Calculated molecular weight of H6ClNOS, 223.0; observed m / z, 224.1 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 10.19 (s, 1H), 8.72 (s, 1H), 8.11 (d, J = 8.8Hz, 2H), 7.62 (d, J = 8.8Hz, 2H).

[0811] Intermediate B15: 3-chloro-1-(4-chlorophenyl)-1H-pyrazole-4-carbaldehyde

[0812]

[0813] At 0 ° C, POCl3 (5.51 g, 3.35 mL, 36.0 mmol, 7.0 equivalents) was added dropwise to DMF (10.0 mL), and the reaction mixture was stirred at 0 ° C for 5 minutes. 1- (4-chlorophenyl) -1,2-dihydro -3H-pyrazol-3-one (1.00 g, 5.14 mmol, 1.0 equivalents) was added to the above mixture, and the resulting reaction mixture was heated to 105 ° C and stirred for 16 hours. After cooling to room temperature, the mixture was poured into crushed ice and a brown solid was precipitated. The solid was collected by filtration and washed with water (30 mL). The solid filter cake was dissolved in DCM (150 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=10 / 1) to give 3-chloro-1-(4-chlorophenyl)-1H-pyrazole-4-carbaldehyde (40.0 mg, 3% yield) as a yellow solid. LC-MS (ESI): C 10The calculated molecular weight of H8N2O is 172.19; no mass spectrometry signal at m / z. 1 H NMR (400MHz, DMSO-d6) δ9.87 (s, 1H), 9.33 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H).

[0814] Intermediate B16: 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde

[0815]

[0816] A solution of 3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (50.0 mg, 305 μmol, 1.0 equiv), copper diacetate (111 mg, 609 μmol, 2.0 equiv), (4-chlorophenyl)boronic acid (71.5 mg, 457 μmol, 1.5 equiv), 2,2'-bipyridine (95.2 mg, 609 μmol, 2.0 equiv), and sodium carbonate (161 mg, 1.5 mmol, 5.0 equiv) in DCE (6.0 mL) was stirred under O2 at 70°C for 5 hours. After cooling to room temperature, the mixture was filtered and quenched with water (20 mL) and extracted with DCM (20 mL x 3). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (EA / PE=3 / 1) to give 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (34.0 mg, 41% yield) as a white solid. LC-MS (ESI): C 11 The calculated molecular weight of H6ClF3N2O is 274.0; no signal at m / z. 1 HNMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.51 (s, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H). Intermediate B17: 1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazole-4-carbaldehyde

[0817]

[0818] To a DMF (5.00 mL) solution of 1H-pyrazole-4-carboxaldehyde (1.95 g, 20.3 mmol, 1.0 equivalent) and Cs2CO3 (13.2 g, 40.5 mmol, 2.0 equivalents) was added 4-(bromomethyl)tetrahydro-2H-pyran (5.44 g, 30.4 mmol, 1.5 equivalents). The reaction mixture was stirred at 80 ° C for 16 hours. After cooling to room temperature, the mixture was diluted with EA (100 mL), washed with brine (50 mL × 4), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (PE / EA = 1 / 1) to give 1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazole-4-carboxaldehyde (2 g, 50% yield) as a yellow solid. LC-MS (ESI): C 10 H 14 Calculated molecular weight of N2O2: 194.11; observed m / z: 195.1 [M+H] + .

[0819] Intermediate B18: 6-(bromomethyl-d2)-2-methyl-2H-indazole

[0820]

[0821] Step A: (2-Methyl-2H-indazol-6-yl)methan-d2-ol

[0822] At 0 ° C, to a solution of methyl 2-methyl-2H-indazole-6-carboxylate (400 mg, 2.10 mmol, 1.0 equivalent) in THF (8.00 mL), LiAlD4 (88.3 mg, 2.10 mmol, 1.0 equivalent) was added portionwise, and the reaction mixture was stirred at 0 ° C for 0.5 hours. The reaction mixture was diluted with EtOAc (30 mL), carefully quenched with sodium sulfate decahydrate, and stirred for 0.5 hours. After filtration, the filtrate was concentrated under reduced pressure to give (2-methyl-2H-indazole-6-yl)methane-d2-ol (340 mg, yield 98%) as a yellow oil. LC-MS (ESI): calculated molecular weight of C9H8D2N2O, 164.20; m / z observed value, 165.1 [M+H] + .

