Heteroaryl compounds as ligand-guided degraders of IRAK4

Abstract

The present application provides compounds and compositions thereof for modulating IRAK4. In some embodiments, compounds and compositions for the treatment of inflammatory or autoimmune diseases are provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 390,888, filed on July 20, 2022, which is incorporated by reference in its entirety into this application for any purpose. Technical Field

[0002] The present invention generally relates to compounds, compositions and methods of making the same, as well as the use of these compounds and compositions for treating inflammatory diseases or autoimmune diseases. Background Art

[0003] The recruitment of immune cells to the site of injury involves the coordinated interaction of a large number of soluble mediators. If stem cell factors appear to play a key role in these processes, including interleukin-1 (IL-1). IL-1 produces a proinflammatory response and leads to tissue degeneration observed in chronic inflammatory conditions. IL-1 is also involved in the processes of bone resorption and adipose tissue regulation. Therefore, IL-1 plays a key role in a large number of pathological conditions including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, cancer and sepsis.

[0004] IL-1 treatment of cells induces the formation of a complex consisting of two IL-1 receptor chains, IL-1R1 and IL-1RAcP, and the resulting heterodimer recruits an adaptor molecule called MyD88, which binds to the IL-1 receptor-associated kinase (IRAK) (Wesche et al., J. Biol. Chem. 1999, 274, 19403-19410; O'Neill et al., J. Leukoc. Biol. 1998, 63, 650-657; Auron, Cytokine Growth Factor Rev. 1998, 9: 221-237; and O'Neill, Biochem. Soc. Trans. 2000, 28, 557-563). Four members of the IRAK family have been identified: IRAK1, IRAK2, IRAK3, and IRAK4. These proteins are characterized by a typical N-terminal death domain that mediates interaction with the MyD88 family adaptor proteins and a centrally located kinase domain. Among the four members of the mammalian IRAK family, IRAK-4 is considered the "master IRAK". IRAK-4 is a serine / threonine kinase that plays a crucial role in signal transduction through the Toll / IL-1 receptor (TIR). Under overexpression conditions, all IRAKs can mediate the activation of nuclear factor-κB and stress-induced mitogen-activated protein kinase (MAPK) signal transduction pathways. Studies have shown that IRAK4 kinase activity is crucial for cytokine production, MAPK activation, and the induction of NF-κB-regulated genes in response to TLR ligands (Koziczak-Holbro M. et al., J. Biol. Chem. 2007, 282, 13552-13560). Given the central role of IRAK4 in Toll-like / IL-1R signaling and immune protection, compounds that modulate IRAK4 function may be useful in treating inflammatory, cell proliferative, and immune-related conditions and diseases associated with IRAK-mediated signaling, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, allergic diseases, psoriasis, asthma, transplant rejection, cancer, and sepsis.

[0005] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). The UPP is important for the regulation of almost all cellular processes. Ubiquitination of proteins is achieved by E3 ubiquitin ligases, which bind to proteins and add ubiquitin molecules to them, thereby marking them for proteasomal degradation.

[0006] The use of UPP for therapeutic purposes has received widespread attention (Zhou et al., Mol. Cell 2000, 6, 751-756). A promising therapy uses proteolytic targeting chimeras, commonly referred to as PROTACs, to achieve the removal of unwanted proteins by protein degradation (Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160-176). PROTAC is a ligand-directed degrader that brings together E3 ligases and target proteins to be degraded. These bivalent molecules are generally composed of E3 ligase ligands that are connected to small molecules bound to the target protein via a linker portion. PROTAC positions the E3 ligase at a position with an appropriate distance and direction from the target protein, causing the latter to ubiquitinate. Then, the ubiquitinated target protein is recognized by the proteasome, thereby being degraded where it is recognized.

[0007] Thus, in one aspect, provided herein are compounds that target IRAK4 for degradation. Summary of the Invention

[0008] In certain embodiments, the present application describes compounds and compositions thereof for use in degrading IRAK4. In various embodiments, the compounds and compositions thereof can be used to treat inflammatory diseases or autoimmune diseases.

[0009]

[0046] A more complete understanding of embodiments of the present invention may be obtained by reference to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

[0010] Embodiment A1 is a compound of formula (I'): or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, monocyclic 5- to 6-membered heteroaryl, or fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 1-4 heteroatoms independently selected from N, O and S, each of which is optionally substituted by 1-3 R 0 group substitution; Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C6 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl, -(6 to 10 membered bridged heterocyclylene)- and C1-C6 alkoxy, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O, or two R 0 The groups together form an oxo group; L 1 is -NH- or a bond; L 2-NHC(O)-, -C(O)NH-, -SO2NH-, -NHSO2- or -(C1-C6 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1-3 heteroatoms selected from N, O and S; L 3 -NR 9 (C1-C6 alkylene)NR 9 -、-NR 9 C(O)(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -、-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, -(6- to 10-membered bridged heterocyclylene)(C1-C6 alkylene) z -, -(7- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -or-(O) z (6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 group substitution; L 4 for phenylene, -N(H)(phenylene), 5- to 6-membered heteroarylene, -N(H)(5- to 6-membered heteroarylene)-, 8- to 10-membered fused bicyclic heteroarylene, or 5- to 6-membered heterocyclylene, wherein the phenylene, heteroarylene, or heterocyclylene is optionally substituted by 1-4 R 10 and wherein the heteroarylene and heterocyclylene groups contain 1 to 3 heteroatoms selected from N, S and O; R 1aand R 1b Each is H or together form an oxo group; R 2 and R 3 are independently H, C1-C6 alkyl or halogen, or R 2 and R 3 Together they form an oxo group; or R 3 and R 11 Together they form a C3-C6 cycloalkylene group; Y is NH, O or a bond; R 4 is C3-C6 cycloalkyl, C1-C6 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C6 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C6 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-5 R 8 group substitution; W is O, -NR 5 - or key; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halogen or -OH, or two R 6 The groups together form a bridged C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halogen, C1-C6 haloalkyl or -OH, or two R 7 The groups together form an oxo group; Each R 8 is independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halogen or -OH, or two R 10 The groups together form an oxo group; Each R 11 and R 12 are independently H, halogen, C3-C6 cycloalkyl, -OH, -NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; or R11 and R 3 Together they form a C3-C6 cycloalkylene group; x is 0 or 1; y is 0, 1, 2, 3, 4, or 5; Each z is independently 0 or 1; X is N or CR 13 ; R 13 is H, halogen, -OH or C1-C6 alkyl; Z 1 is CH or N; and Z 2 is CH or N, The constraint condition is Z 1 and Z 2 Not all are N.

[0011] Embodiment A2 is a compound of Embodiment A1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (I): in: Ring A is phenyl, monocyclic 5- to 6-membered heteroaryl, or fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 1-4 heteroatoms independently selected from N, O and S, each of which is optionally substituted by 1-3 R 0 group substitution; Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C6 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 alkoxy, or two R 0 The groups together form an oxo group; L 1 is -NH- or a bond; L 2 -NHC(O)-, -C(O)NH-, -SO2NH-, -NHSO2-, or a 5-membered heteroarylene group containing 1-3 heteroatoms selected from N, O and S; L 3 -NR 9 (C1-C6 alkylene)NR 9 -、-NR 9 C(O)(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z-、-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -、-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(6- to 10-membered bridged heterocyclylene)(C1-C6 alkylene) z -, -(9- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -or-(O) z (6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 group substitution; L 4 for Phenylene, 5 to 6 membered heteroarylene or 5 to 6 membered heterocyclylene, wherein the phenylene, heteroarylene or heterocyclylene is optionally substituted by 1-4 R 10 Group substituted, and wherein the heteroarylene and heterocyclylene contain 1-3 heteroatoms selected from N and O; R 1a and R 1b Each is H or together form an oxo group; R 2 and R 3 are independently H, C1-C6 alkyl or halogen, or R 2 and R 3 Together they form an oxo group; or R 3 and R 11 Together they form a C3-C6 cycloalkylene group; Y is NH or O; R 4 is C3-C6 cycloalkyl, C1-C6 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C6 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C6 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-5 R 8group substitution; W is O, -NR 5 - or key; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halogen or -OH, or two R 6 The groups together form a bridged C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halogen, C1-C6 haloalkyl or -OH, or two R 7 The groups together form an oxo group; Each R 8 is independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halogen or -OH, or two R 10 The groups together form an oxo group; Each R 11 and R 12 are independently H, halogen, C3-C6 cycloalkyl, -OH, -NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; or R 11 and R 3 Together they form a C3-C6 cycloalkylene group; x is 0 or 1; y is 0, 1, 2, 3, 4, or 5; Each z is independently 0 or 1; X is N or CR 13 ; R 13 is H, halogen or C1-C6 alkyl; Z 1 is CH or N; and Z 2 is CH or N, The constraint condition is Z 1 and Z 2 Not all are N.

[0012] Embodiment A3 is a compound of Embodiment A1 or A2, or a pharmaceutically acceptable salt thereof, wherein Ring A is: (i) optionally through 1-3 R 0 a phenyl group substituted with a phenyl group; and Each R 0 Independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), C1-C3 alkyl, C3-C6 cycloalkyl and C1-C3 alkoxy; (ii) contains 1 to 2 heteroatoms independently selected from N and O and optionally 1 to 3 R 0 a monocyclic 6-membered heteroaryl substituted with a group; and Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), C1-C3 alkyl, C3-C6 cycloalkyl and C1-C3 alkoxy; or (iii) contains 2-4 heteroatoms independently selected from N, O and S and optionally 1-3 R 0 a fused bicyclic 9-membered heteroaryl or heterocyclyl substituted with a group; and Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), C1-C3 alkyl, C3-C6 cycloalkyl, -(6- to 8-membered bridged heterocyclylene)-, and C1-C3 alkoxy, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O, or two R 0 The groups together form an oxo group.

[0013] Embodiment A4 is a compound of Embodiment A3, or a pharmaceutically acceptable salt thereof, wherein Ring A is:

[0014] Embodiment A5 is a compound of any one of Embodiments A1-A4, or a pharmaceutically acceptable salt thereof, wherein: L 2 is -NHC(O)- or -(C1-C3 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1-3 heteroatoms selected from N and O.

[0015] Embodiment A6 is a compound of Embodiment A5, or a pharmaceutically acceptable salt thereof, wherein: L 2 -NHC(O)-,

[0016] Embodiment A7 is a compound of any one of Embodiments A1-A6, or a pharmaceutically acceptable salt thereof, wherein: L 4 for

[0017] Embodiment A8 is a compound of any one of Embodiments A1-A7, or a pharmaceutically acceptable salt thereof, wherein: for W is O, -NR 5 - or key; and R 5 is H or C1-C3 alkyl.

[0018] Embodiment A9 is a compound of any one of Embodiments A1-A8, or a pharmaceutically acceptable salt thereof, wherein: X is N.

[0019] Embodiment A10 is a compound of any one of Embodiments A1-A8, or a pharmaceutically acceptable salt thereof, wherein: X is CR 13 ;and R 13 is H, halogen, -OH or C1-C3 alkyl.

[0020] Embodiment A11 is a compound of any one of Embodiments A1-A10, or a pharmaceutically acceptable salt thereof, wherein: Y is NH; R 4 is C3-C6 cycloalkyl, C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C3 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C3 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-2 R 8 group substitution; and Each R 8 is independently -SO2(C1-C3 alkyl), -C(O)(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, halogen, -CN or -OH.

[0021] Embodiment A12 is a compound of any one of Embodiments A1-A11, or a pharmaceutically acceptable salt thereof, wherein: R 4Methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CH2CH(CH3)2, -CH2CF3, -CH2CH2F, -CH2CF2CH3, -CH(CH3)CF3, -CH2CH2CF3, -CH(CH3)CH2OH, -CH2C(CH3)2OH, -CH2CN, -CH(CH3)CN, -C(CH3)2CN, -CH(CH2CH3)CN, -CH2CH(CH3)CN,

[0022] Embodiment A13 is a compound of any one of Embodiments A1-A12, or a pharmaceutically acceptable salt thereof, wherein: L 3 -NR 9 (C1-C3 alkylene)NR 9 -、-NR 9 C(O)(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C3 alkylene) z -、-NR 9 (C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, -O(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, -(6- to 10-membered bridged heterocyclylene)(C1-C3 alkylene) z -, -(7- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -or-(O) z (6- to 10-membered spiroheterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1 or 2 R 7 group substitution; Each z is independently 0 or 1; Each R 9 are independently H or C1-C3 alkyl; Each R 7 are independently C1-C3 alkyl, halogen, C1-C3 haloalkyl or -OH, or two R 7 The groups together form an oxo group; and Each R 11 and R 12 are independently H or -CH3.

[0023] Embodiment A14 is a compound of Embodiment A13, or a pharmaceutically acceptable salt thereof, wherein: L 3 for

[0024] Embodiment A15 is a compound of any one of Embodiments A1-A14, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (Ia) or (Ia'): in: Ring A is a ring containing 2-4 heteroatoms independently selected from N, O and S, optionally 1-3 R 0 a substituted fused bicyclic 9- to 10-membered heteroaryl group; R 4 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN; and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z 4 At least one of them is N.

[0025] Embodiment A16 is a compound of Embodiment A15, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (If) or (If'):

[0026] Embodiment A17 is a compound selected from the compounds of Table 1 or pharmaceutically acceptable salts thereof.

[0027] Embodiment A18 is a pharmaceutical composition comprising a compound of any one of Embodiments A1-A17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0028] Embodiment A19 is a method of modulating interleukin-1 (IL1) receptor-associated kinase 4 (IRAK4) activity, comprising contacting IRAK4 with an effective amount of a compound of any one of embodiments A1-A17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment A18.

[0029] Embodiment A20 is a method of treating an inflammatory disease or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Embodiments A1-A17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment A18, optionally wherein the inflammatory disease or autoimmune disease is atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoprin-associated periodic syndrome, hidradenitis suppurativa, Bechet's syndrome, or familial cold autoinflammatory syndrome. DETAILED DESCRIPTION definition

[0030] As used herein, the terms "comprising" and "including" are used interchangeably. The terms "comprising" and "including" should be interpreted as specifying the presence of the features or components mentioned, but do not exclude the presence or addition of one or more features or components or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of." Therefore, the term "consisting of" can be used to replace the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0031] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the recited features or components of which it is composed. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any content following the term, except for features or components that are not essential to the technical effect to be achieved.

[0032] As used in this application, the term "or" should be interpreted as an inclusive "or," meaning any one or any combination. Thus, "A, B, or C" means any one of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." An exception to this definition occurs only when a combination of elements, functions, steps, or actions are inherently mutually exclusive in some way.

[0033] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the stated range and, where appropriate, fractions thereof (e.g., tenths and hundredths of integers). In addition, unless otherwise indicated, any numerical range related to any physical characteristic, such as polymer subunits, size, or thickness, stated in this application should be understood to include any integer within the stated range. As used in this application, unless otherwise indicated, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure.

[0034] An "alkyl" group is a group having 1 to 10 carbon atoms (C1-C 10In some embodiments, the alkyl group is a saturated, partially saturated, or unsaturated straight or branched chain acyclic hydrocarbon, typically 1 to 8 carbon atoms (C1-C8 alkyl), or in some embodiments 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), or 2 to 6 carbon atoms (C2-C6 alkyl). In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also known as an alkenyl or alkynyl group. "Alkenyl" is an alkyl group containing one or more carbon-carbon double bonds. "Alkynyl" is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, CH=CH(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, CHC≡C(CH), and CHC≡C(CHCH). Alkyl groups may be substituted or unsubstituted. When alkyl groups described herein are referred to as "substituted," these alkyl groups may be substituted with any one or more substituents such as those present in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocyclylalkoxy, cycloalkylalkoxy, aralkyloxy, heterocyclylalkoxy, heteroarylalkoxy, heterocyclylalkylalkoxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocyclylalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclylalkylamino, heteroaryl Alkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; aralkyloxyamino; hydrazine; hydrazide; hydrazono; azido; nitro; sulfenyl (-SH), alkylsulfenyl; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxyl; ester; carbamate; amide; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; or -B(OH)2.In certain embodiments, when an alkyl group described herein is referred to as "substituted," it may be substituted with any one or more of the substituents found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chlorine, iodine, bromine, or fluorine); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; aminoamine; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

[0035] "Alkyl-OH" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by -OH. For example, "C1-C6 alkyl-OH" refers to a C1-C6 alkyl group substituted with one or more -OH groups. An alkyl-OH group may contain multiple hydroxyl groups attached to the same carbon atom or multiple carbon atoms.

[0036] "Alkyl-CN" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by -CN. For example, "C1-C6 alkyl-CN" refers to a C1-C6 alkyl group substituted with one or more -CN groups. An alkyl-CN group may contain multiple cyano groups attached to the same carbon atom or multiple carbon atoms.

[0037] An "alkoxy" group is an -O-(alkyl) group, wherein alkyl is as defined above.

[0038] A "cycloalkyl" group is a saturated or partially saturated cyclic alkyl group (C3-C4) having a single ring or multiple condensed or bridged rings having 3 to 10 carbon atoms, which may be optionally substituted. 10In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), while in other embodiments, the number of ring carbon atoms is in the range of 3 to 5 (C3-C5 cycloalkyl), in the range of 3 to 6 (a3-C6 cycloalkyl), or in the range of 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl group is a saturated cycloalkyl group. For example, such saturated cycloalkyl groups include monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1 methylcyclopropyl, 2 methylcyclopentyl, 2-methylcyclooctyl, and the like; or polycyclic or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include, inter alia, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl groups may be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol and the like.

[0039] An "aryl" group is a aryl group having 6 to 14 carbon atoms (C6-C8) with a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthracenyl). 14 In some embodiments, the aryl group contains 6 to 14 carbon atoms (C6-C 14 aryl), and in other embodiments contains 6 to 12 carbon atoms (C6-C 12 aryl) or even 6 to 10 carbon atoms (C6-C 10 aryl). Specific aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0040] "Halogen" or "halo" is fluorine, chlorine, bromine or iodine.

[0041] "Haloalkyl" refers to an alkyl group as defined above substituted by one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2 trifluoroethyl, 1,2 difluoroethyl, 3 bromo-2 fluoropropyl, 1,2 dibromoethyl and similar groups thereof. In some embodiments, haloalkyl has one to six carbon atoms and is substituted (C1-C6 haloalkyl) by one or more halogen groups, or haloalkyl has one to three carbon atoms and is substituted (C1-C3 haloalkyl) by one or more halogen groups. Halogen groups may all be identical, or halogen groups may be different. Unless specifically stated otherwise, haloalkyl is optionally substituted.

[0042] "Heteroaryl" is an aromatic ring system having one to four heteroatoms as ring atoms in the heteroaromatic ring system, wherein the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms, and in other embodiments, contains 6 to 9 or even 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-one or isoindolin-1-one), azaindolyl (pyrrolopyridinyl or 1H pyrrolo[2,3-b]pyridinyl), indazolyl, benzimidazolyl (e.g., 1H benzo[d]imidazolyl), imidazolyl The heteroaryl group may be substituted or unsubstituted.

[0043] "Heterocyclyl" is a non-aromatic cycloalkyl group in which one to four ring carbon atoms are independently replaced by heteroatoms selected from O, S, and N. In some embodiments, the heterocyclyl group includes 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclyl group may also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). The heterocycloalkyl group may be substituted or unsubstituted. The heterocyclyl group encompasses saturated and partially saturated ring systems. In addition, regardless of the connection to the rest of the molecule, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring. The phrase also includes bridged polycyclic ring systems containing heteroatoms. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, thioxanyl, dithianyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups may be monosubstituted or substituted more than once, such as, but not limited to, pyridinyl or morpholinyl groups, which are 2-substituted, 3-substituted, 4-substituted, 5-substituted, or 6-substituted, or disubstituted with multiple substituents, such as those listed below.

[0044] When a group described herein other than an alkyl group is referred to as "substituted," it may be substituted with any one or more suitable substituents. Illustrative examples of substituents are those present in the exemplary compounds and embodiments disclosed herein, as well as halogen (chlorine, iodine, bromine, or fluorine); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl; Cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0045] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "phenyl" groups, divalent "heteroaryl" groups, divalent "heterocyclyl" groups, etc. may also be referred to as "alkylene" groups, "phenylene" groups, "heteroarylene" groups, or "heterocyclylene" groups, respectively.

[0046] Embodiments of the present invention are intended to encompass pharmaceutically acceptable salts, tautomers, isotopes, and stereoisomers of the compounds provided herein (eg, compounds of Formula (I') or Formula (I)).

[0047] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base (including inorganic acids and bases and organic acids and bases). Suitable pharmaceutically acceptable base addition salts of Formula (I') or a compound of Formula (I) include, but are not limited to, metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts prepared from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include but are not limited to inorganic and organic acids, such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, sulfuric acid, tartaric acid and tosic acid.Specific non-toxic acid includes hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid and methanesulfonic acid.Therefore, the example of particular salt includes hydrochloride, formate and mesylate. Other options are also known in the art, see, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing, Easton PA (1995).

[0048] As used in this application and unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" refers to one stereoisomer of a particular compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compounds disclosed herein may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0049] The embodiments disclosed herein encompass the use of stereoisomerically pure forms of the compounds disclosed herein as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers can be separated by asymmetric synthesis or using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGrawHill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions page 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., SeparationOf Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F, Enantiomer Separation: Fundamentals and Practical Methods (Springer Science&Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0050] It should also be noted that the compounds disclosed herein may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, the compounds are separated into E and Z isomers. In other embodiments, the compounds are mixtures of E and Z isomers.

[0051] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is present and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0052] As those skilled in the art readily appreciate, various functional groups and other structures may exhibit tautomerism, and all tautomers of Formula (I') or compounds of Formula (I) are within the scope of this application.

[0053] It should also be noted that the compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), sulfur 35( 35 S) or carbon-14 ( 14 C), or may be isotopically enriched, for example with deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15( 15 N) enrichment. As used in this application, an "isotopic configuration" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition different from the natural isotopic composition of the atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of the atom. The term "isotopic composition" is the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are used as therapeutic agents (e.g., cancer therapeutics), research reagents (e.g., binding assay reagents), and diagnostic agents (e.g., in vivo imaging agents). Regardless of whether they are radioactive, all isotopic variants of the compounds described in this application are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, isotopic configurations of the compounds disclosed in this application are provided, for example, such isotopic configurations are compounds enriched with deuterium, carbon 13, and / or nitrogen 15. As used herein, "deuterated" means a substance in which at least one hydrogen (H) has been replaced by deuterium (D or 2 H indicates a)-substituted compound, i.e., the compound is enriched in deuterium at at least one position.

[0054] It will be understood that, regardless of stereoisomerism or isotopic composition, each compound disclosed in this application can be provided in the form of any pharmaceutically acceptable salt discussed in this application. Similarly, it will be understood that isotopic composition can vary independently of the stereoisomerism composition of each compound mentioned in this application. In addition, although limited to those elements present in the corresponding compound disclosed in this application or its salt, isotopic composition can otherwise vary independently of the selection of the pharmaceutically acceptable salt of the corresponding compound.

[0055] It should be noted that if there is a discrepancy between a described structure and the name of that structure, the described structure should be given more consideration.

[0056] As used herein, "treating" refers to the complete or partial alleviation of a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition, or the slowing or prevention of further progression or worsening of those symptoms, or the alleviation or eradication of the cause of the disorder, disease, or condition itself. In one embodiment, the disorder is a neurodegenerative disease or a symptom thereof as described herein.

[0057] As used herein, "prevent" or "prevent" means to delay and / or prevent the complete or partial onset, recurrence, or spread of a disorder, disease, or condition; to prevent a subject from developing a disorder, disease, or condition; or to reduce the risk of a subject developing a disorder, disease, or condition. In one embodiment, the disorder is a neurodegenerative disease as described herein, or a symptom thereof.

[0058] The term "effective amount" in connection with a compound disclosed herein means an amount capable of treating or preventing a disorder, disease or condition disclosed herein, or a symptom thereof.

[0059] As used herein, the term "subject" or "patient" includes animals, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment, mammals, and in another embodiment, humans. In one embodiment, the subject is a human suffering from or at risk of an S1P5-mediated disease or a symptom thereof.