[0823] Step B: 6-(Bromomethyl-d2)-2-methyl-2H-indazole

[0824] To a solution of (2-methyl-2H-indazol-6-yl)methane-d2-ol (340 mg, 2.07 mmol, 1.0 eq) in DCM (5.0 mL) was added triphenylphosphine (815 mg, 3.11 mmol, 1.5 eq) and the mixture was stirred at 50° C. under atmosphere for 5 minutes. A solution of CBr4 (1.03 g, 3.11 mmol, 1.5 eq) in DCM (5.0 mL) was then added to the mixture and the reaction mixture was stirred at 50° C. for 2 hours. After evaporation, the residue was purified by flash column chromatography on silica gel (PE / EA=2 / 1) to give 6-(bromomethyl-d2)-2-methyl-2H-indazole (100 mg, 21% yield) as a yellow solid. LC-MS (ESI): calculated molecular weight of C9H7D2BrN2, 226.01; observed m / z, 227.0 [M+H] + .

[0825] Intermediate B19: 6-(bromomethyl-d2)-1-methyl-1H-indazole

[0826]

[0827] Step A: 1-Methyl-1H-indazole-6-carboxylic acid methyl ester and 2-methyl-2H-indazole-6-carboxylic acid methyl ester

[0828] To 1H- indazole -6- carboxylic acid methyl esters (2.00g, 11.4mmol, 1.0 equivalent) and iodomethane (4.83g, 34.1mmol, 3.0 equivalent) DMF (20mL) solution, cesium carbonate (7.40g, 22.7mmol, 2.0 equivalent) is added, and the reaction mixture is stirred at room temperature for 2 hours. After filtration, the filtrate is diluted with EtOAc (100mL) and washed with saline (30mL × 5). With anhydrous Na2SO4 organic layer is dried, filtered and concentrated under reduced pressure. By flash column chromatography on silica gel purification (PE / EA=1 / 1) residue, 1- methyl -1H- indazole -6- carboxylic acid methyl esters ((1.35g, yield 62%) as yellow solid are obtained, and 2- methyl -2H- indazole -6- carboxylic acid methyl esters (800mg, yield 37%) as yellow oil.

[0829] 1-Methyl-1H-indazole-6-carboxylic acid methyl ester: LC-MS (ESI): C 10 H 10 Calculated molecular weight of N2O2, 190.20; observed m / z, 191.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.30 (s, 3H), 8.17 (s, 1H), 7.92-7.84 (m, 1H), 7.70 (dd, J = 8.4, 1.2Hz, 1H), 4.14 (s, 3H), 3.91 (s, 3H).

[0830] 2-Methyl-2H-indazole-6-carboxylic acid methyl ester: LC-MS (ESI): C 10 H 10 Calculated molecular weight of N2O2, 190.20; observed m / z, 191.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.46 (s, 1H), 8.28 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 1.2 Hz, 1H), 4.23 (s, 3H), 3.88 (s, 3H).

[0831] Step B: (1-Methyl-1H-indazol-6-yl)methan-d2-ol

[0832] At 0 ° C, to a solution of 1-methyl-1H-indazole-6-carboxylic acid methyl ester (700 mg, 3.68 mmol, 1.0 equivalent) in THF (20 mL), LiAlD4 (155 mg, 3.68 mmol, 1.0 equivalent) was added portionwise, and the reaction mixture was stirred at 0 ° C for 0.5 hours. The reaction was diluted with EtOAc (50 mL), quenched with sodium sulfate decahydrate, and stirred for 0.5 hours. After filtering, the filtrate was concentrated under reduced pressure to give (1-methyl-1H-indazole-6-yl)methane-d2-ol (600 mg, yield 99%) as a yellow solid. LC-MS (ESI): molecular weight calculated for C9H8D2N2O, 164.20; m / z observed value, 165.1 [M+H] + .

[0833] Step C: 6-(Bromomethyl-d2)-1-methyl-1H-indazole

[0834] To a solution of (1-methyl-1H-indazol-6-yl)methanol-d2-ol (500 mg, 3.05 mmol, 1.0 equiv) in DCM (5.0 mL) was added triphenylphosphine (1.20 g, 4.57 mmol, 1.5 equiv) and the mixture was stirred at 50° C. under atmospheric pressure for 5 minutes. A solution of CBr4 (1.51 g, 4.57 mmol, 1.5 equiv) in DCM (5.0 mL) was then added dropwise to the mixture and the resulting reaction mixture was stirred at 50° C. for 2 hours. After evaporation, the residue was purified by flash column chromatography on silica gel (PE / EA=2 / 1) to afford 6-(bromomethyl-d2)-1-methyl-1H-indazole (300 mg, 43% yield) as a yellow solid. LC-MS (ESI): calculated molecular weight of C9H7D2BrN2, 226.01; observed m / z, 227.0 [M+H] + Intermediate B20: 4-(3-(bromomethyl-d2)phenyl)-1-(methyl-d3)-1H-pyrazole

[0835]

[0836] Step A: 4-Bromo-1-(methyl-d3)-1H-pyrazole

[0837] To a solution of 4-bromo-1H-pyrazole (1.00 g, 6.80 mmol, 1.0 equiv) in DMF (5.00 mL) was added Cs2CO3 (4.43 g, 13.6 mmol, 2.0 equiv) and iodomethane-d3 (635 μL, 10.2 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 16 hours. After filtration, the mixture was diluted with EA (30 mL), washed with brine (20 mL × 4), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-bromo-1-(methyl-d3)-1H-pyrazole (1.10 g, 98% yield) as a yellow oil. LC-MS (ESI): Molecular weight calculated for C4H2D3BrN2, 162.99; m / z observed, 164.1 [M+H] + .

[0838] Step B: Methyl 3-(1-(methyl-d3)-1H-pyrazol-4-yl)benzoate

[0839] To a 1,4-dibromo-1-(methyl-d3)-1H-pyrazole (500 mg, 3.05 mmol, 1.0 equiv), (3-(methoxycarbonyl)phenyl)boronic acid (658 mg, 3.66 mmol, 1.2 equiv) and potassium carbonate (1.26 g, 9.15 mmol, 3.0 equiv) was added 4-bromo-1-(methyl-d3)-1H-pyrazole (500 mg, 3.05 mmol, 1.0 equiv). To a solution of d-oxane (10.0 mL) and water (0.10 mL) was added Pd(dppf)Cl2 (249 mg, 305 μmol, 0.1 equiv). The reaction mixture was stirred at N2 and 100 ° C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / PE=1 / 1) to give methyl 3-(1-(methyl-d3)-1H-pyrazol-4-yl)benzoate (400 mg, 60% yield) as a yellow oil. LC-MS (ESI): C 12 The calculated molecular weight of H9D3N2O2 is 219.11; the experimental m / z is 220.2 [M+H] + .

[0840] Step C: (3-(1-(methyl-d3)-1H-pyrazol-4-yl)phenyl)methan-d2-ol

[0841] At 0 ° C, to a solution of methyl 3- (1- (methyl -d3) -1H- pyrazol-4-yl) benzoate (400 mg, 1.82 mmol, 1.0 equivalent) in THF (10.0 mL), LiAlD4 (153 mg, 3.65 mmol, 2.0 equivalents) was added. The reaction mixture was stirred at 0 ° C for 40 minutes. The mixture was carefully quenched with sodium sulfate decahydrate (500 mg) and filtered. The filtrate was concentrated under reduced pressure to give (3- (1- (methyl -d3) -1H- pyrazol-4-yl) phenyl) first -d2- alcohol (300 mg, 85% yield) as a white solid. LC-MS (ESI): C 11 Calculated molecular weight of H7D5N2O, 193.12; observed m / z, 194.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.69 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.34-7.25 (m, 2H), 7.14 (d, J = 7.4Hz, 1H).