[0060] Although various features of the invention may be described in the context of a single embodiment, those features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment. Compound

[0061] In one aspect, the present application provides a compound of formula (I') or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, monocyclic 5- to 6-membered heteroaryl, or fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 1-4 heteroatoms independently selected from N, O and S, each of which is optionally substituted by 1-3 R 0 group substitution; Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C6 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl, -(6 to 10 membered bridged heterocyclylene)- and C1-C6 alkoxy, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O, or two R 0 The groups together form an oxo group; L 1 is -NH- or a bond; L 2 -NHC(O)-, -C(O)NH-, -SO2NH-, -NHSO2- or -(C1-C6 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1-3 heteroatoms selected from N, O and S; L 3 -NR 9 (C1-C6 alkylene)NR 9 -、-NR 9 C(O)(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -、-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, -(6- to 10-membered bridged heterocyclylene)(C1-C6 alkylene) z-, -(7- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -or-(O) z (6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 group substitution; L 4 for phenylene, -N(H)(phenylene), 5- to 6-membered heteroarylene, -N(H)(5- to 6-membered heteroarylene)-, 8- to 10-membered fused bicyclic heteroarylene, or 5- to 6-membered heterocyclylene, wherein the phenylene, heteroarylene, or heterocyclylene is optionally substituted by 1-4 R 10 and wherein the heteroarylene and heterocyclylene groups contain 1 to 3 heteroatoms selected from N, S and O; R 1a and R 1b Each is H or together form an oxo group; R 2 and R 3 are independently H, C1-C6 alkyl or halogen, or R 2 and R 3 Together they form an oxo group; or R 3 and R 11 Together they form a C3-C6 cycloalkylene group; Y is NH, O or a bond; R 4 is C3-C6 cycloalkyl, C1-C6 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C6 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C6 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-5 R 8 group substitution; W is O, -NR 5 - or key; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halogen or -OH, or two R 6 The groups together form a bridged C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halogen, C1-C6 haloalkyl or -OH, or two R7 The groups together form an oxo group; Each R 8 is independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halogen or -OH, or two R 10 The groups together form an oxo group; Each R 11 and R 12 are independently H, halogen, C3-C6 cycloalkyl, -OH, -NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; or R 11 and R 3 Together they form a C3-C6 cycloalkylene group; x is 0 or 1; y is 0, 1, 2, 3, 4, or 5; Each z is independently 0 or 1; X is N or CR 13 ; R 13 is H, halogen, -OH or C1-C6 alkyl; Z 1 is CH or N; and Z 2 is CH or N, The constraint condition is Z 1 and Z 2 Not all are N.

[0062] In another aspect, the present application provides a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, monocyclic 5- to 6-membered heteroaryl, or fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 1-4 heteroatoms independently selected from N, O and S, each of which is optionally substituted by 1-3 R 0 group substitution; Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C6 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 alkoxy, or two R 0 The groups together form an oxo group; L1 is -NH- or a bond; L 2 -NHC(O)-, -C(O)NH-, -SO2NH-, -NHSO2-, or a 5-membered heteroarylene group containing 1-3 heteroatoms selected from N, O and S; L 3 -NR 9 (C1-C6 alkylene)NR 9 -、-NR 9 C(O)(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -、-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(6- to 10-membered bridged heterocyclylene)(C1-C6 alkylene) z -, -(9- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -or-(O) z (6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 group substitution; L 4 for Phenylene, 5 to 6 membered heteroarylene or 5 to 6 membered heterocyclylene, wherein the phenylene, heteroarylene or heterocyclylene is optionally substituted by 1-4 R 10 Group substituted, and wherein the heteroarylene and heterocyclylene contain 1-3 heteroatoms selected from N and O; R 1a and R 1b Each is H or together form an oxo group; R 2 and R 3are independently H, C1-C6 alkyl or halogen, or R 2 and R 3 Together they form an oxo group; or R 3 and R 11 Together they form a C3-C6 cycloalkylene group; Y is NH or O; R 4 is C3-C6 cycloalkyl, C1-C6 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C6 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C6 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-5 R 8 group substitution; W is O, -NR 5 - or key; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halogen or -OH, or two R 6 The groups together form a bridged C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halogen, C1-C6 haloalkyl or -OH, or two R 7 The groups together form an oxo group; Each R 8 is independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halogen or -OH, or two R 10 The groups together form an oxo group; Each R 11 and R 12 are independently H, halogen, C3-C6 cycloalkyl, -OH, -NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; or R 11 and R 3 Together they form a C3-C6 cycloalkylene group; x is 0 or 1; y is 0, 1, 2, 3, 4, or 5; Each z is independently 0 or 1; X is N or CR 13 ; R 13 is H, halogen or C1-C6 alkyl; Z 1 is CH or N; and Z 2 is CH or N, The constraint condition is Z 1 and Z 2 Not all are N.

[0063] In some embodiments, Z 1 is CH or N; and Z 2 is CH or N, with the restriction that Z 1 and Z 2 Not all are N. In some embodiments, Z 1 and Z 2 Each is CH. In some embodiments, Z 1 is CH, and Z 2 is N. In some embodiments, Z 1 is N, and Z 2 For CH.

[0064] In some embodiments, ring A is phenyl, a monocyclic 5- to 6-membered heteroaryl, or a fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl groups contain 1-4 heteroatoms independently selected from N, O, and S, each of which is optionally substituted with 1-3 R 0 Group substitution.

[0065] In some embodiments, Ring A is phenyl optionally substituted with 1-3 R0 groups. In some embodiments, Ring A is phenyl optionally substituted with 1-2 R 0 In some embodiments, ring A is optionally substituted with 1 R 0 In some embodiments, ring A is optionally substituted with 2 R 0 In some embodiments, ring A is optionally substituted with 3 R 0 In some embodiments, Ring A is an unsubstituted phenyl group.

[0066] In some embodiments, Ring A is a monocyclic 5- to 6-membered heteroaryl optionally substituted with 1-3 R0 groups, wherein the heteroaryl contains 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring A is optionally substituted with 1 to 2 R 0A monocyclic 5- to 6-membered heteroaryl group substituted with a group, wherein the heteroaryl group contains 1-4 heteroatoms independently selected from N, O and S. In some embodiments, Ring A is optionally substituted with 1 R 0 A monocyclic 5- to 6-membered heteroaryl group substituted with a group, wherein the heteroaryl group contains 1-4 heteroatoms independently selected from N, O and S. In some embodiments, Ring A is optionally substituted with 2 R 0 A monocyclic 5- to 6-membered heteroaryl group substituted with a group, wherein the heteroaryl group contains 1-4 heteroatoms independently selected from N, O and S. In some embodiments, Ring A is optionally substituted with 3 R 0 In some embodiments, Ring A is an unsubstituted monocyclic 5- to 6-membered heteroaryl group, wherein the heteroaryl group contains 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring A is an unsubstituted monocyclic 5- to 6-membered heteroaryl group, wherein the heteroaryl group contains 1-4 heteroatoms independently selected from N, O, and S.

[0067] In some embodiments, Ring A is optionally substituted with 1-3 R 0 A monocyclic 5-membered heteroaryl group substituted with a group, wherein the heteroaryl group contains 1-4 heteroatoms independently selected from N, O and S. In some embodiments, Ring A is optionally substituted with 1-3 R 0 A monocyclic 5-membered heteroaryl group substituted with a group, wherein the heteroaryl group contains 1-2 heteroatoms independently selected from N and O. In some embodiments, Ring A is optionally substituted with 1-3 R 0 A monocyclic 6-membered heteroaryl group substituted with a group, wherein the heteroaryl group contains 1-4 heteroatoms independently selected from N, O and S. In some embodiments, Ring A is optionally substituted with 1-3 R 0 A monocyclic 6-membered heteroaryl group substituted with a group, wherein the heteroaryl group contains 1-3 heteroatoms independently selected from N and O. In some embodiments, Ring A is optionally substituted with 1-3 R 0 A monocyclic 6-membered heteroaryl group substituted with a group, wherein the heteroaryl group contains 1-2 heteroatoms independently selected from N and O. In some embodiments, ring A is optionally substituted with 1-3 R 0 In some embodiments, Ring A is optionally substituted with 1-3 R 0 In some embodiments, Ring A is optionally substituted with 1-3 R 0 In some embodiments, Ring A is optionally substituted with 1-2 R 0 In some embodiments, Ring A is optionally substituted with one R 0In some embodiments, Ring A is optionally substituted with 2 R 0 In some embodiments, Ring A is optionally substituted with 1-3 R 0 In some embodiments, Ring A is optionally substituted with 1-2 R 0 In some embodiments, Ring A is optionally substituted with one R 0 In some embodiments, Ring A is optionally substituted with 2 R 0 In some embodiments, ring A is a pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl group, each of which is optionally substituted with 1-3 R 0 In some embodiments, ring A is pyridyl or pyrimidinyl, each of which is optionally substituted with 1-3 R 0 In some embodiments, ring A is optionally substituted with 1-3 R 0 In some embodiments, ring A is optionally substituted with 1-3 R 0 A pyrimidinyl group substituted with a group.

[0068] In some embodiments, Ring A is

[0069] In some embodiments, Ring A is a fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 1-4 heteroatoms independently selected from N, O, and S, each of which is optionally substituted by 1-3 R 0 In some embodiments, Ring A is a fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl groups contain 2-4 heteroatoms independently selected from N, O and S, each of which is optionally substituted by 1-3 R 0 In some embodiments, Ring A is a fused bicyclic 9-membered heteroaryl or heterocyclic group containing 2-4 heteroatoms independently selected from N, O and S, and is optionally substituted by 1-3 R 0 In some embodiments, Ring A is a fused bicyclic 9-membered heteroaryl or heterocyclic group containing 2-4 heteroatoms independently selected from N, O and S, and is optionally substituted by 1 R 0 In some embodiments, Ring A is a fused bicyclic 9-membered heteroaryl or heterocyclic group containing 2-4 heteroatoms independently selected from N, O and S, and is optionally substituted by 2 R 0In some embodiments, Ring A is a fused bicyclic 9-membered heteroaryl or heterocyclyl containing 2-4 heteroatoms independently selected from N, O and S, and is optionally substituted by 3 R 0 In some embodiments, Ring A is a fused bicyclic 9-membered heteroaryl or heterocyclyl containing 2-4 heteroatoms independently selected from N, O and S, and is optionally substituted by 4 R 0 In some embodiments, Ring A is an unsubstituted fused bicyclic 9-membered heteroaryl or heterocyclyl containing 2-4 heteroatoms independently selected from N, O and S. In some embodiments, Ring A is a fused bicyclic 9-membered heteroaryl containing 2-4 heteroatoms independently selected from N, O and S, and is optionally substituted by 1-3 R 0 In some embodiments, Ring A is a fused bicyclic 9-membered heterocyclic group containing 2-4 heteroatoms independently selected from N, O and S, and is optionally substituted by 1-3 R 0 Group substitution.

[0070] In some embodiments, Ring A is: It should be understood that when -(R 0 ) 0-3 When drawn via a fused bicyclic heteroaryl or heterocyclic group, one or both of the fused rings may be R 0 In some embodiments, only one ring of the fused bicyclic ring is substituted by R 0 In some embodiments, the two rings of the fused bicyclic ring are substituted by R 0 The group is substituted so that the R 0 The total number of groups is 0-3.

[0071] In some embodiments, each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C6 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl, -(6 to 10 membered bridged heterocyclylene)- and C1-C6 alkoxy, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O, or two R 0 In some embodiments, each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), C1-C3 alkyl, C3-C5 cycloalkyl, -(6- to 8-membered bridged heterocyclylene)-, and C1-C3 alkoxy, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O, or two R 0 The groups together form an oxo group.

[0072] In some embodiments, R 0 In some embodiments, R0 is Cl, F or Br. In some embodiments, R 0 In some embodiments, R 0 is F. In some embodiments, R 0 For Br.

[0073] In some embodiments, R 0 It is -CN.

[0074] In some embodiments, R 0 is -NH2.

[0075] In some embodiments, R 0 is -NH(C1-C6 alkyl). 0 is -NH(C1-C3 alkyl). 0 is -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), or -NH(CH(CH3)2). In some embodiments, R 0 is -NH(CH3).

[0076] In some embodiments, R 0 In some embodiments, R0 is C1-C3 alkyl. In some embodiments, R 0 is methyl, ethyl, n-propyl or isopropyl. 0 In some embodiments, R 0 In some embodiments, R 0 In some embodiments, R 0 It is isopropyl.

[0077] In some embodiments, R 0 is a C3-C6 cycloalkyl group. 0 is a C3-C5 cycloalkyl group. 0 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 0 It is cyclopropyl.

[0078] In some embodiments, R 0 In some embodiments, R0 is C1-C3 alkoxy. In some embodiments, R 0 In some embodiments, R 0 In some embodiments, R 0It is -OCH2CH3.

[0079] In some embodiments, R 0 is -(6- to 8-membered bridged heterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O. In some embodiments, R 0 is -(6- to 7-membered bridged heterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O. In some embodiments, R 0 is -(6-membered bridged heterocyclylene)-, wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O. In some embodiments, R 0 is -(7-membered bridged heterocyclylene)-, wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O. In some embodiments, R 0 is -(8-membered bridged heterocyclylene)-, wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O. In some embodiments, R 0 for

[0080] In some embodiments, two R 0 The groups together form an oxo group.

[0081] In some embodiments, Ring A is optionally substituted with 1-3 R 0 phenyl substituted with a group; and each R 0 Independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), C1-C3 alkyl, C3-C6 cycloalkyl and C1-C3 alkoxy.

[0082] In some embodiments, Ring A is

[0083] In some embodiments, Ring A is a monocyclic 6-membered heteroaryl containing 1-2 heteroatoms independently selected from N and O and optionally substituted by 1-3 R 0 Group substituted; and each R 0 Independently selected from halogen, -CN, -NH2, -NH(C1-C6 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 alkoxy.

[0084] In some embodiments, Ring A is:

[0085] In some embodiments, Ring A is a fused bicyclic 9-membered heteroaryl or heterocyclyl containing 2-4 heteroatoms independently selected from N, O and S, and is optionally substituted by 1-3 R 0 Group substituted; and each R 0independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), C1-C3 alkyl, C3-C6 cycloalkyl, -(6- to 8-membered bridged heterocyclylene)-, and C1-C3 alkoxy, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O, or two R 0 The groups together form an oxo group.

[0086] In some embodiments, Ring A is:

[0087] In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 is the key.

[0088] In some embodiments, L 2 -NHC(O)-, -C(O)NH-, -SO2NH-, -NHSO2- or -(C1-C6 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1-3 heteroatoms selected from N, O and S. In some embodiments, L 2 is a 5-membered heteroarylene group containing 1-3 heteroatoms selected from N and O. In some embodiments, L 2 It is -NHC(O)- or triazolylene.

[0089] In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 It is -NHSO2-.

[0090] In some embodiments, L 2 is a 5-membered heteroarylene group containing 1 to 3 heteroatoms selected from N, O and S. In some embodiments, L 2 is a 5-membered heteroarylene group containing 1-3 heteroatoms selected from N and O. In some embodiments, L 2 is a 5-membered heteroarylene group containing 2 nitrogen atoms. 2 is a 5-membered heteroarylene group containing 3 nitrogen atoms. 2 is a 5-membered heteroarylene group containing 1 nitrogen atom and 1 oxygen atom. 2 is a 5-membered heteroarylene group containing 1 nitrogen atom and 1 sulfur atom.2 is a 5-membered to 1-heteroaryl group containing 1 nitrogen atom. 2 is triazolylene, imidazolylene, pyrazolylene, oxazolylene, isoxazolylene or pyrrolylene.

[0091] In some embodiments, L 2 -(C1-C6 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene group contains 1-3 heteroatoms selected from N, O and S. In some embodiments, L 2 -(C1-C3 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene group contains 1-3 heteroatoms selected from N, O and S. In some embodiments, L 2 -(C1-C3 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1-3 heteroatoms selected from N and O. In some embodiments, the 5-membered heteroarylene contains 1-3 nitrogen atoms. In some embodiments, the 5-membered heteroarylene contains 1 nitrogen atom. In some embodiments, the 5-membered heteroarylene contains 2 nitrogen atoms. In some embodiments, the 5-membered heteroarylene contains 3 nitrogen atoms. In some embodiments, the 5-membered heteroarylene contains 1 nitrogen atom and 1 oxygen atom. In some embodiments, the 5-membered heteroarylene contains 1 nitrogen atom and 1 sulfur atom. In some embodiments, the 5-membered heteroarylene is triazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl or pyrrolyl. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, -(C1-C6 alkylene) z - is -CH2-. In some embodiments, -(C1-C6 alkylene) z - is -CH2CH2-. In some embodiments, -(C1-C6 alkylene) z - is -CH2CH2CH2-. In some embodiments, L 2 for

[0092] In some embodiments, L 2 for

[0093] In some embodiments, L 2 for

[0094] In some embodiments, L 3 -NR 9 (C1-C6 alkylene)NR 9 -、-NR 9 C(O)(C1-C6 alkylene)z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -、-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, -(6- to 10-membered bridged heterocyclylene)(C1-C6 alkylene) z -, -(7- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -or-(O) z (6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 group substitution;

[0095] In some embodiments, L 3 -NR 9 (C1-C3 alkylene)NR 9 -、-NR 9 C(O)(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C3 alkylene) z -、-NR 9 (C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9C(O)(phenylene)NR 9 -, -(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, -O(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, -(6- to 10-membered bridged heterocyclylene)(C1-C3 alkylene) z -, -(7- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -or-(O) z (6- to 10-membered spiroheterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1 or 2 R 7 Group substitution.

[0096] In some embodiments, L 3 -NR 9 (C1-C6 alkylene)NR 9 -. In some embodiments, L 3 -NR 9 (C1-C3 alkylene)NR 9 -. In some embodiments, L 3 -NR 9 (CH2)NR 9 -、-NR 9 (CH2CH2)NR 9 -or-NR 9 (CH2CH2CH2)NR 9 -. In some embodiments, L 3 -NR 9 (CH2CH2CH2)NR 9 -.

[0097] In some embodiments, L 3 -NR 9 C(O)(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -NR 9 C(O)(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L3 -NR 9 C(O)(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-3 R 7 In some embodiments, L 3 -NR 9 C(O)(C1-C3 alkylene) z (4 to 7 membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-3 R 7 In some embodiments, L 3 -NR 9 C(O)(C1-C3 alkylene) z (5- to 6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-3 R 7 In some embodiments, L 3 -NR 9 C(O)(C1-C3 alkylene) z (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-3 R 7 In some embodiments, L 3 -NR 9 C(O)(6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-3 R 7 In some embodiments, L 3 -NR 9 C(O)CH2(6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-3 R 7 Group substitution.

[0098] In some embodiments, L 3 -(4- to 7-membered heterocyclylene)CR 11 R 12 -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(4- to 7-membered heterocyclylene)CR 11 R 12 -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(4- to 7-membered heterocyclylene)CR 11 R 12-, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(5- to 6-membered heterocyclylene)CR 11 R 12 -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(6-membered heterocyclylene)CR 11 R 12 -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 Group substitution.

[0099] In some embodiments, L 3 -(4- to 7-membered heterocyclylene)(CO) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(5- to 7-membered heterocyclylene)(CO) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(5- to 7-membered heterocyclylene)(CO) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(6- to 7-membered heterocyclylene)(CO) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -(6- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -(6- to 7-membered heterocyclylene)(CO)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 Group substitution.

[0100] In some embodiments, L 3 -(4 to 7 membered heterocyclylene) (NR 9 ) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7In some embodiments, L 3 -(4 to 7 membered heterocyclylene) (NR 9 ) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(4 to 7 membered heterocyclylene) (NR 9 ) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(5 to 7 membered heterocyclylene) (NR 9 ) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(6 to 7 membered heterocyclylene) (NR 9 ) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -(6- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(6 to 7 membered heterocyclylene) (NR 9 )-, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 Group substitution.

[0101] In some embodiments, L 3 for-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 for-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 for-(NR 9 ) z(4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 for-(NR 9 ) z (5- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 for-(NR 9 ) z (6- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 for-(NR 9 ) z (6- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 for-(NR 6 ) z (6- to 7-membered heterocyclylene)(CH2) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 for-(NR 6 ) z (6- to 7-membered heterocyclylene)(CH2)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 for-(NR 9 ) z (6- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 is -(6- to 7-membered heterocyclylene)(CH2)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -(6- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 Group substitution.

[0102] In some embodiments, L 3 -NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heteroarylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heteroarylene contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -NR 9 (C1-C6 alkylene) z (4 to 7 membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 -NR 9 (C1-C6 alkylene) z (5- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 -NR 9 (C1-C6 alkylene) z (6- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 -NR 9 (C1-C6 alkylene) z (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 -NR 9 (C1-C3 alkylene) z (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 -NR 9 (CH2) z (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 -NR9 (CH2)(6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 -NR 9 (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 Group substitution.

[0103] In some embodiments, L 3 -NR 9 C(O)(phenylene)NR 9 -.

[0104] In some embodiments, L 3 -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(C1-C6 alkylene) z (4 to 7 membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(C1-C6 alkylene) z (5- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(C1-C6 alkylene) z (5- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 -(C1-C3 alkylene) z (5- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 -(C1-C3 alkylene) z (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 is -(CH2)(6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7In some embodiments, L 3 -(CH2CH2)(6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 Group substitution.

[0105] In some embodiments, L 3 -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(C1-C3 alkylene) z (5- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(C1-C3 alkylene) z (5- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(C1-C3 alkylene) z (6-membered heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(CH2)(6-membered heterocyclylene)CH2-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(5- to 6-membered heterocyclylene)CH2-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R7 In some embodiments, L 3 -(7-membered heterocyclylene)CH2-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 Group substitution.

[0106] In some embodiments, L 3 -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -O(C1-C6 alkylene) z (4 to 7 membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -O(C1-C6 alkylene) z (4 to 7 membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 -O(C1-C3 alkylene) z (4 to 7 membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 is -O(C1-C3 alkylene)(4 to 7 membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -O(CH2)(4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -O(4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -O(4- to 6-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 Group substitution.

[0107] In some embodiments, L 3 -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z-, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -O(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -O(C1-C3 alkylene)(4- to 7-membered heterocyclyl)(C1-C3 alkylene)-, wherein the heterocyclyl contains 1-2 nitrogen atoms and is optionally substituted with 1-5 R 7 In some embodiments, L 3 is -O(4- to 7-membered heterocyclylene)(C1-C3 alkylene)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -O(CH2)(4- to 7-membered heterocyclylene)(CH2)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -O(4- to 7-membered heterocyclylene)(CH2)-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -O(4- to 6-membered heterocyclylene)CH2-, wherein the heterocyclylene contains 1-2 nitrogen atoms and is optionally substituted by 1-5 R 7 In some embodiments, the heterocyclylene group is saturated. In some embodiments, the heterocyclylene group is partially unsaturated.

[0108] In some embodiments, L 3-(6- to 10-membered bridged heterocyclylene)(C1-C6 alkylene) z -, wherein the heteroarylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(6- to 10-membered bridged heterocyclylene)(a1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(7- to 9-membered bridged heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(7- to 9-membered bridged heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(7- to 9-membered bridged heterocyclylene)(CH2) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(7- to 9-membered bridged heterocyclylene)-, wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(7-membered bridged heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(9-membered bridged heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-2 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 Group substitution.

[0109] In some embodiments, L 3 -(7- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3-(7- to 10-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(7-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(7-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(7-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(7-membered fused bicyclic heterocyclylene)(CH2) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(7-membered fused bicyclic heterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(8-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(8-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(8-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(8-membered fused bicyclic heterocyclylene)(CH2) z-, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(8-membered fused bicyclic heterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(9-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(9-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(9-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(9-membered fused bicyclic heterocyclylene)(CH2) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(9-membered fused bicyclic heterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 Group substitution.

[0110] In some embodiments, L 3 -(O) z (6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(O) z (7- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(O) z(7- to 9-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene group contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -O(7- to 9-membered spiroheterocyclylene)(C1-C6 alkylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -O(7- to 9-membered spiroheterocyclylene)(CH2)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -O(6- to 10-membered spiroheterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 -(6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -(6- to 10-membered spiroheterocyclylene)(CH2)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 In some embodiments, L 3 is -(6- to 10-membered spiroheterocyclylene)-, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 Group substitution.

[0111] In some embodiments, each R 9 are independently H or C1-C6 alkyl. 9 are independently H or C1-C3 alkyl. 9 are independently H or -CH3.

[0112] In some embodiments, R 9 For H.

[0113] In some embodiments, R 9 is a C1-C6 alkyl group. 9 is a C1-C3 alkyl group. 9 is methyl, ethyl, n-propyl or isopropyl. 9 In some embodiments, R9 In some embodiments, R 9 In some embodiments, R 9 It is isopropyl.

[0114] In some embodiments, each z is independently 0 or 1. In some embodiments, z is 0. In some embodiments, z is 1.

[0115] In some embodiments, each R 7 are independently C1-C6 alkyl, halogen, C1-C6 haloalkyl or -OH, or two R 7 In some embodiments, each R 7 are independently C1-C3 alkyl, halogen, C1-C3 haloalkyl or -OH, or two R 7 In some embodiments, each R 7 are independently -CH3, -CF3, F or -OH, or two R 7 The groups together form an oxo group.

[0116] In some embodiments, R7 is C1-C6 alkyl. 7 is a C1-C3 alkyl group. 7 is methyl, ethyl, n-propyl or isopropyl. 7 In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R 7 It is isopropyl.

[0117] In some embodiments, R 7 In some embodiments, R 7 is Cl, F or Br. In some embodiments, R 7 In some embodiments, R 7 is F. In some embodiments, R 7 For Br.

[0118] In some embodiments, R 7 is a C1-C6 haloalkyl group. 7 is a C1-C6 haloalkyl group containing 1-13 halogen atoms. 7 is C1-C3 haloalkyl. 7 is a C1-C3 haloalkyl group containing 1-7 halogen atoms. 7In some embodiments, R 7 In some embodiments, R 7 is -CHF2.

[0119] In some embodiments, R 7 It is -OH.

[0120] In some embodiments, two R 7 The groups together form an oxo group.

[0121] In some embodiments, each R 11 and R 12 R is independently H, halogen, C3-C6 cycloalkyl, -OH, -NH(C1-C6 alkyl), C1-C6 haloalkyl or C1-C6 alkyl. 11 and R 12 are independently H or C1-C3 alkyl. 11 and R 12 are independently H or -CH3.

[0122] In some embodiments, R 11 is H. In some embodiments, R 11 In some embodiments, R 11 is Cl, F or Br. In some embodiments, R 11 In some embodiments, R 11 is F. In some embodiments, R 11 For Br.

[0123] In some embodiments, R 11 is a C3-C6 cycloalkyl group. 11 is a C3-C5 cycloalkyl group. 11 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 11 In some embodiments, R 11 It is cyclobutyl.

[0124] In some embodiments, R 11 It is -OH.

[0125] In some embodiments, R 11 is -NH(C1-C6 alkyl). 11is -NH(C1-C3 alkyl). 11 is -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), or -NH(CH(CH3)2). In some embodiments, R 11 is -NH(CH3).

[0126] In some embodiments, R 11 is a C1-C6 haloalkyl group. 11 is a C1-C6 haloalkyl group containing 1-13 halogen atoms. 11 is a C1-C3 haloalkyl group. 11 is a C1-C3 haloalkyl group containing 1-7 halogen atoms. 11 In some embodiments, R 11 In some embodiments, R 11 is -CHF2.

[0127] In some embodiments, R 11 is a C1-C6 alkyl group. 11 is a C1-C3 alkyl group. 11 is methyl, ethyl, n-propyl or isopropyl. 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 It is isopropyl.

[0128] In some embodiments, R 12 For H.

[0129] In some embodiments, R 12 In some embodiments, R 12 is Cl, F or Br. In some embodiments, R 12 In some embodiments, R 12 is F. In some embodiments, R 12 For Br.

[0130] In some embodiments, R 12 is a C3-C6 cycloalkyl group. 12is a C3-C5 cycloalkyl group. 12 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 12 In some embodiments, R 12 It is cyclobutyl.

[0131] In some embodiments, R 12 It is -OH.

[0132] In some embodiments, R 12 is -NH(C1-C6 alkyl). 12 is -NH(C1-C3 alkyl). 12 is -NH(CH3), -NH(CH2CH3), -NH(CH2CH2CH3), or -NH(CH(CH3)2). In some embodiments, R 12 is -NH(CH3).

[0133] In some embodiments, R 12 is a C1-C6 haloalkyl group. 12 is a C1-C6 haloalkyl group containing 1-13 halogen atoms. 12 is C1-C3 haloalkyl. 12 is a C1-C3 haloalkyl group containing 1-7 halogen atoms. 12 In some embodiments, R 12 In some embodiments, R 12 is -CHF2.

[0134] In some embodiments, R 12 is a C1-C6 alkyl group. 12 is a C1-C3 alkyl group. 12 is methyl, ethyl, n-propyl or isopropyl. 12 In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 It is isopropyl.

[0135] In some embodiments, R 11 and R12 Each is H. In some embodiments, R 11 and R 12 Each is -CH3. In some embodiments, R 11 and R 12 One of them is H, and R 11 and R 12 The other is -CH3.

[0136] In some embodiments, R 11 and R 3 Together they form a C3-C6 cycloalkylene. In some embodiments, R 11 and R 3 Together they form a C3-C5 cycloalkylene. In some embodiments, R 11 and R 3 Together they form a C4-C6 cycloalkylene. In some embodiments, R 11 and R 3 Together they form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene. In some embodiments, R 11 and R 3 Together they form cyclopropylene.

[0137] In some embodiments, L 3 for:

[0138] In some embodiments, L 4 for phenylene, -N(H)(phenylene), 5- to 6-membered heteroarylene, -N(H)(5- to 6-membered heteroarylene)-, 8- to 10-membered fused bicyclic heteroarylene, or 5- to 6-membered heterocyclylene, wherein the phenylene, heteroarylene, or heterocyclylene is optionally substituted by 1-4 R 10 The heteroarylene and heterocyclylene groups are substituted with N, S and O atoms.

[0139] In some embodiments, L 4 for In some embodiments, R 1a and R 1b Each is H or together form an oxo group. In some embodiments, R 1a and R 1b Each is H. In some embodiments, R 1a and R 1b Together they form an oxo group. In some embodiments, L 4 for In some embodiments, L 4 for

[0140] In some embodiments, L 4 is phenylene, -NH(phenylene), 5- to 6-membered heteroarylene, -N(H)(5- to 6-membered heteroarylene)-, 8- to 10-membered fused bicyclic heteroarylene, or 5- to 6-membered heterocyclylene, each of which is optionally substituted with 1-4 R 10 The heteroarylene and heterocyclylene groups are substituted with N, S and O atoms.

[0141] In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-3 R 10 In some embodiments, L 4 is optionally 1-2 R 10 In some embodiments, L 4 For optionally through 1 R 10 In some embodiments, L 4 is an unsubstituted phenylene group.

[0142] In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-3 R 10 In some embodiments, L 4 is optionally 1-2 R 10 In some embodiments, L 4 For optionally through 1 R 10 In some embodiments, L 4 is unsubstituted -N(H)phenylene.

[0143] In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L is a 5- to 6-membered heteroarylene group substituted with a group, wherein the heteroarylene group contains 1-3 heteroatoms selected from N, S and O. 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-4 R 10In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L is a 5- to 6-membered heteroarylene group substituted with a group, wherein the heteroarylene group contains 2 heteroatoms selected from N and S. 4 is optionally 1-4 R 10 In some embodiments, the 5- to 6-membered heteroarylene group is a pyridylene group, a pyrimidylene group, a pyrazinylene group, a pyridazinylene group, a triazolylene group, an imidazolylene group, a thiazolylene group, a pyrazolylene group, or a pyrrolylene group, each of which is optionally substituted with 1 to 4 R 10 Group substitution.

[0144] In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-4 R 10 A 10-membered fused heteroarylene group substituted by a group, wherein the heteroarylene group contains 1 to 3 nitrogen atoms.

[0145] In some embodiments, L 4 is optionally 1-4 R 10In some embodiments, L is substituted with -N(H)(5- to 6-membered heteroarylene), wherein the heteroarylene contains 1-3 heteroatoms selected from N, S and O. 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, the 5- to 6-membered heteroarylene group is a pyridylene, pyrimidylene, pyrazinylene, pyridazinylene, triazolylene, imidazolylene, thiazolylene, pyrazolylene, or pyrrolylene group, each of which is optionally substituted with 1-4 R 10 Group substitution.

[0146] In some embodiments, L 4 is optionally 1-4 R 10 In some embodiments, L is a 5- to 6-membered heterocyclylene substituted with a group, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O. 4 is optionally 1-4 R 10 In some embodiments, L is a 5-membered heterocyclyl group substituted with a group, wherein the heterocyclyl group contains 1-3 heteroatoms selected from N and O. 4 is optionally 1-4 R 10 In some embodiments, L is a 6-membered heterocyclyl group substituted with a group, wherein the heterocyclyl group contains 1-3 heteroatoms selected from N and O. 4 is optionally 1-4 R 10 In some embodiments, L is a 5- to 6-membered heterocyclylene substituted with a group, wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O. 4 is optionally 1-4 R 10 In some embodiments, L 4 is optionally 1-4 R 10 A 5- to 6-membered heterocyclylene group substituted by a radical, wherein the heterocyclylene group contains one nitrogen atom.

[0147] In some embodiments, each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halogen or -OH, or two R 10In some embodiments, each R 10 are independently C1-C3 alkoxy, C1-C3 alkyl, halogen or -OH, or two R 10 In some embodiments, each R 10 are independently -OCH3, -CH3, Cl, F or -OH, or two R 10 The groups together form an oxo group.

[0148] In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 It is -OCH2CH3.

[0149] In some embodiments, R 10 is a C1-C6 alkyl group. 10 is a C1-C3 alkyl group. 10 is methyl, ethyl, n-propyl or isopropyl. 10 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 It is isopropyl.

[0150] In some embodiments, R 10 In some embodiments, R 10 is Cl, F or Br. In some embodiments, R 10 In some embodiments, R 10 is F. In some embodiments, R 10 For Br.

[0151] In some embodiments, R 10 It is -OH.

[0152] In some embodiments, two R 10 The groups together form an oxo group.

[0153] In some embodiments, L 4 for:

[0154] In some embodiments, R 2 and R 3 are independently H, C1-C6 alkyl or halogen, or R 2 and R 3 Together they form an oxo group. In some embodiments, R 2 and R 3 are independently H, C1-C3 alkyl or halogen. 2 and R 3 are independently H, -CH3 or F. In some embodiments, R 2 and R 3 Together they form an oxo group.

[0155] In some embodiments, R 2 For H.

[0156] In some embodiments, R 2 is a C1-C6 alkyl group. 2 is a C1-C3 alkyl group. 2 is methyl, ethyl, n-propyl or isopropyl. 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 It is isopropyl.

[0157] In some embodiments, R 2 In some embodiments, R 2 is Cl, F or Br. In some embodiments, R 2 In some embodiments, R 2 is F. In some embodiments, R 2 For Br.

[0158] In some embodiments, R 3 For H.

[0159] In some embodiments, R 3 is a C1-C6 alkyl group. 3 is a C1-C3 alkyl group. 3 is methyl, ethyl, n-propyl or isopropyl. 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R3 It is isopropyl.

[0160] In some embodiments, R 3 In some embodiments, R 3 is Cl, F or Br. In some embodiments, R 3 In some embodiments, R 3 is F. In some embodiments, R 3 For Br.

[0161] In some embodiments, R 2 and R 3 Together they form an oxo group.

[0162] In some embodiments, R 3 and R 11 Together they form a C3-C6 cycloalkylene. In some embodiments, R 3 and R 11 Together they form a C3-C5 cycloalkylene. In some embodiments, R 3 and R 11 Together they form a C4-C6 cycloalkylene. In some embodiments, R 3 and R 11 Together they form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene. In some embodiments, R 3 and R 11 Together they form cyclopropylene.

[0163] In some embodiments, x is 0 or 1. In some embodiments, x is 0. In some embodiments, x is 1.

[0164] In some embodiments, Y is NH, O, or a bond. In some embodiments, Y is NH. In some embodiments, Y is O. In some embodiments, Y is a bond.

[0165] In some embodiments, R 4 is C3-C6 cycloalkyl, C1-C6 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C6 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C6 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-5 R 8 In some embodiments, R 4is C3-C6 cycloalkyl, C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C3 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C3 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-2 R 8 Group substitution.

[0166] In some embodiments, R 4 is optionally 1-5 R 8 In some embodiments, R 4 is optionally 1-5 R 8 In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with 1 to 5 R 8 In some embodiments, R 4 is optionally 1-5 R 8 In some embodiments, R 4 is optionally 1-5 R 8 In some embodiments, R 4 is optionally 1-5 R 8 In some variations, R 4 is optionally 1-5 R 8 In some variations, R 4 After 1-2 R 8 In some embodiments, R 4 is an unsubstituted C3-C6 cycloalkyl group.

[0167] In some embodiments, R 4 is C1-C6 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl group is optionally substituted with 1-5 R 8 In some embodiments, R 4 is C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl group is optionally substituted with 1-5 R 8 Group substitution.

[0168] In some embodiments, R 4 is C1-C3 alkylene-(cyclopropyl), wherein the cyclopropyl group is optionally substituted with 1-5 R 8In some embodiments, R 4 is C1-C3 alkylene-(cyclobutyl), wherein the cyclobutyl group is optionally substituted with 1-5 R 8 In some embodiments, R 4 is C1-C3 alkylene-(cyclopentyl), wherein the cyclopentyl is optionally substituted with 1-5 R 8 In some embodiments, R 4 is C1-C3 alkylene-(cyclohexyl), wherein the cyclohexyl group is optionally substituted with 1-5 R 8 In some embodiments, R 4 is -CH2-(C3-C6 cycloalkyl), wherein the cycloalkyl group is optionally substituted with 1-5 R 8 In some embodiments, R 4 is -CH2CH2-(C3-C6 cycloalkyl), wherein the cycloalkyl group is optionally substituted with 1-5 R 8 Group substitution.

[0169] In some embodiments, R 4 is optionally 1-5 R 8 In some embodiments, R 4 is optionally 1-5 R 8 In some embodiments, R 4 is optionally 1-5 R 8 In some embodiments, R 4 is optionally 1-5 R 8 In some variations, R 4 For 1-3 R 8 substituted 4- to 6-membered heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O. In some variations, R 4 For an R 8 substituted 4- to 6-membered heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O. In some variations, R 4 is an unsubstituted 4- to 6-membered heterocyclyl group, wherein the heterocyclyl group contains 1-3 heteroatoms selected from N and O. In some embodiments, the 4- to 6-membered heterocyclyl group is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionally substituted with 1-5 R 8Group substitution.

[0170] In some embodiments, R 4 is C1-C6 alkylene-(4 to 6 membered heterocyclic group), wherein the heterocyclic group is optionally substituted by 1 to 5 R 8 In some embodiments, R 4 is C1-C3 alkylene-(4 to 6 membered heterocyclyl), wherein the heterocyclyl is optionally substituted by 1 to 5 R 8 In some embodiments, R 4 is -CH2(4- to 6-membered heterocyclyl), wherein the heterocyclyl is optionally substituted by 1-5 R 8 In some embodiments, R 4 is -CH2CH2(4- to 6-membered heterocyclyl), wherein the heterocyclyl is optionally substituted by 1-5 R 8 In some embodiments, the 4- to 6-membered heterocyclyl contains 1-2 heteroatoms selected from N and O. In some embodiments, the 4- to 6-membered heterocyclyl contains one nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains one oxygen atom. In some variations, the 4- to 6-membered heterocyclyl is substituted with 1-3 R 8 In some variations, the 4- to 6-membered heterocyclic group is substituted by one R 8 In some variations, the 4- to 6-membered heterocyclyl is unsubstituted. In some embodiments, the 4- to 6-membered heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, azetidinyl, or piperazinyl, each of which is optionally substituted with 1-5 R 8 Group substitution.

[0171] In some embodiments, R 4 is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group is optionally substituted by 1-5 R 8 In some embodiments, R 4 is a 5-membered heteroaryl group, wherein the heteroaryl group is optionally substituted by 1-5 R 8 In some embodiments, R 4 is a 6-membered heteroaryl group, wherein the heteroaryl group is optionally substituted by 1-5 R 8 In some embodiments, R 4is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group is optionally substituted by 1-5 R 8 In some embodiments, R 4 is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group is optionally substituted by 1-5 R 8 In some variations, the 5- to 6-membered heteroaryl group is substituted with 1-3 R 8 In some variations, the 5- to 6-membered heteroaryl group is substituted by one R 8 In some variations, the 5- to 6-membered heteroaryl is unsubstituted. In some embodiments, the 5- to 6-membered heteroaryl is piperidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, or imidazolyl, each of which is optionally substituted with 1-5 R 8 Group substitution.

[0172] In some embodiments, R 4 is C1-C6 alkylene-(5 to 6 membered heteroaryl), wherein the heteroaryl is optionally substituted by 1 to 5 R 8 In some embodiments, R 4 is C1-C6 alkylene-(5-membered heteroaryl), wherein the heteroaryl is optionally substituted by 1-5 R 8 In some embodiments, R 4 is C1-C6 alkylene-(6-membered heteroaryl), wherein the heteroaryl is optionally substituted by 1-5 R 8 In some embodiments, R 4 is C1-C3 alkylene-(5 to 6 membered heteroaryl), wherein the heteroaryl is optionally substituted by 1 to 5 R 8 In some embodiments, R 4 is -CH2-(5- to 6-membered heteroaryl), wherein the heteroaryl is optionally substituted by 1-5 R 8 In some embodiments, R 4 is -CH2CH2-(5- to 6-membered heteroaryl), wherein the heteroaryl is optionally substituted with 1-5 R 8 In some embodiments, R 4 is C1-C3 alkylene-(5 to 6 membered heteroaryl), wherein the heteroaryl is optionally substituted by 1 to 5 R8 In some embodiments, R 4 is C1-C3 alkylene-(5 to 6 membered heteroaryl), wherein the heteroaryl is optionally substituted by 1 to 5 R 8 In some variations, the 5- to 6-membered heteroaryl group is substituted with 1-3 R 8 In some variations, the 5- to 6-membered heteroaryl group is substituted by one R 8 In some variations, the 5- to 6-membered heteroaryl is unsubstituted. In some embodiments, the 5- to 6-membered heteroaryl is piperidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, or imidazolyl, each of which is optionally substituted with 1-5 R 8 Group substitution.

[0173] In some embodiments, R 4 is a C1-C6 alkyl group. 4 is a C1-C3 alkyl group. 4 is a C1-C4 alkyl group. 4 is methyl, ethyl, n-propyl, isopropyl, tert-butyl or -CH2CH(CH3)2. In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 It is -CH2CH(CH3)2.

[0174] In some embodiments, R 4 is a C1-C6 haloalkyl group. 4 is a C1-C6 haloalkyl group containing 1-13 halogen atoms. 4 is C1-C3 haloalkyl. 4 is a C1-C3 haloalkyl group containing 1 to 7 halogen atoms. 4 In some embodiments, R 4 In some embodiments, R 4is -CHF2. In some embodiments, R 4 is a C2-C3 haloalkyl group containing 1-7 halogen atoms. 4 It is -CH2CF3, -CH2CH2F, -CH2CF2CH3, -CH(CH3)CF3 or -CH2CH2CF3.

[0175] In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 It is -CH(CH3)CH2OH or -CH2C(CH3)2OH.

[0176] In some embodiments, R 4 is C1-C6 alkyl-CN. In some embodiments, R 4 is C1-C3 alkyl-CN. In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 is -CH(CH3)CN. In some embodiments, R 4 is -C(CH3)2CN. In some embodiments, R 4 It is -CH(CH2CH3)CN or -CH2CH(CH3)CN.

[0177] In some embodiments, each R 8 is independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN or -OH. In some embodiments, each R 8is independently -SO2(C1-C3 alkyl), -C(O)(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, halogen, -CN or -OH. In some embodiments, each R 8 is independently -SO2CH3, -C(O)CH3, methyl, ethyl, -CH2CF3, F, -CN or -OH.

[0178] In some embodiments, R 8 is -SO2(C1-C6 alkyl). 8 is -SO2(C1-C3 alkyl). 8 In some embodiments, R 8 In some embodiments, R 8 It is -SO2CH2CH2CH3.

[0179] In some embodiments, R 8 is -C(O)(C1-C6 alkyl). 8 is -C(O)(C1-C3 alkyl). 8 is -C(O)CH3. In some embodiments, R 8 is -C(O)CH2CH3. In some embodiments, R 8 It is -C(O)CH2CH2CH3.

[0180] In some embodiments, R 8 is a C1-C6 alkyl group. 8 is a C1-C3 alkyl group. 8 is methyl, ethyl, n-propyl or isopropyl. 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 It is isopropyl.

[0181] In some embodiments, R 8 is a C1-C6 haloalkyl group. 8 is a C1-C6 haloalkyl group containing 1 to 13 halogen atoms. 8 is C1-C3 haloalkyl. 8 is a C1-C3 haloalkyl group containing 1-7 halogen atoms. 8In some embodiments, R 8 In some embodiments, R 8 It is -CH2CF3.

[0182] In some embodiments, R 8 In some embodiments, R 8 is Cl, F or Br. In some embodiments, R 8 In some embodiments, R 8 is F. In some embodiments, R 8 For Br.

[0183] In some embodiments, R 8 It is -CN.

[0184] In some embodiments, R 8 It is -OH.

[0185] In some embodiments, R 4 Methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CH2CH(CH3)2, -CH2CF3, -CH2CH2F, -CH2CF2CH3, -CH(CH3)CF3, -CH2CH2CF3, -CH(CH3)CH2OH, -CH2C(CH3)2OH, -CH2CN, -CH(CH3)CN, -C(CH3)2CN, -CH(CH2CH3)CN, -CH2CH(CH3)CN,

[0186] In some embodiments, W is O, -NR 5 In some embodiments, W is O, -N(H)-, -N(CH3)-, or a bond.

[0187] In some embodiments, W is O.

[0188] In some embodiments, W is a bond.

[0189] In some embodiments, W is -NR 5 -.

[0190] In some embodiments, R 5 is H or C1-C6 alkyl. 5 is H or C1-C3 alkyl.

[0191] In some embodiments, R 5 For H.

[0192] In some embodiments, R 5 is a C1-C6 alkyl group. 5 is a C1-C3 alkyl group. 5 is methyl, ethyl, n-propyl or isopropyl. 5 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 It is isopropyl.

[0193] In some embodiments, W is -N(H)-. In some embodiments, W is -N(C1-C6 alkyl)-. In some embodiments, W is -N(CH3)-.

[0194] In some embodiments, each R 6 are independently C1-C6 alkyl, halogen or -OH, or two R 6 The groups together form a bridged C1-C3 alkylene group. 6 are independently C1-C3 alkyl, halogen or -OH, or two R 6 The groups together form a bridged C1-C2 alkylene group. 6 are independently -CH3, Cl or -OH, or two R 6 The groups together form a bridged C1-C2 alkylene group.

[0195] In some embodiments, R 6 is a C1-C6 alkyl group. 6 is a C1-C3 alkyl group. 6 is methyl, ethyl, n-propyl or isopropyl. 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 It is isopropyl.

[0196] In some embodiments, R 6 In some embodiments, R 6 is Cl, F or Br. In some embodiments, R 6 In some embodiments, R 6is F. In some embodiments, R 6 For Br.

[0197] In some embodiments, R 6 It is -OH.

[0198] In some embodiments, two R 6 The groups together form a bridged C1-C3 alkylene group. In some embodiments, the two R 6 The groups together form a bridged C1-C2 alkylene group. In some embodiments, the two R 6 In some embodiments, the two R 6 In some embodiments, the two R 6 The groups together form a bridged propylene group.

[0199] In some embodiments, y is 0, 1, 2, 3, 4, or 5. In some embodiments, y is 0 or 1. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, y is 5.

[0200] In some embodiments, for:

[0201] In some embodiments, X is N or CR 13 In some embodiments, X is CR 13 ; and R 13 is H, halogen, -OH or C1-C3 alkyl.

[0202] In some embodiments, X is N.

[0203] In some embodiments, X is CR 13 .

[0204] In some embodiments, R 13 is H, halogen, -OH or C1-C6 alkyl. 13 is H, halogen, -OH or C1-C3 alkyl. 13 is H, CH3, -OH or F.

[0205] In some embodiments, R 13 For H.

[0206] In some embodiments, R 13 In some embodiments, R 13is Cl, F or Br. In some embodiments, R 13 In some embodiments, R 13 is F. In some embodiments, R 13 For Br.

[0207] In some embodiments, R 13 It is -OH.

[0208] In some embodiments, R 13 is a C1-C6 alkyl group. 13 is a C1-C3 alkyl group. 13 is methyl, ethyl, n-propyl or isopropyl. 13 In some embodiments, R 13 In some embodiments, R 13 In some embodiments, R 13 It is isopropyl.

[0209] In some embodiments, the compound of formula (I') or (I) is a compound of formula (IA), (IB), (IC), (ID), or (IE): Among them, ring A, R 2 、R 3 、R 4 、R 6 、R 10 、L 1 、L 2 、L 3 , W, X, Y, Z 1 , Z 2 , x and y are as described for formula (I') or (I).

[0210] In some embodiments, the compound of formula (I') or (I) is a compound of formula (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb): Among them, ring A, R 2 、R 3 、R 4 、R 6 、L 3 、L 4 , W, X, Y, Z 1 、z 2 , x and y are as described for formula (I') or (I).

[0211] In some embodiments, the compound of formula (I') or (I) is a compound of formula (Ia): Among them, ring A, R 2 、R 3 、R 4 、R 6 、R 7 、R 10 、R 11 、R 12 、R 13 、L 2 and y are as described for formula (I') or (I); and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z 4 In some embodiments, ring A is a ring containing 2-4 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 R 0 A fused bicyclic 9- to 10-membered heteroaryl group substituted with a group, wherein R 0 As described for formula (I') or (I).

[0212] In some embodiments, the compound of formula (I') or (I) is a compound of formula (Ib) or (Ic): Among them, ring A, R 2 、R 3 、R 4 、R 6 、R 7 、R 10 、R 11 、R 12 、R 13 and y are as described for formula (I') or (I); and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z 4 At least one of them is N.

[0213] In some embodiments, the compound of formula (I') or (I) is a compound of formula (Id) or (Ie): where R 0 、R 2 、R 3 、R 4 、R 6 、R 7 、R 10 、R 11 、R12 、R 13 and y are as described for formula (I') or (I); and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z 4 At least one of them is N.

[0214] In some embodiments, the compound of formula (I') or (I) is a compound of formula (If) or (Ig): where R 0 、R 4 and R 7 As described for formula (I') or (I); and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z 4 At least one of is N. In some embodiments, each R 0 are independently -CN or -NH2; R 4 is C1-C3 alkyl-CN or C3-C6 cycloalkyl optionally substituted with C1-C3 alkyl; and R 7 It is a C1-C3 alkyl group.

[0215] In some embodiments, the compound of formula (I') or (I) is a compound of formula (Ia'): Among them, ring A, R 2 、R 3 、R 4 、R 6 、R 7 、R 10 、R 11 、R 12 、L 2 and y are as described for formula (I') or (I); and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z 4 In some embodiments, ring A is a ring containing 2-4 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 R 0 A fused bicyclic 9- to 10-membered heteroaryl group substituted with a group, wherein R 0 As described for formula (I') or (I).

[0216] In some embodiments, the compound of formula (I') or (I) is a compound of formula (Ib') or (Ic'): Among them, ring A, R 2 、R 3 、R 4 、R 6 、R 7 、R 10 、R 11 、R 12 and y are as described for formula (I') or (I); and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z 4 At least one of them is N.