[0842] Step D: 4-(3-(bromomethyl-d2)phenyl)-1-(methyl-d3)-1H-pyrazole

[0843] To a solution of (3-(1-(methyl-d3)-1H-pyrazol-4-yl)phenyl)methane-d2-ol (300 mg, 1.55 mmol, 1.0 equiv) and triphenylphosphine (611 mg, 2.33 mmol, 1.5 equiv) in DCM (5.00 mL) under N2 was added CBr4 (772 mg, 2.33 mmol, 1.5 equiv). The reaction mixture was stirred at 50 ° C for 2 hours. After evaporation, the residue was purified by flash column chromatography on silica gel (EA / PE=1 / 1) to give 4-(3-(bromomethyl-d2)phenyl)-1-(methyl-d3)-1H-pyrazole (350 mg, 88% yield) as a white solid. LC-MS (ESI): C 11 Calculated molecular weight of H6D5BrN2, 255.04; observed m / z, 256.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.15(s,1H),7.87(s,1H),7.65(s,1H),7.51(d,J=7.6Hz,1H),7.35(t,J=7.6Hz,1H),7.26(d,J=7.6Hz,1H).

[0844] Intermediate B21: 4-(3-(bromomethyl-d2)phenyl)-1-(difluoromethyl)-1H-pyrazole

[0845]

[0846] Step A: Methyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzoate

[0847] To a 1,4-dibromo-1-(difluoromethyl)-1H-pyrazole (500 mg, 2.54 mmol, 1.0 equiv), (3-(methoxycarbonyl)phenyl)boronic acid (548 mg, 3.05 mmol, 1.2 equiv) and cesium carbonate (2.48 g, 7.61 mmol, 3.0 equiv) was added a 1,4-difluoromethyl-1H-pyrazole solution of 4-bromo-1-(difluoromethyl)-1H-pyrazole (500 mg, 2.54 mmol, 1.0 equiv). To a solution of 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (II) (186 mg, 254 μmol, 1.0 equivalent) was added 2- oxane (20.0 mL) and water (5.00 mL). The reaction mixture was stirred at 90 ° C for 2 hours under nitrogen. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified on silica gel (PE / EA=20 / 1) by flash column chromatography to give methyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzoate (580 mg, 90% yield) as a yellow oil. LC-MS (ESI): C 12 H 10Calculated molecular weight of F2N2O2, 252.07; observed m / z, 253.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.37(s,1H),8.24(t,J=1.6Hz,1H),8.02-7.97( m,1H),7.89-7.87(m,1H),7.86(t,J=67.6Hz,1H),7.58(t,J=7.8Hz,1H),3.89(s,3H).

[0848] Step B: (3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)methan-d2-ol

[0849] At 0 ° C, to a solution of methyl 3- (1- (difluoromethyl) -1H- pyrazol-4-yl) benzoate (200 mg, 793 μmol, 1.0 equivalent) in anhydrous THF (10.0 mL), LiAlD4 (66.6 mg, 1.59 mmol, 2.0 equivalents) was added. The reaction mixture was stirred at 0 ° C for 20 minutes. The reaction mixture was carefully quenched with Na2SO4.10H2O and stirred for 30 minutes. After filtration, the filtrate was diluted with water and extracted with ethyl acetate (25 mL × 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on silica gel by flash column chromatography (PE / EA = 4 / 1), providing (3- (1- (difluoromethyl) -1H- pyrazol-4-yl) phenyl) first-d2-ol (158 mg, 88% yield) as a yellow oil. LC-MS (ESI): calculated molecular weight of C11H8D2F2N2O, 226.09; observed m / z, 227.1 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.72(s,1H),8.29(s,1H),7.93(t,J=67.6Hz,1H),7.69-7.55(m,2H),7.41(d,J=7.6Hz,1H),7.32-7.23(m,1H),5.22(s,1H).