[0217] In some embodiments, the compound of formula (I') or (I) is a compound of formula (Id') or (Ie'): where R 0 、R 2 、R 3 、R 4 、R 6 、R 7 、R 10 、R 11 、R 12 and y are as described for formula (I') or (I); and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z 4 At least one of them is N.

[0218] In some embodiments, the compound of formula (I') or (I) is a compound of formula (If') or (Ig'): where R 0 、R 4 and R 7 As described for formula (I') or (I); and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z 4 At least one of is N. In some embodiments, each R 0 are independently -CN or -NH2; R 4 is C1-C3 alkyl-CN or C3-C6 cycloalkyl optionally substituted with C1-C3 alkyl; and R 7 It is a C1-C3 alkyl group.

[0219] In some embodiments, the compound of formula (I') or (I) is a compound of formula (Va) or (Vb): where R 0 、R 2 、R 3 、R 4 、R 6 、R 7 、R 10 、R 11 、R 12 、R 13 , X and y are as described for formula (I') or (I); Ring C is phenylene or pyridinylene; and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z 4 At least one of them is N.

[0220] In the description of this application, it should be understood that each description, variation, embodiment or aspect of a section can be combined with each description, variation, embodiment or aspect of other sections, just as if each combination of descriptions were specifically and individually listed. For example, each description, variation, embodiment or aspect provided herein with respect to Ring A of Formula (I') or (I) can be combined with each description, variation, embodiment or aspect of Ring A of Formula (I') or (I) 1 、L 2 、L 3 、L 4 、R 0 、R 1a 、R 1b 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 , W, X, Y, Z 1 、Z 2Each description, variation, embodiment, or combination of aspects of formula (I') or (I) is as if each combination were specifically and individually listed. It is also understood that, where applicable, all descriptions, variations, embodiments, or aspects of formula (I') or (I) are equally applicable to other formulas detailed in this application and are described equally as if each description, variation, embodiment, or aspect were listed separately and individually for all formulas. For example, where applicable, all descriptions, variations, embodiments, or aspects of Formula (I') or (I) apply equally to any of the formulae detailed in this application, e.g., Formulas (IA), (IB), (IC), (ID), (IE), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ia'), (Ib'), (Ic'), (Id'), (Ie'), (If'), (Ig'), (IIa), (IIb), (IIIa), (IIIb), (IVa), (IVb), (Va), and (Vb) are equally described as if each description, variation, embodiment, or aspect were listed separately and individually for all formulae.

[0221] In some embodiments, a compound is provided that is selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof. Although certain compounds described herein (including those in Table 1) are presented as specific stereoisomers and / or non-stereochemical forms, it is understood that any or all stereochemical forms (including any enantiomeric or diastereomeric forms) and any tautomeric or other forms of any of the compounds of the invention (including those in Table 1) are described herein. Table 1. "or1" and "or2" indicate that the absolute stereochemistry is not determined and that the stereochemistry may be drawn as shown or with the reverse stereochemistry.

[0222] It is understood that in this specification, combinations of substituents and / or variables of the depicted formulae are permissible only if such combinations result in stable compounds.

[0223] In addition, all compounds of formula (I') or (I) that exist in free base or free acid form can be converted into their pharmaceutically acceptable salts by treatment with appropriate inorganic or organic bases or inorganic or organic acids by methods known to those skilled in the art. Salts of compounds of formula (I') or (I) can be converted into their free base or free acid forms by standard techniques. Synthesis method

[0224] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or the methods provided herein. As an example and not limitation, compounds of formula (I') or (I) can be prepared as outlined in Scheme 1 and the Examples herein. It should be noted that one skilled in the art will know how to modify the procedures set forth in the illustrative schemes and Examples to obtain the desired products.

[0225] Compounds of formula (X-1) can be prepared as outlined in Scheme 1. Cereblon binding moiety (CBM) intermediate (CX) is coupled with intermediate a with HATU under basic conditions to form intermediate b, which is then deprotected under acidic conditions to form intermediate c. Subsequent coupling of intermediate c with target binding moiety (TBM) intermediate (AX) yields compounds of formula (X-1). Solution 1.

[0226] Compounds of formula (X-2) can be prepared as outlined in Scheme 2. CBM intermediate (CX) is coupled with intermediate d via reductive amination using NaBH(OAc) to afford intermediate e, which is then deprotected under acidic conditions to form intermediate f. Subsequent coupling of intermediate f with TBM intermediate (AX) affords compounds of formula (X-2). Option 2.

[0227] Compounds of formula (X-3) can be prepared as outlined in Scheme 3. Activation of the alcohol of intermediate g forms mesylated intermediate h, followed by deoxyazidation with NaN3 to give intermediate i. Intermediate i is then coupled with a TBM intermediate (AX) to form intermediate j, which is then deprotected to form intermediate k. Subsequent coupling of intermediate k with a CBM intermediate (CX) yields compounds of formula (X-3). Option 3.

[0228] The synthetic route for compounds of formula (X-4) is summarized in Scheme 4. Intermediate 1 can be coupled with intermediate m using HATU under basic conditions to form intermediate n, which is then activated with methanesulfonyl chloride to form intermediate o. Subsequent deoxygenation with NaN3 affords intermediate p. The ester of intermediate p is deprotected to afford intermediate q, which is then coupled with a CBM intermediate (CX) to form intermediate f. Intermediate f is then coupled with a TBM intermediate (AX) via a copper-catalyzed azide-alkyne cycloaddition to form compounds of formula (X-4). Solution 4.

[0229] Formula (X-7) compounds can be prepared as outlined in Scheme 5. The alcohol of intermediate s is activated with mesyl chloride to form intermediate t, and deoxygenated with NaN3 to give intermediate u. Reduction of the ester of intermediate u gives intermediate v, which is then activated with tosyl chloride to form intermediate w. Subsequently, intermediate w is coupled with a CBM intermediate (CX) under alkaline conditions to give intermediate x, which is then coupled with a TBM intermediate (AX) via a copper-catalyzed azide-alkyne cycloaddition to form a compound of formula (X-7). Option 5.

[0230] The synthetic route of the compound of formula (X-8) is summarized in Scheme 6. Reduction of the carboxylic acid of intermediate y forms intermediate z, which is then oxidized to form intermediate a'. Intermediate a' is then coupled with CBM intermediate (CX) via reductive amination to form intermediate b', which is then deprotected to form intermediate c'. Intermediate c' is coupled with TBM intermediate (AX) via copper-catalyzed azide-alkyne cycloaddition to produce the compound of formula (X-8). Option 6.

[0231] Formula (X-11) compounds can be prepared as outlined in Scheme 7. The alcohol group of intermediate c' is protected with TBDPS to form intermediate d', which is then activated with methanesulfonyl chloride to form intermediate e'. The activated alcohol of intermediate e' can be replaced by a cyano group to form intermediate f', which is then reduced to an aldehyde to form intermediate g'. Further reduction gives intermediate h'. The alcohol group of intermediate h' can be protected with THP to form intermediate i', and then deprotected under acidic conditions to form intermediate j'. Intermediate j' is then oxidized to form intermediate k'. The aldehyde of intermediate k' can be converted to an alkyne via Seyferth-Gilbert homologation to form intermediate L-1, and the alcohol is then deprotected to form intermediate L-2. Next, intermediate L-2 is coupled with a TBM intermediate (AX) via a copper-catalyzed azide-alkyne cycloaddition to form intermediate I', which is then coupled with a CBM intermediate (CX) to form compounds of formula (X-11). Plan 7.

[0232] Compounds of formula (X-15) can be prepared as outlined in Scheme 8. Oxidation of the alcohol group of intermediate m' to an aldehyde provides intermediate n', which is then coupled with intermediate o' via reductive amination to form compounds of formula (X-15). Plan 8. How to use

[0233] Embodiments of the present application provide a method for regulating IRAK4 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I') or (I). Regulation (e.g., inhibition or activation) of IRAK4 can be assessed and confirmed by numerous methods known in the art. Kits and commercially available assays can be used to determine whether IRAK4 has been regulated (e.g., inhibited or activated) and the extent of regulation.

[0234] In one aspect, the present application provides a method of regulating IRAK4, comprising contacting IRAK4 with an effective amount of a compound of formula (I') or (I) or any embodiment or variation thereof. In some embodiments, the compound of formula (I') or (I) inhibits IRAK4. In other embodiments, the compound of formula (I') or (I) activates IRAK4. In some embodiments, the compound of formula (I') or (I) is an agonist of IRAK4. In some embodiments, the compound of formula (I') or (I) is an antagonist of IRAK4.

[0235] In some embodiments, the present application provides a method of targeting IRAK4 for degradation, comprising contacting IRAK4 with an effective amount of a compound of formula (I') or (I) or any embodiment or variation thereof.

[0236] In some embodiments, the compound of formula (I') or (I) modulates the activity of IRAK4 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In some embodiments, the compound of formula (I') or (I) modulates the activity of IRAK4 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 90-100%, 100-100%, 110-100%, 120-100%, 130-100%, 140-100%, 150-100%, 160-100%, 170-100%, 180-100%, 190-100%, 200-100%, 210-100%, 220-100%, 230-100%, 240-100%, 250-100%, 260-100%, 270-100%, 280-100%, 290-100%, 300-100%, 310-100%, 320-100%, 330-100%, 340-100%, 350-100%, 360-100%, 370-100%, 380-100%, 390-100%, 400-100%, 410-100%, 420-100%, 430-100%, 440-100%, 450-100%, 460-100%, 470-100 00%, 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70% or 40-60%.

[0237] Certain embodiments of the present application also provide a method for degrading IRAK4 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I') or (I). IRAK4 degradation can be assessed and confirmed by numerous methods known in the art. Kits and commercially available assays (including cell-based assays) can be used to determine whether IRAK4 has been degraded and the extent of degradation.

[0238] In one aspect, the present application provides a method for degrading IRAK4, comprising contacting IRAK4 with an effective amount of a compound of formula (I') or (I) or any embodiment or variation thereof. In some embodiments, the compound of formula (I') or (I) partially degrades IRAK3. In some embodiments, the compound of formula (I') or (I) completely degrades IRAK4.

[0239] In some embodiments, the compound of formula (I') or (I) degrades IRAK4 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In some embodiments, the compound of formula (I') or (I) degrades IRAK4 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 100-100%, 110-100%, 120-100%, 130-100%, 140-100%, 150-100%, 160-100%, 170-100%, 180-100%, 190-100%, 200-100%, 210-100%, 220-100%, 230-100%, 240-100%, 250-100%, 260-100%, 270-100%, 280-100%, 290-100%, 300-100%, 350-100%, 3 %, 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70% or 40-60%.

[0240] In another aspect, the present application provides a method for treating an inflammatory disease or autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I') or (I). In some embodiments, the present application provides a method for treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I') or (I). In some embodiments, the present application provides a method for treating an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I') or (I). In some embodiments, the present application provides a method for preventing an inflammatory disease or autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I') or (I). In some embodiments, the present application provides a method for preventing an inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I') or (I). In some embodiments, the present application provides a method for preventing an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I') or (I). Non-limiting examples of inflammatory or autoimmune diseases include atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoprin-associated periodic syndromes, hidradenitis suppurativa, Behçet's syndrome, or familial cold autoinflammatory syndrome.

[0241] In some embodiments, administering a compound of formula (I') or (I) to a subject susceptible to an inflammatory disease or autoimmune disease prevents the subject from experiencing any symptoms of an inflammatory disease or autoimmune disease. In some embodiments, administering a compound of formula (I') or (I) to a subject who has not yet shown symptoms of an inflammatory disease or autoimmune disease prevents the subject from experiencing any symptoms of an inflammatory disease or autoimmune disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need can reduce the extent of the subject's inflammatory disease or autoimmune disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need can stabilize the inflammatory disease or autoimmune disease (prevent or delay the worsening of the inflammatory disease or autoimmune disease). In some embodiments, administering a compound of formula (I') or (I) to a subject in need can delay the occurrence or recurrence of an inflammatory disease or autoimmune disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need can slow the progression of an inflammatory disease or autoimmune disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can provide partial relief of an inflammatory disease or autoimmune disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can provide complete relief of an inflammatory disease or autoimmune disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can reduce the dosage of one or more other drugs required for treating an inflammatory disease or autoimmune disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can enhance the effect of another drug for treating an inflammatory disease or autoimmune disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can delay the progression of an inflammatory disease or autoimmune disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can improve the quality of life of a subject suffering from an inflammatory disease or autoimmune disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can prolong the survival of a subject suffering from an inflammatory disease or autoimmune disease.

[0242] In one aspect, the present application provides a method for preventing a subject susceptible to an inflammatory disease or autoimmune disease from developing any symptoms of an inflammatory disease or autoimmune disease, the method comprising administering to the subject a compound of formula (I') or (I). In some embodiments, the present application provides a method for preventing a subject who has not yet shown symptoms of an inflammatory disease or autoimmune disease from developing any symptoms of an inflammatory disease or autoimmune disease, the method comprising administering to the subject a compound of formula (I') or (I).

[0243] In some aspects, the application provides a method for reducing the degree of an inflammatory disease or autoimmune disease in a subject, the method comprising administering a compound of formula (I') or (I) to the subject. In some embodiments, the application provides a method for stabilizing an inflammatory disease or autoimmune disease in a subject, the method comprising administering a compound of formula (I') or (I) to the subject. In some embodiments, the method prevents the inflammatory disease or autoimmune disease from worsening. In some embodiments, the method delays the worsening of the inflammatory disease or autoimmune disease.

[0244] In another aspect, the present application provides a method for delaying the onset or recurrence of an inflammatory disease or an autoimmune disease in a subject, comprising administering a compound of formula (I') or (I) to the subject.

[0245] In some embodiments, the present application provides a method for slowing the progression of an inflammatory disease or autoimmune disease in a subject, the method comprising administering to the subject a compound of formula (I') or (I). In some embodiments, the method provides partial relief of the inflammatory disease or autoimmune disease. In some embodiments, the method provides complete relief of the inflammatory disease or autoimmune disease.

[0246] In other aspects, the present application provides a method for reducing the dosage of one or more other drugs required to treat an inflammatory disease or autoimmune disease in a subject, the method comprising administering to the subject a compound of formula (I') or (I). In some embodiments, the present application provides a method for enhancing the effect of another drug used to treat an inflammatory disease or autoimmune disease in a subject, the method comprising administering to the subject a compound of formula (I') or (I).

[0247] The present application also provides a method for delaying the progression of an inflammatory disease or autoimmune disease in a subject, the method comprising administering a compound of formula (I') or (I) to the subject. In some embodiments, the method improves the quality of life of a subject suffering from an inflammatory disease or autoimmune disease. In some embodiments, the method prolongs the survival of a subject suffering from an inflammatory disease or autoimmune disease.

[0248] In another aspect, the present application provides a method for treating inflammatory symptoms or autoimmune symptoms caused by a disease in a subject in need thereof, comprising administering an effective amount of a compound of formula (I') or (I) to the subject. In some embodiments, the present application provides a method for preventing inflammatory symptoms or autoimmune symptoms caused by a disease in a subject in need thereof, comprising administering an effective amount of a compound of formula (I') or (I) to the subject. In some embodiments, administering a compound of formula (I') or (I) to a subject susceptible to a disease that causes inflammatory symptoms or autoimmune symptoms prevents the subject from experiencing any inflammatory symptoms or autoimmune symptoms. In some embodiments, administering a compound of formula (I') or (I) to a subject who has not yet shown inflammatory symptoms or autoimmune symptoms of a disease that causes inflammatory symptoms or autoimmune symptoms prevents the subject from experiencing any inflammatory symptoms or autoimmune symptoms. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can reduce the extent of the inflammatory symptoms or autoimmune symptoms caused by the disease in the subject. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can stabilize the inflammatory symptoms or autoimmune symptoms of the disease (prevent or delay the worsening of the inflammatory symptoms or autoimmune symptoms). In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can delay the onset or recurrence of inflammatory symptoms or autoimmune symptoms caused by the disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can slow the progression of inflammatory symptoms or autoimmune symptoms caused by the disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can provide partial relief of the disease that causes the inflammatory symptoms or autoimmune symptoms. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can provide complete relief of the disease that causes the inflammatory symptoms or autoimmune symptoms. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can reduce the dosage of one or more other drugs required to treat a disease that causes inflammatory symptoms or autoimmune symptoms. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can enhance the effect of another drug used to treat the inflammatory symptoms or autoimmune symptoms of a disease. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can delay the progression of a disease that causes inflammatory symptoms or autoimmune symptoms. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can improve the quality of life of a subject suffering from a disease that causes inflammatory symptoms or autoimmune symptoms. In some embodiments, administering a compound of formula (I') or (I) to a subject in need thereof can prolong the survival of a subject suffering from a disease that causes inflammatory symptoms or autoimmune symptoms.In some embodiments, the disease is atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoprin-associated periodic syndromes, hidradenitis suppurativa, Behçet's syndrome, or familial cold autoinflammatory syndrome.

[0249] In some embodiments, the compounds of formula (I') or (I) can be used to treat a disorder selected from atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoprin-associated periodic syndromes, hidradenitis suppurativa, Behçet's syndrome, or familial cold autoinflammatory syndrome.

[0250] In some embodiments, the compounds of formula (I') or (I) can be used to treat cancer. In some embodiments, the cancer is a solid tumor, skin cancer, or lymphoma. In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, or stomach cancer, leukemia, benign and malignant lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, benign and malignant melanoma, myeloproliferative disease, sarcoma, Ewing's sarcoma, hemangioendothelioma, Kaposi's sarcoma, sarcoma), liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma, intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, or teratoma. Additional cancers that can be treated using compounds of Formula (I') or (I) include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-BALL, pre-B lymphoma, large B-cell lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0251] In some embodiments, the cancer is breast cancer, colorectal cancer, non-small cell lung cancer, ovarian cancer, renal cancer, sarcoma, melanoma, head and neck cancer, hepatocellular carcinoma, thyroid cancer, multidrug-resistant leukemia, lymphoma, multiple myeloma, esophageal cancer, colorectal cancer, pancreatic cancer, mesothelioma, carcinoma (e.g., adenocarcinoma, including esophageal adenocarcinoma), sarcoma (e.g., spindle cell sarcoma, liposarcoma, leiomyosarcoma, abdominal leiomyosarcoma, sclerosing epithelioid sarcoma), and melanoma (e.g., metastatic malignant melanoma).

[0252] In some embodiments, the compounds of Formula (I') or (I) can be used to treat fibrosis, such as pulmonary interstitial fibrosis, cystic fibrosis, progressive pulmonary fibrosis, and idiopathic pulmonary fibrosis. Pharmaceutical compositions and routes of administration

[0253] The compounds provided herein can be administered to a subject orally, topically or parenterally in conventional formulations such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.

[0254] The compounds disclosed in the present application can be administered to a subject orally, topically or parenterally in the form of conventional preparations, such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations can be prepared by conventional methods using conventional organic or inorganic additives such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate or lemon). The effective amount of the compound of formula (I') or (I) in the pharmaceutical composition may be a level that will exert the desired effect; for example, about 0.005 mg / kg to about 10 mg / kg of subject body weight in a unit dose for oral and parenteral administration.

[0255] The dosage of the compound of formula (I') or (I) to be administered to the subject varies widely and can be based on the judgment of a healthcare practitioner. Generally speaking, the compounds disclosed herein can be administered one to four times a day at the following dosages: about 0.001 mg / kg subject weight to about 10 mg / kg subject weight, but the above dosages can be appropriately varied depending on the subject's age, weight, and medical condition, as well as the type of administration. In one embodiment, the dosage is about 0.001 mg / kg subject weight to about 5 mg / kg subject weight, about 0.01 mg / kg subject weight to about 5 mg / kg subject weight, about 0.05 mg / kg subject weight to about 1 mg / kg subject weight, about 0.1 mg / kg subject weight to about 0.75 mg / kg subject weight, or about 0.25 mg / kg subject weight to about 0.5 mg / kg subject weight. In one embodiment, a dose is administered once daily. In any given case, the amount of the compound of formula (I') or (I) administered will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0256] In some embodiments, the compound of Formula (I') or (I) is administered to a subject at a dose of about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day.

[0257] In another embodiment, provided herein are unit dose formulations comprising about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg of a compound of Formula (I') or (I).

[0258] In a specific embodiment, the application provides a unit dose formulation comprising about 0.1 mg or 100 mg of a compound of formula (I') or (I).

[0259] In another embodiment, the application provides a unit dose formulation comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a compound of formula (I') or (I).

[0260] The compound of formula (I') or (I) can be administered once, twice, three times, four times or more daily. In a specific embodiment, a dose of 100 mg or less is administered once daily, and a dose exceeding 100 mg is administered twice daily in an amount equal to half the total daily dose.

[0261] The compound of formula (I') or (I) can be administered orally for convenience reasons. In one embodiment, when administered orally, the compound of formula (I') or (I) is administered with a meal and water. In another embodiment, the compound of formula (I') or (I) is dispersed in water or fruit juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0262] The compounds disclosed herein can also be administered to the ear, nose, eye, or skin intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, transmucosally, via inhalation, or topically. The mode of administration is at the discretion of the healthcare practitioner and may depend in part on the site of the medical condition.

[0263] In one embodiment, the application provides a capsule containing a compound of formula (I') or (I) without additional carriers, excipients, or vehicles.

[0264] In another embodiment, the present application provides a composition comprising an effective amount of a compound of formula (I') or formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may comprise an excipient, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0265] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories and suspensions and the like. The composition may be formulated to contain a daily dose or a suitable portion of a daily dose in a dosage unit form, which may be a single tablet or capsule or a suitable volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt such as a hydrochloride. In general, all compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing a compound of formula (I') or (I) with a suitable carrier or diluent and filling an appropriate amount of the mixture in a capsule. Common carriers and diluents include, but are not limited to, inert powdered substances, such as many different types of starch; powdered cellulose, especially crystalline and microcrystalline cellulose; sugars, such as fructose, mannitol and sucrose; cereal flour and similar edible powders.

[0266] Tablets can be prepared by direct compression, wet granulation or dry granulation. Its formulation is usually mixed with a diluent, a binder, a lubricant and a disintegrant as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (e.g., sodium chloride) and powdered sugar. Powdered cellulose derivatives are also suitable. Typical tablet binders are, for example, the following substances: starch, gelatin and sugars, such as lactose, fructose, glucose and the like. Natural gums and synthetic gums are also suitable, including gum arabic, alginates, methylcellulose, polyvinyl pyrrolidone and the like. Polyethylene glycol, ethyl cellulose and waxes can also serve as binders.

[0267] Lubricants may be necessary for tablet formulations to prevent tablets and punches from sticking to the dye. Lubricants can be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wetted to break up the tablet and release the compound. They include starch, clay, cellulose, fucoidan, and gum. More particularly, for example, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation exchange resins, alginic acid, guar gum, citrus pulp, carboxymethyl cellulose, and sodium lauryl sulfate can be used. Tablets can be coated with sugar as a flavoring and sealant, or coated with a film-forming protective agent to change the dissolution characteristics of the tablet. The composition can also be formulated into chewable tablets, for example, by using a substance such as mannitol in the formulation.

[0268] When it is desired to administer the compound of formula (I') or (I) in the form of a suppository, a typical base may be used. Cocoa butter is a traditional suppository base, which may be modified by adding waxes to slightly raise its melting point. Water-miscible suppository bases containing, inter alia, polyethylene glycols of various molecular weights are widely used.

[0269] The effects of the compound of formula (I') or (I) can be delayed or prolonged by appropriate formulations. For example, slowly soluble pills of the compound of formula (I') or (I) can be prepared and mixed into tablets or capsules or as a sustained-release implantable device. This technology also includes making pills with several different dissolution rates and filling capsules with a mixture of pills. The tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even parenteral formulations can be made long-lasting by dissolving or suspending the compound of formula (I') or (I) in an oily or emulsifying medium that slowly disperses it in the serum. Exemplary embodiments

[0270] The present invention is further described by the following embodiments. Where appropriate and feasible, the features of each embodiment may be combined with any other embodiment.

[0271] Embodiment 1. A compound of formula (I'), or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, monocyclic 5- to 6-membered heteroaryl, or fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 1-4 heteroatoms independently selected from N, O and S, each of which is optionally substituted by 1-3 R 0 group substitution; Each R 0independently selected from halogen, -CN, -NH2, -NH(C1-C6 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl, -(6 to 10 membered bridged heterocyclylene)- and C1-C6 alkoxy, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O, or two R 0 The groups together form an oxo group; L 1 is -NH- or a bond; L 2 -NHC(O)-, -C(O)NH-, -SO2NH-, -NHSO2- or -(C1-C6 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1-3 heteroatoms selected from N, O and S; L 3 -NR 9 (C1-C6 alkylene)NR 9 -、-NR 9 C(O)(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -、-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, -(6- to 10-membered bridged heterocyclylene)(C1-C6 alkylene) z -, -(7- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -or-(O) z (6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 group substitution; L4 for phenylene, -N(H)(phenylene), 5- to 6-membered heteroarylene, -N(H)(5- to 6-membered heteroarylene)-, 8- to 10-membered fused bicyclic heteroarylene, or 5- to 6-membered heterocyclylene, wherein the phenylene, heteroarylene, or heterocyclylene is optionally substituted by 1-4 R 10 and wherein the heteroarylene and heterocyclylene groups contain 1 to 3 heteroatoms selected from N, S and O; R 1a and R 1b Each is H or together form an oxo group; R 2 and R 3 are independently H, C1-C6 alkyl or halogen, or R 2 and R 3 Together they form an oxo group; or R 3 and R 11 Together they form a C3-C6 cycloalkylene group; Y is NH, O or a bond; R 4 is C3-C6 cycloalkyl, C1-C6 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C6 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C6 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-5 R 8 group substitution; W is O, -NR 5 - or key; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halogen or -OH, or two R 6 The groups together form a bridged C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halogen, C1-C6 haloalkyl or -OH, or two R 7 The groups together form an oxo group; Each R 8 is independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halogen or -OH, or two R 10 The groups together form an oxo group; Each R 11 and R 12 are independently H, halogen, C3-C6 cycloalkyl, -OH, -NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; or R 11 and R 3 Together they form a C3-C6 cycloalkylene group; x is 0 or 1; y is 0, 1, 2, 3, 4, or 5; Each z is independently 0 or 1; X is N or CR 13 ; R 13 is H, halogen, -OH or C1-C6 alkyl; Z 1 is CH or N; and Z 2 is CH or N, The constraint condition is Z 1 and Z 2 Not all are N.

[0272] Embodiment 2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, monocyclic 5- to 6-membered heteroaryl, or fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 1-4 heteroatoms independently selected from N, O and S, each of which is optionally substituted by 1-3 R 0 group substitution; Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C6 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 alkoxy, or two R 0 The groups together form an oxo group; L 1 is -NH- or a bond; L 2 -NHC(O)-, -C(O)NH-, -SO2NH-, -NHSO2-, or a 5-membered heteroarylene group containing 1-3 heteroatoms selected from N, O and S; L 3 -NR 9 (C1-C6 alkylene)NR 9-、-NR 9 C(O)(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -、-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(6- to 10-membered bridged heterocyclylene)(C1-C6 alkylene) z -, -(9- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -or-(O) z (6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 group substitution; L 4 for Phenylene, 5 to 6 membered heteroarylene or 5 to 6 membered heterocyclylene, wherein the phenylene, heteroarylene or heterocyclylene is optionally substituted by 1-4 R 10 Group substituted, and wherein the heteroarylene and heterocyclylene contain 1-3 heteroatoms selected from N and O; R 1a and R 1b Each is H or together form an oxo group; R 2 and R 3 are independently H, C1-C6 alkyl or halogen, or R 2 and R 3 Together they form an oxo group; or R 3 and R 11 Together they form a C3-C6 cycloalkylene group; Y is NH or O; R 4is C3-C6 cycloalkyl, C1-C6 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C6 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C6 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-5 R 8 group substitution; W is O, -NR 5 - or key; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halogen or -OH, or two R 6 The groups together form a bridged C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halogen, C1-C6 haloalkyl or -OH, or two R 7 The groups together form an oxo group; Each R 8 is independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halogen or -OH, or two R 10 The groups together form an oxo group; Each R 11 and R 12 are independently H, halogen, C3-C6 cycloalkyl, -OH, -NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; or R 11 and R 3 Together they form a C3-C6 cycloalkylene group; x is 0 or 1; y is 0, 1, 2, 3, 4, or 5; Each z is independently 0 or 1; X is N or CR 13 ; R 13 is H, halogen or C1-C6 alkyl; Z 1 is CH or N; and Z2 is CH or N, The constraint condition is Z 1 and Z 2 Not all are N.

[0273] Embodiment 3. A compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: Z 1 and Z 2 Each is CH.

[0274] Embodiment 4. The compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: Z 1 is CH; and Z 2 is N.

[0275] Embodiment 5. The compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: Z 1 is N; and Z 2 For CH.

[0276] Embodiment 6. A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: Ring A is optionally substituted with 1-3 R 0 a phenyl group substituted with a phenyl group; and Each R 0 Independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), C1-C3 alkyl, C3-C6 cycloalkyl and C1-C3 alkoxy.

[0277] Embodiment 7. The compound according to embodiment 6, or a pharmaceutically acceptable salt thereof, wherein: Ring A is

[0278] Embodiment 8. A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a monocyclic 6-membered heteroaryl containing 1-2 heteroatoms independently selected from N and O and optionally substituted by 1-3 R 0 group substitution; and Each R 0 Independently selected from halogen, -CN, -NH2, -NH(C1-C6 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 alkoxy.

[0279] Embodiment 9. The compound according to embodiment 8 or a pharmaceutically acceptable salt thereof, wherein: Ring A is

[0280] Embodiment 10. The compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl containing 2-4 heteroatoms independently selected from N, O and S, and is optionally substituted by 1-3 R 0 group substitution; and Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), C1-C3 alkyl, C3-C6 cycloalkyl, -(6- to 8-membered bridged heterocyclylene)-, and C1-C3 alkoxy, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O, or two R 0 The groups together form an oxo group.

[0281] Embodiment 11. The compound according to embodiment 10, or a pharmaceutically acceptable salt thereof, wherein: Ring A is

[0282] Embodiment 12. A compound according to any one of Embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein: L 1 It is -NH-.

[0283] Embodiment 13. A compound according to any one of Embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein: L 1 is the key.

[0284] Embodiment 14. A compound according to any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein: L 2 -(C1-C3 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1-3 heteroatoms selected from N and O.

[0285] Embodiment 15. The compound according to embodiment 14, or a pharmaceutically acceptable salt thereof, wherein: L 2 for

[0286] Embodiment 16. A compound according to any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein: L 2 It is -NHC(O)- or triazolylene.

[0287] Embodiment 17. The compound according to embodiment 16, or a pharmaceutically acceptable salt thereof, wherein: L 2 It is -NHC(O)-.

[0288] Embodiment 18. The compound according to embodiment 16, or a pharmaceutically acceptable salt thereof, wherein: L 2 for

[0289] Embodiment 19. A compound according to any one of Embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, wherein: L 4 for and R 1a and R 1b Each is H or together form an oxo group.

[0290] Embodiment 20. The compound according to embodiment 19, or a pharmaceutically acceptable salt thereof, wherein: L 4 for

[0291] Embodiment 21. The compound according to embodiment 19, or a pharmaceutically acceptable salt thereof, wherein: L 4 for

[0292] Embodiment 22. A compound according to any one of Embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, wherein: L 4 is phenylene, -NH(phenylene), 5- to 6-membered heteroarylene, -N(H)(5- to 6-membered heteroarylene)-, 8- to 10-membered fused bicyclic heteroarylene, or 5- to 6-membered heterocyclylene, each of which is optionally substituted with 1-4 R 10 The heteroarylene and heterocyclylene groups are substituted with N, S and O atoms.

[0293] Embodiment 23. The compound according to embodiment 22, or a pharmaceutically acceptable salt thereof, wherein: Each R 10 are independently C1-C3 alkoxy, C1-C3 alkyl, halogen or -OH, or two R 10 The groups together form an oxo group.

[0294] Embodiment 24. The compound according to embodiment 23, or a pharmaceutically acceptable salt thereof, wherein: Each R 10are independently -OCH3, -CH3, Cl, F or -OH, or two R 10 The groups together form an oxo group.

[0295] Embodiment 25. A compound according to any one of embodiments 22 to 24, or a pharmaceutically acceptable salt thereof, wherein: L 4 for

[0296] Embodiment 26. A compound according to any one of embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein: x is 0.

[0297] Embodiment 27. A compound according to any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein: x is 1.

[0298] Embodiment 28. A compound according to any one of Embodiments 1 to 25 and 27, or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are independently H, C1-C3 alkyl or halogen.

[0299] Embodiment 29. The compound according to embodiment 28, or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are independently H, -CH3 or F.

[0300] Embodiment 30. A compound according to any one of embodiments 1 to 25 and 27, or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 Together they form an oxo group.

[0301] Embodiment 31. A compound according to any one of Embodiments 1 to 25 and 27, or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 11 Together they form a C3-C5 cycloalkylene group.

[0302] Embodiment 32. The compound according to embodiment 31, or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 11 Together they form cyclopropylene.

[0303] Embodiment 33. A compound according to any one of embodiments 1 to 32, or a pharmaceutically acceptable salt thereof, wherein: y is either 0 or 1.

[0304] Embodiment 34. A compound according to any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, wherein: Each R 6 are independently C1-C3 alkyl, halogen or -OH, or two R 6 The groups together form a bridged C1-C2 alkylene group.

[0305] Embodiment 35. The compound according to embodiment 34, or a pharmaceutically acceptable salt thereof, wherein: Each R 6 are independently -CH3, Cl or -OH, or two R 6 The groups together form a bridged C1-C2 alkylene group.

[0306] Embodiment 36. A compound according to any one of embodiments 1 to 35, or a pharmaceutically acceptable salt thereof, wherein: for

[0307] Embodiment 37. A compound according to any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, wherein: W is O, -NR 5 - or key; and R 5 is H or C1-C3 alkyl.

[0308] Embodiment 38. The compound according to embodiment 37, or a pharmaceutically acceptable salt thereof, wherein: W is O, -N(H)-, -N(CH3)- or a bond.

[0309] Embodiment 39. A compound according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof, wherein: X is N.

[0310] Embodiment 40. A compound according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof, wherein: X is CR 13 ;and R 13 is H, halogen, -OH or C1-C3 alkyl.

[0311] Embodiment 41. The compound according to embodiment 40, or a pharmaceutically acceptable salt thereof, wherein: R 13is H, CH3, -OH or F.

[0312] Embodiment 42. A compound according to any one of Embodiments 1 to 41, or a pharmaceutically acceptable salt thereof, wherein: Y is NH.

[0313] Embodiment 43. A compound according to any one of embodiments 1 to 41, or a pharmaceutically acceptable salt thereof, wherein: Y is O or a bond.

[0314] Embodiment 44. A compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, wherein: R 4 is C3-C6 cycloalkyl, C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C3 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C3 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-2 R 8 Group substitution.

[0315] Embodiment 45. The compound according to embodiment 44, or a pharmaceutically acceptable salt thereof, wherein: Each R 8 is independently -SO2(C1-C3 alkyl), -C(O)(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, halogen, -CN or -OH.

[0316] Embodiment 46. The compound according to embodiment 45, or a pharmaceutically acceptable salt thereof, wherein: Each R 8 is independently -SO2CH3, -C(O)CH3, methyl, ethyl, -CH2CF3, F, -CN or -OH.

[0317] Embodiment 47. A compound according to any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof, wherein: R 4Methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CH2CH(CH3)2, -CH2CF3, -CH2CH2F, -CH2CF2CH3, -CH(CH3)CF3, -CH2CH2CF3, -CH(CH3)CH2OH, -CH2C(CH3)2OH, -CH2CN, -CH(CH3)CN, -C(CH3)2CN, -CH(CH2CH3)CN, -CH2CH(CH3)CN,

[0318] Embodiment 48. A compound according to any one of embodiments 1 to 47, or a pharmaceutically acceptable salt thereof, wherein: L 3 -NR 9 (C1-C3 alkylene)NR 9 -、-NR 9 C(O)(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C3 alkylene) z -、-NR 9 (C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, -O(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, -(6- to 10-membered bridged heterocyclylene)(C1-C3 alkylene) z -, -(7- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -or-(O) z (6- to 10-membered spiroheterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1 or 2 R 7 group substitution; and Each z is independently 0 or 1.

[0319] Embodiment 49. A compound according to any one of embodiments 1 to 48, or a pharmaceutically acceptable salt thereof, wherein: Each R 9 are independently H or C1-C3 alkyl.

[0320] Embodiment 50. The compound according to embodiment 49, or a pharmaceutically acceptable salt thereof, wherein: Each R 9 are independently H or -CH3.

[0321] Embodiment 51. A compound according to any one of embodiments 1 to 50, or a pharmaceutically acceptable salt thereof, wherein: Each R 7 are independently C1-C3 alkyl, halogen, C1-C3 haloalkyl or -OH, or two R 7 The groups together form an oxo group.

[0322] Embodiment 52. The compound according to embodiment 51, or a pharmaceutically acceptable salt thereof, wherein: Each R 7 are independently -CH3, -CF3, F or -OH, or two R 7 The groups together form an oxo group.

[0323] Embodiment 53. A compound according to any one of embodiments 1 to 52, or a pharmaceutically acceptable salt thereof, wherein: Each R 11 and R 12 are independently H or C1-C3 alkyl.

[0324] Embodiment 54. The compound according to embodiment 53, or a pharmaceutically acceptable salt thereof, wherein: Each R 11 and R 12 are independently H or -CH3.

[0325] Embodiment 55. A compound according to any one of embodiments 1 to 48, or a pharmaceutically acceptable salt thereof, wherein: L 3 for

[0326] Embodiment 56. A compound according to any one of Embodiments 1 to 3, 10, 11, 13 to 18, 22 to 25, 27 to 38, 40 to 42, 44 to 48 and 51 to 55, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (Ia): in: Ring A is a ring containing 2-4 heteroatoms independently selected from N, O and S, optionally 1-3 R 0 a fused bicyclic 9- to 10-membered heteroaryl group substituted with a group; and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z 4 At least one of them is N.

[0327] Embodiment 57. The compound according to embodiment 56, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ib) or (Ic):

[0328] Embodiment 58. The compound according to embodiment 56 or 57, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Id) or (Ie):

[0329] Embodiment 59. A compound according to any one of Embodiments 56 to 58, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (If) or (Ig):

[0330] Embodiment 60. The compound according to embodiment 59, or a pharmaceutically acceptable salt thereof, wherein: Each R 0 are independently -CN or -NH2; R 4 is C1-C3 alkyl-CN or C3-C6 cycloalkyl optionally substituted with C1-C3 alkyl; and R 7 It is a C1-C3 alkyl group.

[0331] Embodiment 61. A compound according to any one of Embodiments 1, 2, 10, 11, 13 to 18, 22 to 25, 27 to 38, 39, 42, 44 to 48, and 51 to 54, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (Ia'): in: Ring A is a ring containing 2-4 heteroatoms independently selected from N, O and S, optionally 1-3 R 0 a fused bicyclic 9- to 10-membered heteroaryl group substituted with a group; and Z 3 and Z 4 are independently N or CH, with the proviso that Z 3 and Z4 At least one of them is N.

[0332] Embodiment 62. The compound according to embodiment 61, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ib') or (Ic'):

[0333] Embodiment 63. The compound according to embodiment 61 or 62, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Id') or (Ie'):

[0334] Embodiment 64. A compound according to any one of Embodiments 61 to 63, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (If') or (Ig'):

[0335] Embodiment 65. The compound according to embodiment 64, or a pharmaceutically acceptable salt thereof, wherein: Each R 0 are independently -CN or -NH2; R 4 is C1-C3 alkyl-CN or C3-C6 cycloalkyl optionally substituted with C1-C3 alkyl; and R 7 It is a C1-C3 alkyl group.

[0336] Embodiment 66. A compound selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.

[0337] Embodiment 67. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 66 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0338] Embodiment 68. A method of modulating interleukin-1 (IL1) receptor-associated kinase 4 (IRAK4) activity, comprising contacting IRAK4 with an effective amount of a compound according to any one of embodiments 1 to 66 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 67.

[0339] Embodiment 69. A method of treating an inflammatory disease or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 66 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 67.

[0340] Embodiment 70. The method according to embodiment 69, wherein the inflammatory disease or autoimmune disease is atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoprin-associated periodic syndromes, hidradenitis suppurativa, Behçet's syndrome, or familial cold autoinflammatory syndrome. Example

[0341] The following examples are presented by way of illustration and not limitation. Compounds were named using the automatic name generation tool provided by ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures with the support of the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures described in the illustrative examples to obtain the desired products.

[0342] Salts of the compounds described herein can be prepared by standard methods, such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification or stirring the product after chromatographic purification with a solution of an acid (e.g., aqueous HCl).

[0343] As used in certain chemical structures provided in the following examples, the designations of specific atoms preceded by "*," "or1," or "or2" indicate that the absolute stereochemistry of the designated atom is not determined.

[0344] The following abbreviations may be used in connection with this application. abbreviation ACN or MeCN: acetonitrile ADMP: 2-azido-1,3-dimethylimidazolinium hexafluorophosphate aq: aqueous solution BCA method: Bicinchoninic acid assay CBM: cereblon binding part CV: column volume d: day DABCO: 1,4-diazabicyclo[2.2.2]octane DAST: Diethylaminosulfur trifluoride DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMA: dimethylacetamide DMAP: 4-dimethylaminopyridine DMAP: 4-dimethylaminopyridine DME: dimethoxyethane DMF: dimethylformamide DMP: Dess-Martin Periodinane EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Equiv or eq.: equivalent ESI: electrospray ionization EtOAc: ethyl acetate FA: Formic acid FBS: Fetal bovine serum FC: Flash chromatography h: hour HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBt: Hydroxybenzotriazole HPLC: High Performance Liquid Chromatography IBX: 2-iodoacylbenzoic acid LCMS: Liquid chromatography mass spectrometry MeOH: methanol MeTHF: methyltetrahydrofuran min: minutes MsCl: methanesulfonyl chloride MSD: Mass Selective Detector MTBE: Methyl tert-butyl ether NBS: N-bromosuccinimide NFSI: N-fluorobis(benzenesulfonyl)amine Pd(dppf)Cl2: [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd(DTBPF)Cl2: [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride PdCl2(dppf)CH2Cl2 or Pd(dppf)Cl2·DCM: [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with dichloromethane PET ether: petroleum ether PS: Penicillin-Streptomycin PPTS: Pyridinium p-toluenesulfonate prep: preparation quant.: quantitative RT or rt: room temperature rt: retention time sat.: saturated SFC: Supercritical Fluid Chromatography TBAF: Tetrabutylammonium fluoride TBDPS: tert-butyldiphenylsilyl TBDPS: tert-butyldiphenylsilyl TBM: target binding moiety TEA: triethylamine TFA: trifluoroacetic acid TFAA: trifluoroacetic anhydride THF: Tetrahydrofuran THP: Tetrahydropyran TLC: Thin layer chromatography UPLC: Ultra-Performance Liquid Chromatography Synthesis Example Synthetic CBM molecules

[0345] The numbers of intermediate compounds mentioned in this section and in other sections are limited to the respective sections. For example, intermediate 3 in General Procedure CBM-1 and intermediate 3 in General Procedure CBM-2 are described in different sections and therefore refer to different compounds. Common Procedure CBM-1 where Z 3 is N or CH.

[0346] Step 1a: A sealed tube was charged with 1a, tert-butyl piperazine-1-carboxylate 2a (1.1 equiv), DIPEA (3.0 equiv), and DMSO (15 mL). The tube was sealed and heated at 90°C for 72 h. The reaction progress was followed by HPLC. Upon completion, the reaction mixture was directly purified by reverse phase chromatography. Pure fractions were combined and concentrated under reduced pressure to yield the product.

[0347] Step 1b: To an oven-dried 40 mL vial equipped with a magnetic stir bar was added 3-(6-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione 1b (500 mg, 1.55 mmol), tert-butyl piperazine-1-carboxylate 2a (1.5 equiv), DABCO (3.0 equiv) and (Ir(ppy)2(dtbbpy)PF6 (1 mol%), followed by DMA (10 mL) under ambient atmosphere. Nickel dibromide; 1,2-dimethoxyethane (5 mol%) was then added as a solution in DMA (0.5 mL) under N2. The reaction was placed in front of a 30 W blue LED lamp at 25°C for 96 h. The material was added dropwise to water and the solid formed was filtered and concentrated. The residue was purified by preparative HPLC to give the product.

[0348] Step 1c: To a 0.15 M solution of 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1b, potassium (1-tert-butoxycarbonyl-4-piperidinyl)-trifluoroborohydride 2b, and 2,4,6-trimethylpyridine (1.8 equiv) in 1,4-dioxane in a Schlenk flask was added a solution of (Ir[dF(CF3)ppy]2(dtbpy))PF6 (2 mol%) in 1,4-dioxane (1 mL). This was followed by the addition of a solution of Ni-dtbbpy-Br2 (10 mol%) in 1,4-dioxane (1 mL) that had been sonicated for 1 minute. The reaction mixture was degassed three times using a freeze-pump-thaw method. The flask was then placed under a dry nitrogen atmosphere and sealed with parafilm. The reaction mixture was stirred under blue LED light for 4 days. The solution was evaporated until dry and then dissolved in DMSO for purification by reverse phase chromatography. The pure fractions were combined to obtain the product.

[0349] Step 2: TFA (20 eqiv) was added to a solution of 3 in CH2Cl2 (0.2 M) and the mixture was stirred at room temperature for 2 h. After completion by HPLC, the volatiles were removed in vacuo and the residue was co-evaporated with MeCN (3 ×) and MTBE (2 ×). The residue was purified by reverse phase chromatography. The pure fractions were concentrated under reduced pressure to obtain the product CBM-1 as a TFA salt. Example S1. 2-(2,6-dioxo-3-piperidinyl)-5-piperazin-1-yl-isoindoline-1,3-dione trifluoroacetate (C-2)

[0350] Step 1'. Preparation of tert-butyl 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate (2'): A sealed tube was charged with 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindolin-1,3-dione 1' (2.0 g, 7.24 mmol), tert-butyl piperazine-1-carboxylate (1.4 g, 7.52 mmol), DIPEA (3.87 mL, 22.2 mmol) and DMSO (15 mL). The tube was sealed and heated at 90°C for 72 h. The progress of the reaction was followed by HPLC. Upon completion, the reaction mixture was directly purified by reverse phase chromatography on C18 RediSep RfGold using 5-95% MeOH / 0.1% formic acid in H2O as eluent. Pure fractions were combined and concentrated under reduced pressure to afford 2' (2.86 g, 89% yield) as a yellow solid.

[0351] LCMS method 1: 99.9% purity at 215 nm, [M-tBu+H]+ =387.2 m / z, [M+Na] + =466.2m / z.

[0352] 1 H NMR (400MHz, DMSO-d6) δppm 1.42 (s, 9H), 1.99-2.09 (m, 1H), 2.52-2.64 (m, 2H), 2.82-2.95 (m, 1H), 3.47 (m, 8H), 5.07 (dd, J=13.0 , 5.4Hz, 1H), 7.24 (dd, J=8.6, 2.2Hz, 1H), 7.35 (d, J=2.0Hz, 1H), 7.70 (d, J=8.3Hz, 1H), 11.08 (s, 1H).

[0353] Step 2'. Preparation of 2-(2,6-dioxo-3-piperidinyl)-5-piperazin-1-yl-isoindoline-1,3-dione trifluoroacetate (C-2): TFA (10.55 mL, 129.5 mmol) was added to a solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate 2' (2.87 g, 6.48 mmol) in CH2Cl2 (30 mL) and the mixture was stirred at room temperature for 2 h. After completion by HPLC, the volatiles were removed in vacuo and the residue was co-evaporated with MeCN (3×) and MTBE (2×). The residue was purified by C18 RediSep Rf Gold reverse phase chromatography using 5-20% MeCN / 0.05% TFA / H2O as eluent. Pure fractions were concentrated under reduced pressure to afford C-2 as a yellow solid (2.52 g, 85% yield) as a TFA salt.

[0354] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =343.2m / z.

[0355] 1 H NMR (400MHz, DMSO-d6) δppm 1.95-2.10(m, 1H), 2.52-2.64(m, 2H), 2.82-2.97(m, 1H), 3.18-3.31(m, 4H), 3.62-3.73(m, 4H), 5.09(dd, J =12.8, 5.5Hz, 1H), 7.33 (dd, J=8.8, 2.2Hz, 1H), 7.46 (d, J=2.0Hz, 1H), 7.76 (d, J=8.3Hz, 1H), 11.09 (s, 1H). Example S2. 3-(1-oxo-6-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (C-7)

[0356] Step 1". Preparation of tert-butyl 4-[2-(2,6-dioxo-3-piperidinyl)-3-oxo-isoindolin-5-yl]piperazine-1-carboxylate (3"): To an oven-dried 40 mL vial equipped with a magnetic stir bar under ambient atmosphere were added 3-(6-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione 1" (500 mg, 1.55 mmol), tert-butyl piperazine-1-carboxylate 2" (432 mg, 2.32 mmol), DABCO (521 mg, 4.64 mmol) and (Ir(ppy)2(dtbb) py) PF6 (14.2 mg, 15.47 μmol) was added, followed by DMA (10 mL). Nickel dibromide; 1,2-dimethoxyethane (23.9 mg, 77.4 μmol) was then added as a solution in DMA (0.5 mL) under N2. The reaction was placed 6 cm in front of a 30W blue LED lamp at 25°C for 96 h. LCMS showed mainly product. The combined 8 batches were added dropwise to water (200 mL), the solid formed was filtered and concentrated. The product was purified by preparative HPLC (column: Phenomenex The residue was purified by luna c18 (250 mm × 100 mm × 10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 16%-46%, 25 min) to give tert-butyl 4-[2-(2,6-dioxo-3-piperidinyl)-3-oxo-isoindolin-5-yl]piperazine-1-carboxylate 3" (2.5 g, 47.1% yield) as a gray solid.