[0850] Step C: 4-(3-(Bromomethyl-d2)phenyl)-1-(difluoromethyl)-1H-pyrazole

[0851] To a solution of (3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)methane-d2-ol (145 mg, 641 μmol, 1.0 eq) in DCM (10.0 mL) were added triphenylphosphine (252 mg, 961 μmol, 1.5 eq) and carbon tetrabromide (319 mg, 961 μmol, 1.5 eq). The reaction mixture was stirred at 50 ° C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=10 / 1) to give 4-(3-(bromomethyl-d2)phenyl)-1-(difluoromethyl)-1H-pyrazole (172 mg, 93% yield) as a white solid. LC-MS(ESI):C 11 Calculated molecular weight of H7D2BrF2N2, 288.00; observed m / z, 289.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.75 (s, 1H), 8.29 (s, 1H), 7.85 (t, J = 59.2Hz, 1H), 7.83 (d, J = 7.6Hz, 1H), 7.67-7.63 (m, 1H), 7.43-7.35 (m, 2H).

[0852] Intermediate B22: 4-(3-(bromomethyl-d2)phenyl)-1-methyl-1H-pyrazole

[0853]

[0854] Step A: Methyl 3-(1-methyl-1H-pyrazol-4-yl)benzoate

[0855] To a 1,4-dibromo-1-methyl-1H-pyrazole (6.00 g, 37.3 mmol, 1.0 equiv), (3-(methoxycarbonyl)phenyl)boronic acid (8.05 g, 44.7 mmol, 1.2 equiv) and potassium carbonate (15.5 g, 112 mmol, 3.0 equiv) was added 4-bromo-1-methyl-1H-pyrazole (6.00 g, 37.3 mmol, 1.0 equiv). To a solution of d- 1- methyl -1H- pyrazol-4-yl) benzoic acid methyl ester (6.50 g, 80% yield) was added Pd (dppf) Cl2 (1.52 g, 1.86 mmol, 0.05 equiv). The reaction mixture was stirred at N2 and 100 ° C for 3 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (ethyl acetate in petroleum ether, 50% v / v) to give 3- (1-methyl -1H- pyrazol-4-yl) benzoic acid methyl ester (6.50 g, 80% yield) as a yellow oil. LC-MS (ESI): C 12 H 12 Calculated molecular weight of N2O2, 216.09; observed m / z, 217.1 [M+H] + .

[0856] Step B: (3-(1-methyl-1H-pyrazol-4-yl)phenyl)methane-d2-ol

[0857] At 0 ° C, to a solution of methyl 3- (1-methyl -1H- pyrazol-4-yl) benzoate (7.50g, 34.7mmol, 1.0 equivalent) in anhydrous THF (50.0mL), LiAlD4 (2.18g, 52.0mmol, 1.5 equivalents) was added portionwise. The reaction mixture was stirred at 0 ° C for 40 minutes. Thereafter, sodium sulfate decahydrate (5g) was carefully added to the above mixture and filtered. The filtrate was concentrated under reduced pressure to give (3- (1-methyl -1H- pyrazol-4-yl) phenyl) methyl -d2-ol (5.30g, yield 80%) as a white solid. LC-MS (ESI): C 11 H 10 Calculated molecular weight of D2N2O, 190.11; observed m / z, 191.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.70 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.34-7.26 (m, 2H), 7.15 (d, J = 7.4Hz, 1H), 3.87 (s, 3H).