[0357] 1 H NMR (400MHz, DMSO-d6) δ: 10.97 (s, 1H), 7.45 (d, J=8.8Hz, 1H), 7.30-7.27 (m, 1H), 7.20 (d, J=2.0Hz, 1H), 5.13-5.08 (m, 1H), 4.30 (dd, J=16.8Hz, 51 .6Hz, 2H), 3.48 (d, J=4.8Hz, 4H), 3.16 (d, J=5.2Hz, 4H), 2.92-2.68 (m, 1H ), 2.62-2.51(m, 1H), 2.41-2.37(m, 1H), 2.01-1.99(m, 1H), 1.45(s, 9H).

[0358] Step 2". 3-(1-Oxo-6-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (C-7): tert-Butyl 4-[2-(2,6-dioxo-3-piperidinyl)-3-oxo-isoindolin-5-yl]piperazine-1-carboxylate 3" (5 g, 11.7 mmol) was added to HCl (12 N, 15 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. LCMS showed mostly product. The reaction mixture was diluted with MeCN (500 mL) at 0-10 °C, the solid formed was filtered and the filter cake was dried to give the product 12 g. Based on this yield, 5 g of starting material gave 3-(1-oxo-6-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione C-7 (4.3 g, HCl salt, 100% yield) as a grey solid.

[0359] 1 H NMR (400MHz, DMSO-d6) δ: 10.98 (s, 1H), 9.34 (s, 2H), 7.49 (d, J = 5.2Hz, 1H), 7.33-7.27 (m, 2H), 5.13-5.09 (m, 1H), 4.30 (dd, J = 17.2Hz, J =58.2Hz, 2H), 3.46 (d, J = 4.8Hz, 4H), 3.23 (d, J = 4.8Hz, 1H), 2.93-2.78 (m, 1H), 2.62-2.51 (m, 1H), 2.48-2.37 (m, 1H), 2.01-1.98 (m, 1H).

[0360] CBM intermediates prepared using General Procedure CBM-1 are summarized in Table 2. Table 2. CBM intermediates prepared via general procedure CBM-1 Common Procedure CBM-2

[0361] Step 1: To a solution of amine 1 (1 eq.) and carbonyl 2 (1.2 eq.) in DCM (0.24 M) was added NaBH(OAc) 3 (1.2 eq.) and AcOH (1 eq.). The mixture was stirred at room temperature. After LCMS showed complete conversion, the reaction mixture was quenched with water, extracted, dried, filtered, and evaporated under reduced pressure. The crude mixture was then purified by normal phase flash chromatography to obtain 3.

[0362] Step 2: To a solution of 3 (1 eq.) in THF (0.1 M) was added a solution of 4 M HCl in dioxane (15 eq.). The reaction mixture was stirred at room temperature. After 1 h, LCMS showed complete conversion. The solvent was removed under reduced pressure and the residue was co-evaporated with MeCN (3×). The residue was dried under high vacuum to afford CBM-2. Example S3. 3-[4-(4-piperidinylmethylamino)phenyl]piperidine-2,6-dione (C-6)

[0363] Step 1 '. Preparation of tert-butyl N-[4-[[1-[4-(2,6-dioxo-3-piperidinyl)phenyl]-4-piperidinyl]oxymethyl]cyclohexyl]carbamate (3): To a solution of 3-(4-aminophenyl)piperidine-2,6-dione 1' (250 mg, 1.22 mmol, 1 eq.) and tert-butyl 4-formylpiperidine-1-carboxylate 2' (310 mg, 1.45 mmol, 1.19 eq.) in DCM (5 mL, 0.24 M) was added NaBH(OAc) 3 (310 mg, 1.46 mmol, 1.19 eq.) and AcOH (0.07 mL, 1.22 mmol, 1 eq.). The mixture was stirred at room temperature. After overnight, LCMS showed complete conversion to compound 3. The reaction mixture was quenched with water, extracted 3 times with DCM, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude mixture was then purified by normal phase flash chromatography (40 g column, solid deposited, eluting 0% to 100% heptane / EtOAc over 15CV, product eluted at 100% EtOAc). Fractions were combined and concentrated to afford 3' (440 g, 89% yield) as a white solid.

[0364] LCMS method 1: 96.8% purity at 215 nm, [M-Boc+H] + =302.2.

[0365] 1 H NMR (400MHz, DMSO-d6) δppm 0.96-1.09 (m, 2H), 1.39 (s, 9H), 1.63-1.77 (m, 3H), 1.94-2.14 (m, 2H), 2.40-2.48 (m, 1H), 2.54-2.76 (m, 3H), 2.88 (br t, J=5.7Hz, 2H), 3.62 (dd, J=10.5, 5.1Hz, 1H), 3.94 (br d, J=11.7Hz, 2H), 5.61 (t, J=5.7Hz, 1H), 6.51 (d, J=8.6Hz, 2H), 6.89 (d, J=8.3Hz, 2H), 10.72 (s, 1H).

[0366] Step 2'. Preparation of 3-[4-(4-piperidinylmethylamino)phenyl]piperidine-2,6-dione (C-6): To tert-butyl 4-[[4-(2,6-dioxo-3-piperidinyl)anilino]methyl]piperidine-1-carboxylate 3' (419 mg, 1.04 mmol, 1 eq.) in THF (10.4 mL, 0.1 M) was added 4 M HCl in dioxane (3.91 mL, 15.65 mmol, 15 eq.). The reaction mixture was stirred at room temperature. After 1 h, LCMS showed complete conversion to compound 4. The solvent was removed under reduced pressure and the residue was co-evaporated with MeCN (3x). The residue was dried under high vacuum to afford C-6 (353 mg, quantitative yield) as a white solid.

[0367] LCMS method 1: 97.8% purity at 215 nm, [M+H] + =302.2.

[0368] 1 H NMR (400MHz, DMSO-d6) δppm 1.39 (q, J=11.8Hz, 2H), 1.86-2.04 (m, 4H), 2.06-2.21 (m, 1H), 2.40-2.48 (m, 1H), 2.59-2.71 (m, 1H), 2.83 (q, J=11.6Hz, 2H), 3.04 (br d, J=5.6Hz, 2H), 3.21-3.31(m, 2H), 3.68-3.80(m, 1H), 6.80-7.02(m, 2H) , 7.03-7.14(m, 2H), 8.59-8.77(m, 1H), 8.83-8.99(m, 1H), 10.79(s, 1H).

[0369] CBM intermediates prepared using General Procedure CBM-2 are summarized in Table 3. Table 3. CBM intermediates prepared via general procedure CBM-2. Common Procedure CBM-3 wherein X is N or CR as defined in formula (I') or (I) 13 .

[0370] Step 1: To a flask under N2, amine 1 (1 eq.), carboxylic acid 2 (1 eq.), and DIPEA (5 eq.) in DMF (0.12 M) were added. The resulting solution was stirred at room temperature. PyAOP (1.3 eq.) or other coupling reagent was then added all at once. The reaction was stirred at room temperature. Upon completion, the reaction mixture was directly loaded for reverse phase purification, and the clean fractions were combined and concentrated to yield product 3.

[0371] Step 2: To a solution of amide 3 (1 eq.) in DCM (0.13 M) was added TFA (15 eq.) or other deprotecting agents. The reaction mixture was stirred at room temperature. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was co-evaporated with THF and toluene to afford CBM-3. Example S4. 4-amino-N-[4-(2,6-dioxo-3-piperidinyl)phenyl]benzamide (C-10)

[0372] Step 1'. Preparation of tert-butyl N-[4-[[4-(2,6-dioxo-3-piperidinyl)phenyl]carbamoyl]phenyl]carbamate (3'): To a round-bottom flask under N2 was added 3-(4-aminophenyl)piperidine-2,6-dione 1' (300 mg, 1.47 mmol, 1 eq.), 4-(tert-butoxycarbonylamino)benzoic acid 2' (348.5 mg, 1.47 mmol, 1 eq.), and DIPEA (1.28 mL, 7.34 mmol, 5 eq.) in DMF (12.2 mL, 0.12 M). The resulting solution was stirred at room temperature for 10 minutes. Then, PyAOP (995.65 mg, 1.91 mmol, 1.3 eq.) was added all at once. The reaction was stirred at room temperature. After 16 h, LCMS showed complete conversion to compound 2. The reaction mixture was directly loaded for reverse phase FC purification (50 g C18 column, liquid sediment (reaction mixture), 5% MeCN / 0.1% HCOOH over 3CV, then 5 to 40% MeCN / 0.1% HCOOH over 2CV, then 40 to 100% MeCN / 0.1% HCOOH over 15CV, product eluted at 60% MeCN). Fractions were combined and concentrated to give 3' (267 mg, 43% yield) as a tan solid.

[0373] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =424.2.

[0374] 1H NMR (400MHz, DMSO-d6) δppm 1.49 (s, 9H), 2.00-2.10 (m, 1H), 2.13-2.26 (m, 1H), 2.45-2.48 (m, 1H), 2.61-2.73 (m, 1H), 3.82 (dd, J=11.2, 4.6Hz, 1H), 7.19 ( d, J=8.6Hz, 2H), 7.58 (d, J=8.8Hz, 2H), 7.70 (d, J=8.6Hz, 2H), 7.89 (d, J=8.8Hz, 2H), 9.68 (s, 1H), 10.07 (s, 1H), 10.82 (s, 1H).

[0375] Step 2'. Preparation of 4-amino-N-[4-(2,6-dioxo-3-piperidinyl)phenyl]benzamide (C-10): To a solution of tert-butyl N-[4-[[[4-(2,6-dioxo-3-piperidinyl)phenyl]carbamoyl]phenyl]carbamate 3' (267 mg, 0.63 mmol, 1 eq.) in DCM (5 mL, 0.13 M) was added TFA (1.03 mL, 12.61 mmol, 15 eq.). The reaction mixture was stirred at room temperature. After 30 minutes, LCMS showed complete conversion to compound 4. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated with THF (2x) and toluene (2x) to give C-10 (207 mg, 69% yield) as a trifluoroacetate salt as a tan solid.

[0376] LCMS method 1: 92.3% purity at 215 nm, [M-CF3COOH+H] + =324.2.

[0377] 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.00-2.06 (m, 1H), 2.13-2.24 (m, 1H), 2.44-2.49 (m, 1H), 2.61-2.72 (m, 1H), 3.81 (dd, J = 11.1, 5.0 Hz, 1H), 6.72 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 9.83 (s, 1H), 10.81 (s, 1H). Loss of three protons. Example S5. N-[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]piperidine-4-carboxamide hydrochloride (C-16)

[0378] Step 1". Preparation of tert-butyl 4-[[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]carbamoyl]piperidine-1-carboxylate (3"): 1-(4-Aminophenyl)hexahydropyrimidine 2,4-dione 1" (191 mg, 0.931 mmol, 1.1 equiv) and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 2" (194 mg, 0.846 mmol, 1.0 equiv) were dissolved in DMF (4.7 mL), followed by the addition of DIPEA (1.47 mL, 8.46 mmol, 10.0 equiv) and HATU (418 mg, 1.10 mmol, 1.3 equiv). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was directly injected onto a column for reverse phase flash chromatography purification (MeCN / 0.1% HCOOH (aq), 5% (3 CV) → 100%, 100 g RediSep Rf C18Aq, 10CV, λ=214-254 nm). Evaporation of fractions yielded 3 (211 mg, 0.507 mmol, 60% yield) as a yellow solid.

[0379] LCMS method 1: 99.9% purity at 215 nm, [Mt-Bu+H] + =317.2.

[0380] 1 H NMR (400MHz, DMSO-d6) δppm 1.39-1.42(m, 9H), 1.42-1.54(m, 2H), 1.77(br d, J=11.5Hz, 2H), 2.44-2.49 (m, 1H), 2.69 (t, J=6.7Hz, 2H), 2.72-2.94 (m, 2H), 3.73 (t, J=6.7Hz, 2H), 3.99 (br d, J=11.7Hz, 2H), 7.24 (d, J=8.9Hz, 2H), 7.59 (d, J=8.8Hz, 2H), 9.96 (s, 1H), 10.32 (s, 1H).

[0381] Step 2". Preparation of N-[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]piperidine-4-carboxamide hydrochloride (C.16): HCl 4.0 M in 1,4-dioxane (1.5 mL, 6.00 mmol, 10.0 equiv) was added to tert-butyl 4-[[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]carbamoyl]piperidine-1-carboxylate 3" (250 mg, 0.600 mmol, 1.0 equiv), and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure, and the residue was dried under high vacuum to remove all volatiles. The crude product C-16 (212 mg, 0.600 mmol, quantitative yield) was obtained as a white solid and used as such in the next step.

[0382] LCMS method 1: 99.9% purity at 215 nm, [M-HCl+H] + =317.2.

[0383] 1 H NMR (400MHz, DMSO-d6) δppm 1.72-1.89 (m, 2H), 1.91-2.03 (m, 2H), 2.59-2.66 (m, 1H), 2.69 (t, J=6.7Hz, 2H), 2.84-3.01 (m, 2H ), 3.30-3.33 (m, 2H), 3.74 (t, J = 6.7Hz, 2H), 7.25 (d, J = 8.8Hz, 2H), 7.59 (d, J = 8.8Hz, 2H), 8.41 (br s, 1H), 8.70 (br s, 1H), 10.11 (s, 1H), 10.33 (s, 1H).

[0384] CBM intermediates prepared using General Procedure CBM-3 are summarized in Table 4. Table 4. CBM intermediates prepared via general procedure CBM-3 Common Procedure CBM-4 (CBM-4A and CBM-4B) General Procedure CBM-4A where R 7 and R 10 As defined in formula (I') or (I).

[0385] LCMS method 1.Column: Kinetex XB-C18, 75 x 3.0 mm, 2.6 μm. Temperature: 45°C, Flow rate: 1.0 mL / min, Run time: 5.0 min. Mobile phase conditions: Mobile phase-A: 5.0 mM ammonium formate pH 3.3: CH3CN (98:02), Mobile phase-B: CH3CN: Buffer (98:02), Gradient: Initially 98% mobile phase A and 2% mobile phase B linearly gradient to 100% mobile phase B over 4.1 min, followed by a 0.5 min hold. MSD positive.

[0386] LCMS method 2. Column: Kinetex XB-C18, 75 x 3.0 mm, 2.6 μm. Temperature: 45°C, Flow rate: 1.0 mL / min, Run time: 5.0 min. Mobile phase conditions: Mobile phase A: 5.0 mM ammonium formate pH 3.3: CH3CN (98:02), Mobile phase B: CH3CN: Buffer (98:02), Gradient: Initially 80% mobile phase A and 20% mobile phase B linearly gradient to 100% mobile phase B over 4.0 min, followed by a 0.5 min hold. MSD positive.

[0387] LCMS method 3. Column: Kinetex XB-C18, 50 × 4.6 mm, 5.0 μm. Temperature: 45°C, flow rate: 1.5 mL / min, run time: 6.0 min. Mobile phase conditions: Mobile phase A: 0.1% TFA / H2O, Mobile phase B: 0.1% TFA / ACN, Gradient: Initially 95% mobile phase A and 5% mobile phase B linearly gradient to 95% mobile phase B over 2.5 min, followed by a 1.5 min hold. MSD positive.

[0388] Step A. Preparation of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine B In a sealed tube, 2,6-dibenzyloxy-3-bromo-pyridine A (1.0 g, 2.701 mmol, 1.0 eq.), bis(pinacolato)diboron (1.0 g, 4.051 mmol, 1.5 eq.), KOAc (795.2 mg, 8.103 mmol, 3.0 eq.), and Pd(dppf)Cl2·DCM (220.57 mg, 0.270 mmol, 0.1 eq.) were dissolved in 1,4-dioxane (4.0 mL, 0.6 M) and sparged with nitrogen for 10 minutes. The tube was sealed and heated at 90°C overnight. The reaction mixture was cooled to room temperature. The reaction was filtered through celite, washed with MeTHF, and the filtrate was evaporated. The residue was purified by normal phase flash chromatography (ISco, 24 g, eluting from 0% EtOAc / heptane to 10% EtOAc over 18 CV) to give 900 mg of bis(pinacolato)-contaminated B. A second purification by normal phase flash chromatography (80 g SNAP column; elution: 0% EtOAc / heptane over 2 CV, then 0 to 4.5% EtOAc / heptane over 15 CV, product eluted at 4.1% EtOAc) gave 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine B (210 mg, 19% yield) as a white solid.

[0389] LCMS method 1: Retention time: 1.915 min, [M-Pin+H] + =336.2 and 2.290 min, [M+H] + =418.2; 99.9% purity at 215 nm.

[0390] 1 H NMR (400MHz, DMSO-d6) δppm 1.28 (s, 12H), 5.38 (d, J=5.9Hz, 4H), 6.42 (d, J=7.8Hz, 1H), 7.24-7.40 (m, 6H), 7.40-7.44 (m, 2H), 7.53 (d, J=7.1Hz, 2H), 7.84 (d, J=7.8Hz, 1H).

[0391] Step 1: Cs2CO3 (2.0 eq.) was added to a flame-dried sealed tube, and heterocycle 2 (1.1 eq.), bromo-iodine 1 (1.0 eq.), XantPhos (0.2 eq.) and Pd2(dba)3 (0.1 eq.) were dissolved in dry 1,4-dioxane (0.2 M). The mixture was degassed by sparging with nitrogen for 10 minutes. The tube was sealed and the mixture was stirred at 110°C. After complete conversion of the starting material, the reaction mixture was cooled to room temperature. Ethyl acetate and water were added, the phases were separated, the aqueous phase was extracted 3 times with ethyl acetate, and the combined organic phases were then washed once with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase flash chromatography, and the fractions were subsequently combined and concentrated to give the bromide product 3.

[0392] Step 2: A sealed tube was charged with K 3 PO 4 (2.3 eq.), bromide 3 (1.0 eq.), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine B (1.2 eq.) and Pd(PPh 3 ) 4 (0.1 eq.). The mixture was degassed by sparging with nitrogen for 10 minutes. A solution of 1,4-dioxane (0.08 M) and water (0.08 M) was added, followed by degassed by sparging with nitrogen for 10 minutes. The vial was sealed and the reaction was heated at 90° C. overnight. After complete conversion of the starting material, the mixture was cooled to room temperature, the reaction was filtered through celite, washed with EtOAc and the filtrate was evaporated. The residue was purified by normal phase flash chromatography, and the fractions were subsequently combined and concentrated to give pyridine 5.

[0393] Step 3: A solution of pyridine 5 (1.0 eq.) in THF / EtOH (0.05 M) was degassed for 15 minutes, followed by degassed Pd(OH)2 (0.2 eq.) by sparging with nitrogen for 5 minutes. Hydrogen was then bubbled into the reaction mixture for 5 minutes, and the mixture was stirred in a hot water bath at 50°C under a hydrogen atmosphere. The mixture was allowed to cool to room temperature. Ethyl acetate and water were added and the phases separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal phase flash chromatography, and the fractions were then combined and concentrated to give glutarimide 6.

[0394] Step 4: To a solution of glutarimide 6 (1.0 eq.) was added 4M HCl in dioxane (54 eq.). The reaction was stirred at room temperature. After overnight, LCMS showed complete conversion to product. The reaction mixture was concentrated under reduced pressure and co-evaporated with acetonitrile three times to give product CBM-4A, which was used directly in the next step. General Procedure CBM-4B where R7 and R 10 As defined in formula (I') or (I).

[0395] Step 1: A solution of bromide 1 (1.20 g, 6.09 mmol, 1 eq.) and tert-butyl prop-2-enoate 2 (1.05 eq.) in anhydrous THF (0.5 M) was cooled to 0 ° C under nitrogen. tBuOK (0.1 eq.) was added and the reaction was stirred at 0 ° C and allowed to slowly warm to room temperature. After completion, the reaction mixture was filtered through a celite pad, rinsed with EtOAc, and the filtrate was concentrated to dryness. The residue was purified by reverse phase flash chromatography, and the fractions were combined and partially concentrated to dryness. The suspension was then distributed between a saturated aqueous solution of NaHCO3 and EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to dryness to give 3.

[0396] Step 2: Bromide 3 (1 eq.), heterocycle 4 (1.2 eq.), Cs2CO3 (2 eq.), XPhos (0.2 eq.) and 1,4-dioxane (0.1 M) were added to a sealed tube. The reaction mixture was sparged with nitrogen for 10 min, and Pd2(dba)3.CHCl3 (0.1 eq.) was quickly added. The reaction mixture was sparged with nitrogen for another 10 min and then stirred at 90°C. Upon completion, the reaction mixture was filtered through a celite pad, rinsed with EtOAc, and the filtrate was concentrated to dryness. The residue was purified by reverse phase flash chromatography, and the fractions were combined and partially concentrated to dryness. The suspension was then partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The layers were separated, and the aqueous layer was back-extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated to dryness to give 5.

[0397] Step 3: 5 (1 eq.), acetic acid (0.2 M) and concentrated sulfuric acid (4 eq.) were added to a sealed tube. The reaction mixture was stirred at 118°C. Upon completion, the volatiles were removed under reduced pressure and the residue was purified by reverse phase flash chromatography. The fractions were combined and concentrated to give CBM-4B, which was used as is in the next step. Example S6. 3-(4-(Piperazin-1-yl)phenyl)piperidine-2,6-dione (C-12)

[0398] Step 1'. Preparation of (2,6-bis(benzyloxy)pyridin-3-yl)borous acid 2': To a stirred solution of 2,6-bis(benzyloxy)-3-bromopyridine 1' (30.0 g, 81 mmol, 1.0 eq.) in THF (300 mL) at -78 ° C., n-BuLi (48.6 mL, 122 mmol, 1.5 eq.) was added and stirred at the same temperature for 30 min. Trimethyl borate (10.86 mL, 97 mmol, 1.2 eq.) was then added dropwise and stirring was continued for another 30 min at the same temperature. The reaction was quenched with a saturated aqueous solution of ammonium chloride (300 mL) and acidified using a 1.5 N HCl solution to maintain pH 3-4. The reaction mixture was extracted with ethyl acetate (3×500 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was triturated with petroleum ether (1000 mL) to afford (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid 2' (16 g, 50.1% yield) as an off-white solid.

[0399] LCMS method 1: retention time: 3.003 min, 85.56% purity at 220 nm, [M+H] + =336.0.

[0400] 1 H NMR (400MHz, DMSO-d6): δppm 5.35 (s, 2H), 5.42 (s, 2H), 6.45 (d, J=8.0Hz, 1H), 7.30-7.47 (m, 10H), 7.60 (s, 2H), 7.90 (d, J=7.6Hz, 1H)

[0401] Step 2'. Preparation of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate 4': To a stirred solution of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate 3' (20 g, 58.6 mmol, 1.0 eq.) in 200 mL of 1,4-dioxane:water (7:3) was added (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid 2' (23.57 g, 70.3 mmol, 1.2 eq.), followed by dipotassium hydrogen phosphate (20.42 g, 117 mmol, 2.0 eq.). The resulting reaction mixture was degassed with N2 for 15 min, and PdCl2(dppf).CH2Cl2 (4.79 g, 5.86 mmol, 0.1 eq.) was added to the reaction mixture. The reaction mixture was then heated at 85°C in a sealed tube for 3 h. The reaction mixture was cooled to room temperature, poured into ice-cold water, and extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography using silica gel (230-400 mesh) with 10% ethyl acetate / petroleum ether to afford tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate 4′ (30 g, 85% yield) as an off-white solid.

[0402] LCMS method 2: retention time: 2.326 min, 92.15% purity at 220 nm, [M+H] + =552.2.

[0403] Step 3'. Preparation of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate 5': To a stirred solution of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate 4' (47 g, 85 mmol, 1.0 eq.) in ethyl acetate (700 mL) was added Pd(OH)2 (5.98 g, 42.6 mmol, 0.5 eq.). The reaction mixture was stirred at room temperature under an H2 atmosphere for 12 h. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate 5' (24 g, 71.7% yield) as an off-white solid.

[0404] LCMS method 3: retention time: 1.781 min, 95.26% purity at 220 nm, [M+H] + =374.3.

[0405] Step 4'. Preparation of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione C-12. To a stirred solution of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate 5 (2.0 g, 4.17 mmol, 1 eq.) in DCM (20 mL, 0.208 M) at 0 °C was added anhydrous HCl / 1,4-dioxane (10.42 mL, 41.7 mmol, 4.0 M in dioxane). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. It was concentrated under reduced pressure to give crude 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione 2HClC-12 (1.9 g) as a brown solid. It was used in the next step without further purification.

[0406] LCMS method 4: retention time: 0.307 min, [M+H] + =274.2. Example S7. 3-(2-Methoxy-4-piperazin-4-ium-1-yl-phenyl)piperidine-2,6-dione hydrochloride (C-34)

[0407] Step 1 '. Preparation of tert-butyl 4-(4-bromo-3-methoxy-phenyl)piperazine-1-carboxylate (3'): Cs2CO3 (2.08 g, 6.39 mmol, 2 eq.), tert-butyl piperazine-1-carboxylate 2' (654.7 mg, 3.52 mmol, 1.1 eq.), 1-bromo-4-iodo-2-methoxy-benzene 1' (1 g, 3.2 mmol, 1 eq.), XantPhos (369.81 mg, 0.64 mmol, 0.2 eq.) and Pd2(dba)3 (292.63 mg, 0.32 mmol, 0.1 eq.) were added to a flame-dried sealed tube and dissolved in anhydrous 1,4-dioxane (16 mL, 0.2 M). The mixture was degassed by sparging with nitrogen for 10 minutes. The tube was sealed and the mixture was stirred at 110 ° C. After overnight, LCMS showed that the starting material was completely converted into compound 3. The reaction mixture was cooled to room temperature. Ethyl acetate and water were added, the phases separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were then washed once with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal phase flash chromatography (80 g silica gel column, elution: 0 to 10% MeOH / DCM over 10 CV, followed by 10% MeOH until the product washed out). The fractions were combined and concentrated to afford 3' (742 mg, 62% yield) as a light yellow solid.