[0858] Step C: 4-(3-(Bromomethyl-d2)phenyl)-1-methyl-1H-pyrazole

[0859] To a solution of (3-(1-methyl-1H-pyrazol-4-yl)phenyl)methane-d2-ol (500 mg, 2.63 mmol, 1.0 equiv) in DCM (10.0 mL) at room temperature, triphenylphosphine (1.03 g, 3.94 mmol, 1.5 equiv) was added. Subsequently, a solution of perbromomethane (1.31 g, 3.94 mmol, 1.5 equiv) in DCM (3 mL) was added to the above mixture under N2, and the resulting mixture was stirred at N2 and 50°C for 2 hours. After evaporation, the residue was purified on silica gel by flash column chromatography (ethyl acetate / petroleum ether, 17% v / v) to give 4-(3-(bromomethyl-d2)phenyl)-1-methyl-1H-pyrazole (490 mg, 74% yield) as a white solid. LC-MS (ESI): C 11 Calculated molecular weight of H9D2BrN2, 252.02; observed m / z, 253.2 [M+H] + Intermediate B23: 3-(1-(methyl-d3)-1H-pyrazol-4-yl)benzaldehyde

[0860]

[0861] Step A: 4-Bromo-1-(methyl-d3)-1H-pyrazole

[0862] To DMF (60.0mL) solution of 4-bromo-1H-pyrazoles (3.00g, 20.4mmol, 1.0 equivalents), cesium carbonate (13.3g, 40.8mmol, 2.0 equivalents) is added, and the reaction mixture is stirred at room temperature for 1 hour.Afterwards CD3I (5.92g, 2.54mL, 40.8mmol, 2.0 equivalents) is added dropwise in the above mixture, and gained reaction mixture is stirred at room temperature overnight.Reactant mixture is diluted and filtered with EA (200mL).Filtrate is washed with salt water (100mLx5), through anhydrous Na2SO4, is dried, filtered and concentrated under reduced pressure, obtains 4-bromo-1-(methyl-d3)-1H-pyrazoles (2.40g, yield 72%) as yellow oil. LC-MS (ESI): calculated molecular weight of C4H2D3BrN2, 162.98; observed m / z, 164.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.85(s,1H),7.44(s,1H).

[0863] Step B: 3-(1-(methyl-d3)-1H-pyrazol-4-yl)benzaldehyde

[0864] To a 1,4-dichlorobenzene solution of (3-formylphenyl)boronic acid (2.00 g, 13.3 mmol, 1.0 equiv), 4-bromo-1-(methyl-d3)-1H-pyrazole (2.84 g, 17.3 mmol, 1.3 equiv) and cesium carbonate (13.0 g, 40.0 mmol, 3.0 equiv) was added. To a solution of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (976 mg, 1.33 mmol, 0.1 equiv) in oxane (70.0 mL) and water (20.0 mL) was added. The reaction mixture was stirred at 90 ° C under nitrogen for 1 hour. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (PE / EA=2 / 1) to give 3-(1-(methyl-d3)-1H-pyrazol-4-yl)benzaldehyde (1.85 g, 73% yield) as a yellow oil. LC-MS (ESI): C 11 Calculated molecular weight of H7D3N2O, 189.10; observed m / z, 190.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),8.27(s,1H),8.09(s,1H),7.97(s,1H),7.93-7.88(m,1H),7.73(d,J=7.6Hz,1H),7.59(t,J=7.6Hz,1H).

[0865] Intermediate B24: 4-(4-Formyl-1H-pyrazol-1-yl)benzonitrile

[0866]

[0867] At 0 ° C, to a solution of 1H-pyrazole-4-carboxaldehyde (5.0 g, 52.0 mmol, 1.0 equivalent) in DMF (50 mL), NaH (60% suspended in oil) (1.5 g, 62.4 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at 0 ° C for 0.5 hours. 4-Fluorobenzonitrile (6.9 g, 57.2 mmol, 1.1 equivalents) was added to the above mixture, and the reaction mixture was stirred at 25 ° C for 16 hours. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine (100 mL × 4), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (PE / EA = 2 / 1) to obtain 4- (4-formyl -1H- pyrazol-1-yl) benzonitrile (3.0 g, yield 29%) as a white solid. LC...

Claims

1. A compound of formula (I'): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: X is -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-; Y is -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-; Each Z is independently -C(R 3 )2-、-NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-; p is 0, 1, or 2; Every R 3 are independently deuterium, 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, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace; Two R 3 together to form an oxo group; or Two R 3 Together with the carbon atom to which it is attached, it forms 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; Every R 4 are independently hydrogen or C 1-6 Alkyl, which is optionally substituted by one or more R u replace; Ring A is C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; R 1 is hydrogen or -MLQR 2 ; M is absent, -(C=O)-, -S(=O)- or -S(=O)2-; L does not exist or [W] r ; r is an integer from 1 to 3; Each W is independently -C(R L )2-、C 3-4 carbocyclylene or 3 to 4 membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is optionally substituted by one or more R u replace; Every R L are independently hydrogen, deuterium, 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 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace; or Two R L Together with the carbon atom to which it is attached, it forms 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; Q does not exist, -NR Q -, -O-, -C(=O)-, -S(=O)- or -S(=O)2-; R Q is hydrogen or C 1-6 Alkyl, which is optionally substituted by one or more R u replace; R 2 C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R 2a replace; Every R 2a 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, -(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 -(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, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace; or Two R's 2a Together with the atoms to which it is bonded, it forms C 3-8 carbocyclyl or 3 to 8 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace; R A , R C and R E is independently at each occurrence 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; q is an integer from 0 to 2; If valence permits, s is an integer from 0 to 12; e is an integer selected from 0 to 5; U is -CH2- or -C(=O)-; R 5 For hydrogen, deuterium, C 1-6 Haloalkyl or C 1-6 Alkyl; and t is an integer from 0 to 2; in: Every 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, -(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 -(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, alkylene, 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 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 carbocyclyl and 3- to 12-membered heterocyclyl; 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; Every R a Independently for 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; Every 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 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 it is attached, it forms a 3- to 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more R z replace; Where R a , R b , R c and R d is independently and optionally replaced at each occurrence by one or more R z Replacement; and Every R z 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 A carbocyclic group or a 3- to 6-membered heterocyclic group.

2. The compound according to claim 1, wherein when p is 0, then X and Y are not both -C(R 3 )2; and when p is 1, then not all of X, Y and Z are -C(R 3 )2.

3. The compound according to claim 1, wherein X is -O- and Y is -C(R 3 )2-.

4. The compound according to claim 1, wherein X is -C(R 3 )2- and Y is -O-.

5. The compound according to claim 1, wherein X is -NR 4 - and Y is -C(R 3 )2-.

6. The compound according to any one of claims 1 to 5, wherein p is 0 or 1.

7. The compound according to claim 1, wherein the compound is a compound of formula (I'-1-ii), (I'-1-iii), (I'-1-iv), (I'-1-v), (I'-1-vi), (I'-1-vii), (I'-1-ix) or (I'-1-xii): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

8. The compound according to any one of claims 1 to 7, wherein Ring A is a 3- to 12-membered heterocyclic ring.

9. A compound according to any one of claims 1 to 8, wherein yes wherein m and n are independently integers from 0 to 2.

10. The compound according to claim 9, wherein the compound is a compound of formula (I'-2-ii), (I'-2-iii), (I'-2-iv), (I'-2-v), (I'-2-vi), (I'-2-vii), (I'-2-ix) or (I'-2-xii) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

11. The compound according to claim 9 or 10, wherein m and n are each 1.

12. A compound according to any one of claims 1 to 11, wherein R 1 It's hydrogen.

13. A compound according to any one of claims 1 to 11, wherein R 1 Yes -LR 2 .

14. The compound according to claim 13, wherein L is -C(R L )2-.

15. The compound according to claim 14, wherein each R L are independently hydrogen, deuterium, 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, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

16. The compound according to claim 14, wherein each R L are independently hydrogen, deuterium or C 1-6 alkyl.

17. The compound of claim 14, wherein L is -CH2-.

18. A compound according to any one of claims 13 to 17, wherein R 2 C 6-10 Aryl or 5- to 10-membered heteroaryl, C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R 2a replace.