[0408] LCMS method 1: 98.5% purity at 215 nm, [M+H] + =373.2.

[0409] 1 H NMR (400MHz, chloroform-d) δppm 1.49 (s, 9H), 3.13 (t, J=5.0Hz, 4H), 3.59 (t, J=5.0Hz, 4H), 3.88 (s, 3H), 6.41 (dd, J=8.7, 2.6Hz, 1H), 6.45-6.51 (m, 1H), 7.38 (d, J=8.6Hz, 1H).

[0410] Step 2'. Preparation of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridinyl)-3-methoxy-phenyl]piperazine-1-carboxylate (5'): A sealed tube was charged with K3PO4 (194.91 mg, 0.92 mmol, 2.27 eq.), tert-butyl 4-(4-bromo-3-methoxy-phenyl)piperazine-1-carboxylate 3' (150 mg, 0.40 mmol, 1 eq.), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine B (202.32 mg, 0.48 mmol, 1.2 eq.) and Pd(PPh3)4 (46.69 mg, 0.04 mmol, 0.1 eq.). The mixture was degassed by sparging with nitrogen for 10 minutes. Add a solution of 1,4-dioxane (4.04mL, 0.08M) and water (1.01mL, 0.08M), then degas the mixture by sparging with nitrogen for 10 minutes. Seal the bottle and heat the reactant at 90°C overnight. After overnight, LCMS shows that the starting material is completely converted into compound 5'. The mixture is cooled to room temperature, the reactant is filtered through diatomaceous earth, washed with EtOAc and the filtrate is evaporated. The residue is purified by normal phase flash chromatography (40g silica gel column, elution: 5 to 50% EtOAc / heptane over 10CV, product is washed out at 25% EtOAc). Each fraction is combined and concentrated to obtain 5' (195.9mg, 77% yield) as a yellow solid.

[0411] LCMS method 1: 92.0% purity at 215 nm, [M+H] + =582.2.

[0412] 1H NMR (400MHz, chloroform-d) δppm 1.50 (s, 9H), 3.19 (t, J=5.OHz, 4H), 3.61 (t, J=5.2Hz, 4H), 3.72 (s, 3H), 5.33 (s, 2H), 5.39 (s, 2H), 6.41-6.45 (m, 1H) , 6.51-6.57(m, 2H), 7.17-7.21(m, 1H), 7.22-7.26(m, 1H), 7.28-7.39(m, 7H), 7.41-7.45(m, 2H), 7.49-7.53(m, 1H).

[0413] Step 3'. Preparation of tert-butyl 4-[4-(2,6-dioxo-3-piperidinyl)-3-methoxy-phenyl]piperazine-1-carboxylate (6'): A solution of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridinyl)-3-methoxy-phenyl]piperazine-1-carboxylate 5' (140 mg, 0.24 mmol, 1 eq.) in THF / EtOH (0.86 mL: 0.86 mL, 0.05 M) was degassed for 15 minutes, followed by degassing Pd(OH)2 (33.8 mg, 0.05 mmol, 0.2 eq.) by sparging with nitrogen for 5 minutes. Hydrogen was then bubbled into the reaction mixture for 5 minutes, and the mixture was stirred in a hot water bath at 50°C under a hydrogen atmosphere for 4 hours. The mixture was allowed to cool to room temperature. Ethyl acetate and water were added and the phases separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal phase flash chromatography (40 g silica gel column, elution: 0 to 100% MeOH / DCM over 30 CV). The fractions were combined and concentrated to provide 6' (30 mg, 23% yield) as a light blue solid.

[0414] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =404.2.

[0415] 1 H NMR (400MHz, chloroform-d) δppm 1.49 (s, 9H), 2.03-2.15 (m, 1H), 2.26 (s, 1H), 2.57-2.67 (m, 1H), 2.69-2.78 (m, 1H), 3.14 (t, J=5. 2Hz, 4H), 3.58 (t, J=5.2Hz, 4H), 3.80 (s, 3H), 6.46-6.52 (m, 2H), 6.97-7.04 (m, 1H), 7.86 (s, 1H).

[0416] Step 4'. Preparation of 3-(2-methoxy-4-piperazin-4-ium-1-yl-phenyl)piperidine-2,6-dione hydrochloride (C-34): To a solution of tert-butyl 4-[4-(2,6-dioxo-3-piperidinyl)-3-methoxy-phenyl]piperazine-1-carboxylate 6' (30 mg, 0.07 mmol, 1 eq.) was added HCl 4M / dioxane (1 mL, 4 mmol, 54 eq.). The reaction was stirred at room temperature. After overnight, LCMS showed complete conversion to the product. The reaction mixture was concentrated under reduced pressure and co-evaporated with acetonitrile three times to afford C-34 (35 mg, quantitative yield) as a gray solid, which was used directly in the next step and assumed to be in the form of the hydrochloride salt.

[0417] LCMS method 1: 99.9% purity at 215 nm, [M-HCl+H] + =304.4. Example S8. 3-(2-Methoxy-4-piperazin-4-ium-1-yl-phenyl)piperidine-2,6-dione hydrochloride (C-29)

[0418] Step 1 '. Preparation of 4- [4- [4- [tert-butoxycarbonyl (methyl) amino] -1-piperidinyl] phenyl] -4-cyano - butyric acid tert-butyl ester (3 '): In a flame-dried sealed tube, Cs2CO3 (1.01 g, 3.084 mmol, 2.0 eq.), N-methyl-N- (4-piperidinyl) carbamic acid tert-butyl ester 2 ' (396.6 mg, 1.850 mmol, 1 The mixture was degassed by sparging with nitrogen for 10 minutes. The tube was sealed and the mixture was stirred at 90°C for 16 hours. The reaction was filtered through celite, washed with EtOAc, and the filtrate was evaporated. The residue was purified by normal phase flash chromatography (80 g silica gel column, elution: 0 to 50% heptane / EtOAc over 15 CV, the product eluting at 45% EtOAc was the only product absorbing at 254 nm). The fractions were combined and concentrated to give tert-butyl 4-[4-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidinyl]phenyl]-4-cyano-butyrate 3' (660 mg, 83% yield) as an orange oil.

[0419] LCMS method 1: retention time: 2.061 min, 88.3% purity at 215 nm, [M+H] + =458.2.

[0420] 1 H NMR (400MHz, DMSO-d6) δppm 0.79-0.88(m, 1H), 1.21-1.28(m, 1H), 1.36-1.41(m, 18H), 1.60(br d, J=9.5Hz, 2H), 1.68-1.79(m, 2H), 1.92-2.09(m, 2H), 2.21-2.29(m, 2H), 2.67(s, 3H), 2.70-2.75(m, 1H), 3.79(br d, J=12.7Hz, 2H), 4.07 (t, J=7.5Hz, 1H), 6.97 (d, J=8.6Hz, 2H), 7.18 (d, J=8.8Hz, 2H).

[0421] Step 2'. Preparation of 3-[4-[4-(methylamino)-1-piperidinyl]phenyl]piperidine-2,6-dione sulfuric acid (C-29): To an aqueous mixture of tert-butyl 4-[4-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidinyl]phenyl]-4-cyano-butyrate 3' (866. mg, 1.892 mmol) in acetic acid (9.5 mL, 0.2 M) was added concentrated H2SO4 (0.3 mL, 5.677 mmol, 3.0 eq.). The reaction mixture was vigorously stirred at 120°C for 1 hour and then concentrated. The crude material was dissolved in a minimum amount of water and purified by reverse phase chromatography using a 40 g C18 column (elution: 0% MeCN / 0.1% HCOOH over 4 CV, then 0% to 10% MeCN / 0.1% HCOOH over 15 CV, the product eluted at 5% MeCN). Pure fractions were combined and concentrated to afford 3-[4-[4-(methylamino)-1-piperidinyl]phenyl]piperidine-2,6-dionesulfate C-29 (265 mg, 34% yield) as a yellow oil.

[0422] LCMS method 1: retention time: 0.588 min, 97.7% purity at 215 nm, [M+H] + =302.2.

[0423] 1H NMR (400MHz, DMSO-d6) δppm 1.49-1.62(m, 2H), 1.96-2.05(m, 2H), 2.10-2.18(m, 1H), 2.42-2.48(m, 1H), 2.56(s, 3H), 2.59-2.75(m, 3H), 3.10(br t, J=11.4Hz, 1H), 3.67-3.83 (m, 3H), 4.76 (br d, J=15.9Hz, 1H), 6.91 (br d, J=8.6Hz, 2H), 7.05 (br d, J=8.3Hz, 2H), 8.24 (s, 1H), 10.77 (br s, 1H). Example S9. Acetic acid; 3-(5-piperazin-1-yl-2-pyridinyl)piperidine-2,6-dione (C-37)

[0424] Step 1 '. Preparation of tert-butyl 4-(5-bromo-2-pyridyl)-4-cyano-butyrate (3'): A solution of 2-(5-bromo-2-pyridyl)acetonitrile 1' (1.20 g, 6.09 mmol, 1 eq.) and tert-butyl prop-2-enoate 2' (820 mg, 6.39 mmol, 1.05 eq.) in anhydrous THF (12 mL) was cooled to 0 ° C under nitrogen. tBuOK (74 mg, 0.61 mmol, 0.1 eq.) was added and the reaction was stirred at 0 ° C (keeping the ice bath slowly warming to room temperature). After 16 h, LCMS showed that the conversion was not complete. The reaction mixture was filtered through a celite pad, rinsed with EtOAc, and the filtrate was concentrated to dryness. The residue was purified by reverse phase flash chromatography (100 g C18 column, liquid sediment (DMSO), elution: 5% MeCN / 0.1% HCOOH over 3 CV, then 5 to 40% MeCN / 0.1% HCOOH over 2 CV, then 40 to 100% MeCN / 0.1% HCOOH over 14 CV). The fractions were combined and partially concentrated to dryness. The suspension was then partitioned between saturated aqueous NaHCO and EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organics were dried over NaSO, filtered, and concentrated to dryness to afford 3' (466 mg, 24% yield) as a brown oil.

[0425] LCMS method 1: 96.6% purity at 215 nm, [M-tBu+H] + =269.0.

[0426] 1H NMR (400MHz, CDCl3) δppm 1.46 (s, 9H), 2.20-2.37 (m, 2H), 2.38-2.54 (m, 2H), 4.13 (dd, J=8.4, 6.2Hz, 1 H), 7.34 (d, J=8.3Hz, 1H), 7.87 (dd, J=8.3, 2.4Hz, 1H), 8.67 (d, J=2.0Hz, 1H).

[0427] Step 2'. Preparation of tert-butyl 4-[6-(4-tert-butoxy-1-cyano-4-oxo-butyl)-3-pyridinyl]piperazine-1-carboxylate (5'): To a sealed tube was added tert-butyl 4-(5-bromo-2-pyridinyl)-4-cyano-butyrate 3' (336 mg, 1.03 mmol, 1 eq.), tert-butyl piperazine-1-carboxylate 4' (229 mg, 1.23 mmol, 1.2 eq.), Cs2CO3 (664 mg, 2.04 mmol, 2 eq.), XPhos (102 mg, 0.21 mmol, 0.2 eq.) and 1,4-dioxane (10 mL). The reaction mixture was sparged with nitrogen for 10 min and Pd2(dba)3.CHCl3 (98 mg, 0.09 mmol, 0.1 eq.) was added rapidly. The reaction mixture was sparged with nitrogen for another 10 min and then stirred at 90°C. After 14.5h, LCMS showed complete conversion. The reaction mixture was filtered through a diatomaceous earth plate, rinsed with EtOAc, and the filtrate was concentrated to dryness. The residue was purified by reverse phase flash chromatography (100g C18 column, liquid sediment (DMSO), elution: 5% MeCN / 0.1% HCOOH over 3CV, then 5 to 30% MeCN / 0.1% HCOOH over 2CV, then 30 to 80% MeCN / 0.1% HCOOH over 17CV). Each fraction was merged and partially concentrated to dryness. The suspension was then distributed between a saturated aqueous solution of NaHCO and EtOAc. The layers were separated and the aqueous layer was stripped with EtOAc. The combined organic matter was dried over NaSO, filtered and concentrated to dryness to obtain 5' (285mg, 60% yield) as an orange oil.

[0428] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =431.3.

[0429] 1H NMR (400MHz, CDCl3) δppm 1.45(s, 9H), 1.49(s, 9H), 2.22-2.34(m, 2H), 2.36-2.49(m, 2H), 3.16-3.22(m, 4H), 3.58-3.6 3 (m, 4H), 4.05 (t, J=7.3Hz, 1H), 7.16-7.22 (m, 1H), 7.24-7.30 (m, 1H), 8.27 (d, J=2.7Hz, 1H).

[0430] Step 3'. Preparation of acetic acid; 3-(5-piperazin-1-yl-2-pyridinyl)piperidine-2,6-dione (C-37): To a sealed tube was added tert-butyl 4-[6-(4-tert-butoxy-1-cyano-4-oxo-butyl)-3-pyridinyl]piperazine-1-carboxylate 5' (280 mg, 0.65 mmol, 1 eq.), acetic acid (3.3 mL) and concentrated sulfuric acid (255 mg, 2.60 mmol, 4 eq.). The reaction mixture was stirred at 118°C. After 70 min, LCMS showed complete conversion. The volatiles were removed under reduced pressure and the residue was purified by reverse phase flash chromatography (20 g C18Aq column, liquid deposit (HO), elution: 0% MeCN / 0.1% HCOOH over 8 CV). The fractions were combined and concentrated to afford C-37 (300 mg, 98% yield) as a yellow solid, which was used as is in the next step.

[0431] LCMS method 1: 85.5% purity at 215 nm, [M-2CH3COOH+H] + =275.1.

[0432] CBM intermediates prepared using General Procedure CBM-4 are summarized in Table 5. Table 5. CBM intermediates prepared via general procedure CBM-4 Common Procedure CBM-5 Example S10. 3-[4-[2-(4-piperidinyl)ethynyl]phenyl]piperidine-2,6-dione hydrochloride (C-21)

[0433] Step 1. Preparation of tert-butyl 4-[2-[4-(2,6-dioxo-3-piperidinyl)phenyl]ethynyl]piperidine-1-carboxylate (3): A solution of 3-(4-bromophenyl)piperidine-2,6-dione 1 (250 mg, 0.932 mmol, 1.0 eq.), tert-butyl 4-ethynylpiperidine-1-carboxylate 2 (234.1 mg, 1.118 mmol, 1.2 eq.), CuI (17.76 mg, 0.093 mmol, 0.1 eq.), DIPEA (1.62 mL, 9.320 mmol, 10.0 eq.) and PdCl(PPh) (65.45 mg, 0.093 mmol, 0.1 eq.) in THF (6.2 mL, 0.15 M) was degassed by sparging with nitrogen for 20 minutes. The reaction was stirred at room temperature for 48 hours. The reaction was filtered through celite, washed with MeTHF, and the filtrate was evaporated. The residue was purified by normal phase flash chromatography (40 g silica gel column, elution: 0 to 20% CH2Cl2 / EtOAc over 15 CV, product eluted at 7% EtOAc). The fractions were combined and concentrated to afford tert-butyl 4-[2-[4-(2,6-dioxo-3-piperidinyl)phenyl]ethynyl]piperidine-1-carboxylate 3 (183 mg, 49% yield) as a yellow solid.

[0434] LCMS method 1: retention time: 1.820 min, 92.8% purity at 215 nm, [M-Boc+H] + =297.2; [M-tBu+H] + =341.2; [M+Na] + =419.2.

[0435] 1 H NMR (400MHz, DMSO-d6) δppm 1.40(s, 9H), 1.44-1.55(m, 3H), 1.76-1.85(m, 2H), 1.96-2.05(m, 1H), 2.13-2.26(m, 1H), 2.60-2.71(m, 1H), 2.81-2.90(m, 1H), 3. 14 (brt, J=9.7Hz, 2H), 3.59-3.68 (m, 2H), 3.88 (dd, J=11.7, 4.9Hz, 1H), 7.20 (d, J=8.1Hz, 2H), 7.36 (d, J=8.3Hz, 2H), 10.84 (s, 1H).

[0436] Step 2. Preparation of 3-[4-[2-(4-piperidinyl)ethynyl]phenyl]piperidine-2,6-dione hydrochloride (C-21): A mixture of tert-butyl 4-[2-[4-(2,6-dioxo-3-piperidinyl)phenyl]ethynyl]piperidine-1-carboxylate 3 (180. mg, 0.454 mmol, 1.0 eq.) and 4M HCl / 1,4-dioxane (1.5 mL, 6.0 mmol, 13.0 eq.) in DCM (4.5 mL, 0.1 M) was stirred at room temperature for 0.5 h under nitrogen. The mixture was concentrated under reduced pressure and co-evaporated with acetonitrile three times to afford 3-[4-[2-(4-piperidinyl)ethynyl]phenyl]piperidine-2,6-dione hydrochloride C-21 (150 mg, 98% yield) as a yellow solid.

[0437] LCMS method 1: retention time: 1.121 min, 99.9% purity at 215 nm, [M-HCl+H] + =297.2.

[0438] 1 H NMR (400MHz, DMSO-d6) δppm 1.75-1.85 (m, 3H), 2.00-2.05 (m, 2H), 2.19 (qd, J=12.3, 4.4Hz, 1H), 2.61-2.72 (m, 1H), 2.96-3.04 (m, 4H), 3.17-3.24 (m, 2H), 3.89 (dd, J=11.7, 4.9Hz, 1H), 7.22 (d, J=8.1Hz, 2H), 7.38 (d, J=8.3Hz, 2H), 8.78-8.95 (m, 2H), 10.85 (s, 1H).

[0439] CBM intermediates prepared using General Procedure CBM-5 are summarized in Table 6. Table 6. CBM intermediates prepared via general procedure CBM-5 Common Procedure CBM-6 Example S11. 3-(4-(Piperidin-4-yl)phenyl)piperidine-2,6-dione (C-25)

[0440] Step 1. Preparation of tert-butyl 4-[4-(2,6-dioxo-3-piperidinyl)phenyl]piperidine-1-carboxylate (3): A solution of tert-butyl 4-(p-toluenesulfonyloxy)piperidine-1-carboxylate 1 (1.01 g, 2.84 mmol), 3-(4-bromophenyl)piperidine-2,6-dione 2 (772.8 mg, 2.88 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (74.9 mg, 0.28 mmol), KI (535.7 mg, 3.23 mmol), 4-ethylpyridine (0.3 mL, 2.64 mmol) and Mn (339.1 mg, 6.18 mmol) in DMA (14 mL) was purged with nitrogen for 10 min. NiBr2.DME (104.6 mg, 0.34 mmol) was then added and nitrogen was bubbled through the solution for an additional 5 min. After 19 h at 80 °C, the reaction mixture was cooled to room temperature and partitioned between EtOAc (50 mL) and brine (50 mL). The organic phase was separated, washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by reverse phase chromatography (C18-100 g, 5-100% MeCN / 0.1% aqueous formic acid, 20 CV) afforded tert-butyl 4-[4-(2,6-dioxo-3-piperidinyl)phenyl]piperidine-1-carboxylate 3 (504.6 mg, 1.35 mmol, 48% yield) as a light pink solid.

[0441] 1 H NMR (400MHz, DMSO-d6) δppm 1.41 (s, 9H), 1.44-1.54 (m, 2H), 1.74 (br d, J=12.6Hz, 2H), 1.98-2.06 (m, 1H), 2.10-2.23 (m, 1H), 2.45 (br t, J=3.9Hz, 1H), 2.60-2.71 (m, 2H), 2.73-2.91 (m, 2H), 3.81 (dd, J=11.4, 4.8Hz, 1H), 4.07 (br d, J=11.2Hz, 2H), 7.11-7.16 (m, 2H), 7.18-7.23 (m, 2H), 10.81 (s, 1H). LCMS (ESI+, m / z): [M-tBu+H] + =317.2.

[0442] Step 2. Preparation of 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione (C-25): To a solution of tert-butyl 4-[4-(2,6-dioxo-3-piperidinyl)phenyl]piperidine-1-carboxylate 3 (137. mg, 0.3700 mmol) in 1,4-dioxane (1.8 mL) at room temperature was added HCl in dioxane (1.8 mL, 7.2 mmol) (3:03 PM). The resulting solution was stirred at room temperature. After one hour, the reaction mixture was concentrated on a rotary evaporator. The residue was dissolved in 1,4-dioxane (1.8 mL) and HCl in dioxane (1.8 mL, 7.2 mmol) was added. The mixture was stirred at room temperature for 3.5 h. After HPLC analysis showed complete conversion, the mixture was concentrated on a rotary evaporator to give 119.6 mg of product C-25 as a light yellow solid (quantitative yield). The product was 99.9% pure by HPLC (2.5 min run, 215 nm).

[0443] Luna C18 50 x 3 mm 45°C C-25 retention time (product) = 1.170 min.

[0444] CBM intermediates prepared using General Procedure CBM-6 are summarized in Table 7. Table 7. CBM intermediates prepared via general procedure CBM-6 Common Procedure CBM-7 Example S12. 3-[4-(4-Piperidinylmethoxy)phenyl]piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (C-33)

[0445] Step 1. Preparation of tert-butyl 4-[[4-(2,6-dioxo-3-piperidinyl)phenoxy]methyl]piperidine-1-carboxylate (3): To a Schlenk flask were added quinuclidine (8.29 mg, 0.07 mmol, 0.1 eq.), NiCl2.DME (8.2 mg, 0.04 mmol, 0.05 eq.), 3-(4-bromophenyl)piperidine-2,6-dione 1 (200 mg, 0.75 mmol, 1 eq.), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (8.37 mg, 0.01 mmol, 0.01 eq.), K2CO3 (103.1 mg, 0.75 mmol, 1 eq.) and dtbbpy (10.01 mg, 0.04 mmol, 0.05 eq.) in MeCN (5 mL, 0.15 M). The flask was placed under nitrogen, followed by the addition of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate 2 (401.5 mg, 1.86 mmol, 2 eq.). The Schlenk flask was then frozen at -78°C, placed on a high vacuum pump under nitrogen and slowly heated to room temperature using a water bath. This procedure was performed three times, ensuring the absence of oxygen in the Schlenk tube. The tube was then illuminated under a blue LED light over the weekend. After three days, LCMS showed major conversion to compound 3. The solvent was evaporated under reduced pressure, and the crude mixture was purified by reverse phase FC purification (50 g C18 gold column, liquid sediment (DMSO), 5% MeOH / 0.1% HCOOH over 4CV, then 5 to 80% MeOH / 0.1% HCOOH over 10CV, then 80% MeOH / 0.1% HCOOH over 4CV, the product eluted at 80% MeOH). The fractions were combined and concentrated to afford 3 (126 mg, 42% yield) as a yellow solid.

[0446] LCMS method 1: 99.9% purity at 215 nm, [Mt-Bu+H] + =347.2.

[0447] 1 H NMR (400MHz, chloroform-d) δppm 1.13-1.35 (m, 4H), 1.46-1.48 (m, 9H), 1.82 (br d, J=14.7Hz, 2H), 1.90-2.03 (m, 1H), 2.18-2.32 (m, 2H), 2.60-2.81 (m, 4H), 3.74 (dd, J=9.5, 5 .4Hz, 1H), 3.80 (d, J=6.4Hz, 2H), 6.89 (d, J=8.6Hz, 2H), 7.13 (d, J=8.6Hz, 2H), 7.92 (brs, 1H).

[0448] Step 2. Preparation of 3-[4-(4-piperidinylmethoxy)phenyl]piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (C-33): To a solution of tert-butyl 4-[[4-(2,6-dioxo-3-piperidinyl)phenoxy]methyl]piperidine-1-carboxylate 3 (126 mg, 0.31 mmol, 1 eq.) in DCM (1 mL, 0.31 M) was added TFA (0.36 mL 4.7 mmol, 15 eq.). The reaction mixture was stirred at room temperature. After 2 h, LCMS showed complete conversion to compound 4. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated with toluene (2×) and MeCN (2×) to afford C-33 (157 mg, quantitative yield) as a trifluoroacetate salt as a yellow solid.

[0449] LCMS method 1: 91.8% purity at 215 nm, [M-CF3COOH+H] + =303.2.

[0450] 1 H NMR (400MHz, DMSO-d6) δppm 1.37-1.52(m, 2H), 1.88-1.96(m, 2H), 1.96-2.20(m, 3H), 2.43-2.48(m, 1H), 2.60-2.70(m, 1H), 2.84-2.97(m, 2H), 3.28-3.33(m, 1H), 3 .73-3.81 (m, 1H), 3.81-3.87 (m, 2H), 6.89 (d, J=8.6Hz, 2H), 7.12 (d, J=8.6Hz, 2H), 8.14-8.29 (m, 1H), 8.48-8.61 (m, 1H), 10.78 (s, 1H). 1 One proton is missing in the H NMR spectrum.