19. The compound according to claim 18, wherein R 2 is optionally represented by one or more R 2a Substituted phenyl.

20. The compound according to claim 18, wherein R 2 is optionally represented by one or more R 2a Substituted 5- to 10-membered heteroaryl.

21. The compound according to claim 18, wherein R 2 is optionally represented by one or more R 2a Substituted C 5-10 Carbocyclic group.

22. The compound according to claim 18, wherein R 2 is optionally represented by one or more R 2a Substituted 9- to 10-membered heterocyclyl.

23. A compound according to any one of claims 19-22, wherein each R 2a 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 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

24. A compound according to any one of claims 19-22, wherein each R 2a are independently oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkylamino, 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)2NR c R d 、-NR c S(=O)2R a 、-NR b C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkylene, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace.

25. A compound according to any one of claims 1 to 24, wherein each R 3 are independently hydrogen, deuterium, 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, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

26. A compound according to any one of claims 1-24, wherein each R 3 are independently hydrogen, deuterium or C 1-6 alkyl.

27. A compound according to any one of claims 1-26, wherein each R 4 are independently hydrogen or C 1-6 alkyl.

28. A compound according to any one of claims 1 to 27, wherein R A , R C and R E is independently at each occurrence 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, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace.

29. The compound according to claim 28, wherein each R A are independently halogen, -OH or C 1-6 alkyl.

30. The compound according to claim 28, wherein each R C are independently halogen, -CN or C 1-6 alkyl.

31. The compound according to any one of claims 1-30, wherein e is 0.

32. A compound according to any one of claims 1-31, wherein U is -CH2-.

33. A compound according to any one of claims 1 to 32, wherein R 5 For hydrogen.

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

35. The compound according to claim 1, wherein the compound is a compound of formula (I'): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 1 is hydrogen or -LR 2 ; L is -C(R L )2-; Every R L are independently hydrogen, deuterium, 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, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace; R 2 C 6-10 Aryl or 5- to 10-membered heteroaryl, C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by one or more R 2a replace; Every R 2a are independently oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkylamino, 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)2NR c R d 、-NR c S(=O)2R a 、-NR b C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkylene, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R u replace; R A and R C is independently at each occurrence 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, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more R u replace; e is 0; X is -O- or -NR 4 -; Every R 4 are independently hydrogen or C 1-6 alkyl; Y is -CH2- or -O-; and p is 0 or 1.

36. The compound of claim 1, wherein the compound is selected from the compounds in Table 1 and Table 2 and pharmaceutically acceptable salts thereof.

37. A pharmaceutical composition comprising a compound according to any one of claims 1-36 and a pharmaceutically acceptable excipient.

38. 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 1-36 or contacting the biological sample with a compound according to any one of claims 1-36.

39. Use of a compound according to any one of claims 1 to 36 in the preparation of a medicament for degrading IKZF2 protein in a subject or a biological sample.

40. The compound of any one of claims 1-36, for use in degrading IKZF2 protein in a subject or biological sample.

41. 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 1-36.

42. Use of a compound according to any one of claims 1-36 in the preparation of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

43. A compound according to any one of claims 1-36 for use in treating or preventing a disease or disorder in a subject in need thereof.

44. The method, use or compound of any one of claims 41-43, wherein the disease or condition is an IKZF2-mediated disease or condition.

45. The method, use or compound of any one of claims 41-43, wherein the disease or condition is T-cell leukemia, T-cell lymphoma, Hodgkin's lymphoma or non-Hodgkin's 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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