[0451] CBM intermediates prepared using General Procedure CBM-7 are summarized in Table 8. Table 8. CBM intermediates prepared via general procedure CBM-7. Common Procedure CBM-8 Example S13. 3-[4-[4-(Hydroxymethyl)-1-piperidinyl]phenyl]piperidine-2,6-dione (C-38)

[0452] Step 1. Preparation of tert-butyl-(cyclopent-3-en-1-ylmethoxy)-dimethyl-silane (2): To a solution of cyclopent-3-en-1-ylmethanol 1 (1 g, 10.19 mmol, 1 eq.) in DMF (4 mL, 2.5 M) was added imidazole (0.83 g, 12.23 mmol, 1.2 eq.) and tert-butyldimethylsilyl chloride (2.0 g, 13.25 mmol, 1.3 eq.). After stirring at room temperature for 30 minutes under a nitrogen atmosphere, TLC showed complete conversion to compound 2. Water was added to the reaction mixture and extracted twice with EtOAc. The organic phase was washed twice with water and then with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude mixture was then purified by normal phase flash chromatography (80 g gold column, solid deposit, elution 0% to 40% heptane / EtOAc over 20CV, product eluted at 10% EtOAc). The fractions were combined and concentrated to afford 2 (2.28 g, quantitative yield) as a colorless oil.

[0453] 1 H NMR (400 MHz, chloroform-d) δ ppm 0.05 (s, 6H), 0.90 (s, 9H), 2.04-2.19 (m, 2H), 2.35-2.52 (m, 3H), 3.49 (d, J=6.8 Hz, 2H), 5.65 (s, 2H).

[0454] Step 2. Preparation of (5R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]hexane-1,5-diol (3): Under nitrogen, a solution of tert-butyl-(cyclopent-3-en-1-ylmethoxy)-dimethyl-silane 2 (2.2 g, 10.36 mmol, 1 eq.) in t-BuOH (35 mL, 0.2 M) and THF (17.5 mL, 0.2 M) was stirred at room temperature for 5 minutes, followed by the addition of OsO (0.66 mL, 4.0% w / w in H O, 0.104 mmol, 0.01 eq.) and NMO (1.46 g, 12.43 mmol, 1.2 eq.). After stirring at room temperature under nitrogen for 18 h, TLC showed complete conversion to compound 3. The mixture was concentrated to remove t-BuOH and THF, and the residue was dissolved in ethyl acetate (150 mL) and washed with 10% aqueous NaSO (2 x 15 mL), saturated aqueous NaHCO (15 mL), and saturated aqueous NaCl (15 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was then purified by normal phase flash chromatography (80 g silica gel column, elution: 0 to 10% methanol / dichloromethane over 14 CV, product eluting at 10% methanol). The fractions were combined and concentrated to afford 3 (2.44 g, 88% yield) as a brown oil.

[0455] 1 H NMR (400 MHz, chloroform-d) δ ppm 0.04 (s, 6H), 0.89 (s, 9H), 1.64-1.74 (m, 2H), 1.75-1.87 (m, 2H), 2.40-2.53 (m, 1H), 3.47 (d, J=5.4 Hz, 2H), 4.09-4.17 (m, 2H).

[0456] Step 3. Preparation of 3-[[tert-butyl(dimethyl)silyl]oxymethyl]glutaraldehyde (4): A solution of (1S,2R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopentane-1,2-diol 3 (2.4 g, 9.74 mmol, 1 eq.) in THF (35 mL, 0.19 M) and H2O (17.5 mL, 0.19 M) was stirred at room temperature for 5 minutes under nitrogen, followed by the addition of NaIO4 (2.5 g, 11.69 mmol, 1.2 eq.). After stirring at room temperature for 1 h under nitrogen, TLC (CHCl / MeOH 95:5, KMnO4 staining) showed complete conversion to compound 4. The mixture was concentrated to remove THF, followed by the addition of brine (40 mL). The aqueous phase was then extracted three times with ethyl acetate (3×75 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (150 mL) and stirred at room temperature in the presence of a large excess of magnesium sulfate for 16 h. The solid was filtered and the organic phase was concentrated and dried under high vacuum to give 4 (2.04 g, 86% yield) as a colorless oil.

[0457] 1 H NMR (400 MHz, chloroform-d) δ ppm 0.03 (s, 6H), 0.88 (s, 9H), 2.41-2.49 (m, 2H), 2.51-2.60 (m, 2H), 2.69-2.82 (m, 1H), 3.57 (d, J=5.6 Hz, 2H), 9.78 (s, 2H).

[0458] Step 4. Preparation of 3-[4-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-piperidinyl]phenyl]piperidine-2,6-dione (6): To a solution of 3-(4-aminophenyl)piperidine-2,6-dione 5 (250 mg, 1.22 mmol, 1 eq.) and 3-[[tert-butyl(dimethyl)silyl]oxymethyl]glutaraldehyde 4 (360 mg, 1.47 mmol, 1.2 eq.) in DCE (12.2 mL, 0.1 M) was added NaBH(OAc) (649 mg, 3.06 mmol, 2.5 eq.). The mixture was stirred at room temperature. After 2 h, LCMS showed complete conversion to compound 6. The reaction mixture was partitioned between DCM (20 mL) and saturated aqueous NaHCO (15 mL). The organic phase was separated and the aqueous layer was extracted with DCM (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated under reduced pressure to afford 6 (413 mg, 81% yield) as a white solid which was used as such without further purification.

[0459] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =417.4.

[0460] 1 H NMR (400MHz, chloroform-d) δppm 0.06 (s, 6H), 0.91 (s, 9H), 1.28-1.41 (m, 2H), 1.61-1.68 (m, 1H), 1.82 (br d, J=12.5Hz, 2H), 2.19-2.33 (m, 2H), 2.57-2.77 (m, 4H), 3.49 (d, J=6.4Hz, 2 H), 3.66-3.76 (m, 3H), 6.93 (d, J=8.8Hz, 2H), 7.08 (d, J=8.6Hz, 2H), 7.90 (br s, 1H).

[0461] Step 5. Preparation of 3-[4-[4-(hydroxymethyl)-1-piperidinyl]phenyl]piperidine-2,6-dione (C-38): To 3-[4-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-piperidinyl]phenyl]piperidine-2,6-dione 6 (410 mg, 0.98 mmol, 1 eq.) in DCM (12.2 mL, 0.08 M) was added dioxane (12.3 mL, 49.20 mmol, 50 eq.) containing 4 M HCl. The reaction mixture was stirred at room temperature. After 1.5 h, LCMS showed complete conversion to compound 7. The solvent was removed under reduced pressure, and the residue was co-evaporated with toluene and then co-evaporated with MeCN. The residue was dried under high vacuum to give C-38 (453 mg, quantitative yield) as an off-white solid, which was used as is in the next step.

[0462] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =303.4.

[0463] CBM intermediates prepared using General Procedure CBM-8 are summarized in Table 9. Table 9. CBM intermediates prepared via general procedure CBM-8 Common Procedure CBM-9 Example S14. tert-Butyl 4-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (C-40)

[0464] Step 1. General procedure for the preparation of compound (2): To a solution of 2-(4-bromophenyl)acetonitrile 1 (100 g, 510 mmol) in DMF (1000 mL) was added Me2NH-BH3 (30 g, 510 mmol) and t-BuONa (73.5 g, 765 mmol). After the addition, the reaction was stirred at 80 ° C for 1 hour. TLC (petroleum ether / ethyl acetate, 10: 1) showed that the starting material was consumed. The reaction mixture was quenched with water (250 mL), extracted with ethyl acetate (300 mL×2), and the combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to give 2-(4-bromophenyl)propionitrile 2 (49 g, 45.7% yield) as an orange oil.

[0465] 1H NMR (400MHz, CDCl3) δ7.47-7.43 (m, 2H), 7.19-7.15 (m 2H), 3.82-3.77 (m 1H), 1.56 (d, J=3.2Hz, 1H).

[0466] Step 2. General procedure for the preparation of compound (4): To a solution of 2-(4-bromophenyl)propionitrile 2 (49 g, 233 mmol) in toluene (500 mL) was added tert-butyl propane-2-enoate 3 (59.8 g, 467 mmol), K CO (64.4 g, 467 mmol) and benzyltriethylammonium chloride (10.6 g, 46.7 mmol). The reaction mixture was stirred at 90 ° C for 16 hours. HPLC showed that the starting material was exhausted. The reaction mixture was cooled to room temperature and filtered, and the filter cake was washed with ethyl acetate (200 mL). The combined organic layers were concentrated to give crude 4-(4-bromophenyl)-4-cyano-pentanoic acid tert-butyl ester 4 (80 g, crude material) as an orange oil, which was used in the next step without any further purification.

[0467] 1 H NMR (400MHz, CDCl3) δ: 7.47-7.45 (m, 2H), 7.26-7.23 (m, 2H), 2.33-2.29 (m, 1H), 2.18-2.04 (m, 3H), 1.64 (s, 3H), 1.34 (s, 9H).

[0468] Step 3. General procedure for the preparation of compound (6): To a solution of tert-butyl 4-(4-bromophenyl)-4-cyano-pentanoate 4 (130 g, 384 mmol) and tert-butyl piperazine-1-carboxylate 5 (78.7 g, 423 mmol) in 1,4-dioxane (1500 mL) was added CsCO (250 g, 769 mmol), Pd(dba) (12.3 g, 13.45 mmol) and Xphos (9.16 g, 19.2 mmol). The reaction was degassed with N for 5 min and then stirred at 90° C. for 16 h. TLC (petroleum ether / ethyl acetate, 2:1) showed the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (1000 mL) and the combined organic layers were concentrated. The residue was purified by MPLC to give tert-butyl 4-[4-(4-tert-butoxy-1-cyano-1-methyl-4-oxo-butyl)phenyl]piperazine-1-carboxylate 6 (143.5 g, 84.2% yield) as a grey solid.

[0469] 1H NMR (400MHz, CDCl3) δ: 7.25 (t, J=8.8Hz, 2H), 6.84 (d, J=8.8Hz, 2H), 3.51 (t, J=4.8Hz, 2H), 3.08 (t, J=4.8Hz, 2H), 2.32-2.13(m, 1H), 2.11-2.05(m, 3H), 1.62(s, 3H), 1.42(s, 9H), 1.33(s, 9H).

[0470] Step 4. General procedure for the preparation of compound (7): To a solution of tert-butyl 4-[4-(4-tert-butoxy-1-cyano-1-methyl-4-oxo-butyl)phenyl]piperazine-1-carboxylate 6 (100 g, 225 mmol) in DCE (2000 mL) was added MsOH (65 g, 676 mmol) and TFAA (127 g, 451 mmol). The reaction mixture was stirred at 90 ° C for 16 hours. TLC (petroleum ether / ethyl acetate, 2: 1) showed that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated. The crude material 7 as an orange oil was used in the step without any further purification and was based on the theoretical amount (64.8 g).

[0471] Step 5. General procedure for preparing compound (C-40): To a solution of 3-methyl-3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione 7 (64.8 g, 226 mmol) in MeCN (1000 mL) was added Boc2O (100 g, 458 mmol) and K2CO3 (187 g, 1.35 mol). The reaction mixture was stirred at 20 ° C for 5 hours. TLC (petroleum ether / ethyl acetate, 1: 1) showed that the reaction was complete. The reaction mixture was diluted with DCM (1000 mL) and EtOH (1000 mL), stirred for 1 hour and filtered, the filter cake was washed with DCM (1000 mL), and the organic layer was concentrated to give a crude product, which was combined with a total of 230 g of crude material on page 11. The mixture was diluted with ethyl acetate (2000 mL), water (1000 mL), stirred at 20 ° C for 1 hour, and then filtered. The filter cake was dried to give 85 g of product (as batch 1). The mother liquor was separated and the organic layer was concentrated. The residue was purified by preparative HPLC to give 11.2 g of product. A total of 96.2 g of product was obtained. Based on this, 64.8 g of starting material gave 61.8 g of product C-40 as a gray solid (yield 71%).

[0472] 1H NMR (400MHz, CDCl3) δ: 10.86 (s, 1H), 7.12 (d, J = 8.8Hz, 2H), 6.94 (d, J = 8.8Hz, 2H), 3.44 (t, J = 4.8Hz, 2H), 3.09 (t, J=4.8Hz, 2H), 2.51-2.41 (m, 1H), 2.33-2.30 (m, 3H), 2.07-2.04 (m, 2H), 1.42 (s, 9H), 1.39 (s, 3H).

[0473] CBM intermediates prepared using General Procedure CBM-9 are summarized in Table 10. Table 10. CBM intermediates prepared via general procedure CBM-9 Common Procedure CBM-10 Example S15. (3R)-3-Fluoro-3-[4-(4-piperidinyl)phenyl]piperidine-2,6-dione; Dihydrochloride (C-46 and C-46i)

[0474] Step 1. Preparation of tert-butyl 3-(4-bromophenyl)-2,6-dioxo-piperidine-1-carboxylate (2): To a suspension of 3-(4-bromophenyl)piperidine-2,6-dione (1) (400 mg, 1.491 mmol) and DMAP (4-dimethylaminopyridine) (18.2 mg, 0.15 mmol) in MeCN (10 mL) was added BocO (645 mg, 2.985 mmol). The reaction was stirred at room temperature for 2.5 h and monitored by HPLC / TLC. The reaction mixture was partitioned between DCM and saturated aqueous NH4Cl. The layers were separated and the aqueous phase was extracted with DCM (1 x 20 mL). The combined organic layers were dried over Na SO , filtered and concentrated to dryness, which was then purified by flash chromatography over SiO 120 g by eluting with EtOAc / heptane (1% CV 0%, then 8% CV 0-30% EtOAc, then 4CV 30% EtOAc). The desired product eluted at approximately 25-30% (at 225 nm). Pure fractions were collected and concentrated to dryness to afford 2 (285 mg, 0.7740 mmol, 52% yield) as an orange semi-solid.

[0475] LCMS method 1: The product is unstable in water.

[0476] 1H NMR (400MHz, DMSO-d6) δppm 1.49(s, 9H), 2.01-2.10(m, 1H), 2.27-2.41(m, 1H), 2.66-2.76(m, 1H), 2.84- 2.96 (m, 1H), 4.11-4.20 (m, 1H), 7.24 (d, J=8.3Hz, 2H), 7.58 (d, J=8.3Hz, 2H).

[0477] Step 2. Preparation of tert-butyl 3-(4-bromophenyl)-3-fluoro-2,6-dioxo-piperidine-1-carboxylate (3): To a flame-dried flask under nitrogen was added 1 M NaHMDS in THF (1.94 mL, 1.94 mmol) and freshly distilled THF (5.5 mL). The solution was cooled to -78°C and a solution of tert-butyl 3-(4-bromophenyl)-2,6-dioxo-piperidine-1-carboxylate (2) (650 mg, 1.77 mmol) in THF (4.5 mL) was added dropwise. After the addition, the dry ice bath was replaced with an ice bath, and the reaction was stirred at 0°C for 45 min. The reaction was then cooled back to -78°C, and a solution of NFSI (612.32 mg, 1.94 mmol) in THF (4.5 mL) was added dropwise. After the addition, the dry ice bath was replaced with an ice bath again, and the reaction was stirred at 0°C for 60 min. After completion, the reaction mixture was quenched with saturated NH4Cl aqueous solution, then extracted with EtOAc (3 times), and washed with salt water (once). The combined organic layer was dried over Na2SO4, filtered and concentrated to dryness to obtain a crude off-white solid. The crude material was purified by normal phase chromatography by eluting with EtOAc / heptane (1CV 0%EtOAc, then 12CV 0-30%EtOAc, then 3CV 30%EtOAc). The product was washed out at approximately 27%EtOAc. The fractions containing the product contaminated by NFSI were collected and concentrated to dryness. The mixture was used for the next step without additional purification steps. 3 (348mg, 0.712mmol, 40% yield).

[0478] LCMS method 1: 96.6% purity at 215 nm, [M-Boc+H]+ = 286.0.

[0479] 1 H NMR (400MHz, DMSO-d6) δppm 1.52 (s, 9H), 1.99-2.05 (m, 1H), 2.10-2.25 (m, 1H), 2.53-2.67 (m, 1H), 2.79-3.04 (m, 1H), 7.34-7.49 (m, 2H), 7.63-7.77 (m, 2H).

[0480] 19 F NMR (377MHz, DMSO-d6) δppm-149.19--148.99 (m, 1F).

[0481] Step 3. Preparation of 3-(4-bromophenyl)-3-fluoro-piperidine-2,6-dione (4): To a flask was added tert-butyl 3-(4-bromophenyl)-3-fluoro-2,6-dioxo-piperidine-1-carboxylate (3) (345. mg, 0.6 mmol), water (7 mL) and MeCN (7 mL). The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a white solid. To remove residual amounts of NFSI from the previous step, the crude material was purified by reverse phase chromatography by eluting with MeCN / 0.1% FA (aq. (5-100%). The product eluted at approximately 50-55% MeCN. The pure fractions were concentrated under reduced pressure to give 4 (160 mg, 0.559 mmol, 93% yield) as a white solid.

[0482] LCMS method 1: 99.9% purity at 215 nm, [M+2H] + =288.0.

[0483] 1 H NMR (400MHz, DMSO-d6) δppm 2.31-2.44 (m, 2H), 2.69-2.81 (m, 2H), 7.41 (d, J=8.3Hz, 2H), 7.68 (d, J=8.3Hz, 2H), 11.44 (br s, 1H).

[0484] 19 F NMR (377MHz, DMSO-d6) δppm-150.17--149.95 (m, 1F).

[0485] Step 4. Preparation of tert-butyl 4-[4-[rac-(3R)-3-fluoro-2,6-dioxo-3-piperidinyl]phenyl]piperidine-1-carboxylate (6,6′): To a flame-dried sealed tube was added tert-butyl 4-(p-toluenesulfonyloxy)piperidine-1-carboxylate (5) (195.68 mg, 0.55 mmol), 3-(4-bromophenyl)-3-fluoro-piperidine-2,6-dione (4) (90. mg, 0.31 mmol), NiBr2·DME (9.71 mg, 0.03 mmol), 4,4′-di-tert-butyl-2,2′-bipyridine (8.44 mg, 0.03 mmol), KI (54.83 mg, 0.33 mmol), manganese powder (35.43 mg, 0.64 mmol), DMA (2 mL) and 4-ethylpyridine (0.04 mL, 0.3100 mmol). The reaction mixture was sprayed with N2 for 15 min and then the tube was sealed. The reaction mixture was stirred at 80 ° C overnight. After completion, the mixture was poured into 0.5M HCl and extracted with EtOAc (3×). The combined organic phase was washed with salt water (1×) and flowed through a diatomaceous earth plate and MgSO4, concentrated under reduced pressure. The crude material was purified by reverse phase chromatography by eluting with water containing MeCN (5-60%) / 0.1% FA (aqueous solution). The product was washed out at 60% MeCN. The pure fractions were merged and concentrated under reduced pressure to obtain the product as a white solid. The material was sent to chiral SFC to separate stereoisomers 6, 6' (both isomers were 160 mg, 0.559 mmol, 93% yield). After SFC, there were 2 isomers: chiral separation 1 was named 6, and chiral separation 2 was named 6'. Arbitrary designation of stereochemistry.

[0486] LCMS method 1: 99.9% purity at 215 nm [M-Boc] + =291.2m / z.

[0487] 1 H NMR (400MHz, DMSO-d6) δppm 1.42(s, 9H), 1.46-1.58(m, 2H), 1.72-1.80(m, 2H), 2.25-2.37(m, 2H), 2 .66-2.93(m, 5H), 4.00-4.15(m, 2H), 7.32-7.40(m, 4H), 11.36(brs, 1H).

[0488] 19 F NMR (377MHz, DMSO-d6) δppm-146.87--146.48 (m, 1F).

[0489] Step 5. Preparation of (3R)-3-fluoro-3-[4-(4-piperidinyl)phenyl]piperidine-2,6-dione; dihydrochloride salt (7): To a flask was added tert-butyl 4-[4-[(3R)-3-fluoro-2,6-dioxo-3-piperidinyl]phenyl]piperidine-1-carboxylate (6) (85 mg, 0.22 mmol), 1,4-dioxane (1.5 mL), and 4M HCl in dioxane (1.36 mL, 5.44 mmol). The reaction mixture was stirred at room temperature for 1 h. Upon completion, the reaction was co-evaporated with toluene (2×) and MeCN (2×) to afford C-46 (81 mg, 0.2025 mmol, 93% yield), which was used as is in the next step.

[0490] LCMS method 1: 90.7% purity at 215 nm, [M+H] + =291.2.

[0491] Step 5'. Preparation of (3R)-3-fluoro-3-[4-(4-piperidinyl)phenyl]piperidine-2,6-dione; dihydrochloride salt (C-46i): To a solution of tert-butyl 4-[4-[(3S)-3-fluoro-2,6-dioxo-3-piperidinyl]phenyl]piperidine-1-carboxylate 6' (88. mg, 0.23 mmol) in 1,4-dioxane (1.13 mL) was added HCl in dioxane (1.41 mL, 5.63 mmol). The reaction was stirred at room temperature for 1 h, then concentrated in vacuo and rinsed with MeCN to give the crude product C-46i (73.5 mg, 0.2249 mmol, 99.9% yield) as a tan solid. This was used as is in the next step.

[0492] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =291.2.

[0493] CBM intermediates prepared using General Procedure CBM-10 are summarized in Table 11. Table 11. CBM intermediates prepared via general procedure CBM-10 Common Procedure CBM-11 (CBM-11A and CBM-11B) Common Procedure CBM-11A where R 7 As defined in formula (I') or (I).

[0494] Step-1': A suspension of (R)-3-(4-bromophenyl)-3-methylpiperidine-2,6-dione 1 (1.0 g, 3.54 mmol), heterocycle 2 (1.5 eq.) and sodium tert-butoxide (3.0 eq.) in toluene (0.089 M) was purged with nitrogen for 5 min. Pd2(dba)3 (0.08 eq.) and Xantphos (0.16 eq.) were added to the reaction mixture under nitrogen, which was then heated to 110 ° C. After the reaction was completed, RM was slowly poured into 10.0% acetic acid aqueous solution. RM was then extracted with ethyl acetate. The separated organic layer was washed with water and then with a brine solution. The combined organic layer was then dried over sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by column chromatography using silica gel to give compound 3.

[0495] Step 2': To a stirred solution of compound 3 (1.0 eq.) in 1,4-dioxane (0.16 M) was added 4.0 M HCl in dioxane (5.0 eq.) at room temperature. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was then concentrated under reduced pressure to afford the crude product CBM-11, which was used in the next step without further purification. Common Procedure CBM-11B where R 7 As defined in formula (I') or (I).

[0496] Step 1. Preparation of 2-(4-bromophenyl)propionitrile 2: To a solution of 2-(4-bromophenyl)acetonitrile 1 (5.0 g, 25.5 mmol) in DMF (50 mL) was added sodium tert-butoxide (3.68 g, 38.3 mmol) followed by BH3.NHMe2 (1.878 mL, 25.5 mmol). The resulting reaction mixture was stirred at 80°C for 1 h. The reaction mixture was cooled to room temperature, treated with ice-cold water and extracted with EtOAc (2 x 150 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography using silica gel (230-400 mesh) with 6% ethyl acetate in petroleum ether to give 2-(4-bromophenyl)propionitrile 2 (2.6 g, 12.38 mmol, 48.5% yield) as a light yellow oil.

[0497] Step 2. Preparation of (R)-tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate 4a and (S)-tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate 4b: To a solution of 2-(4-bromophenyl)propionitrile 2 (3.8 g, 18.09 mmol) in toluene (40 mL) was added tert-butyl acrylate 3' (4.64 g, 36.2 mmol), K2CO3 (5.00 g, 36.2 mmol) and benzyltriethylammonium chloride (0.824 g, 3.62 mmol). The resulting reaction mixture was heated to 90 ° C and stirred for 16 h. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography using silica gel (230-400 mesh) with 5% ethyl acetate in petroleum ether to afford a racemic mixture of tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate (5.5 g, 16.26 mmol, 90% yield) as a light yellow liquid. 4.5 g of this material was purified by chiral SFC to afford (R)-tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate 4a (1.8 g) and (S)-tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate 4b (1.76 g).

[0498] SFC method: CHIRALPAKAD-H, 250×4.6 mm, 5.0 μm. Flow rate: 3.0 mL / min. Co-solvent: 10.0% IPA.

[0499] Step 3. Preparation of compound 6: To a stirred solution of (R)-4-(4-bromophenyl)-4-cyanopentanoate 4a (1.0 eq.) in 1,4-dioxane (0.3 M) was added heterocycle 5 (1.1 eq.), followed by Cs2CO3 (3.0 eq.). The resulting reaction mixture was degassed with nitrogen for 10 min, and then RuPhos-Pd-G4 (0.02 eq.) was added. The reaction mixture was heated to 90 ° C and stirred. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using silica gel to obtain product 6.

[0500] Step 4. Preparation of CBM-11: To a stirred solution of 6 (1.0 eq.) in AcOH (0.2 M) was added H2SO4 (2.0 eq.). The resulting reaction mixture was heated to 120°C and stirred. The reaction mixture was concentrated under reduced pressure to afford the product CBM-11. Example S16. (R)-3-Methyl-3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (C-73)

[0501] LCMS method 1.Kmetex XB-C18, 75×3.0 mm, 2.6 μm, temperature: room temperature, flow rate: 1.0 mL / min, run time: 5 minutes, mobile phase conditions: mobile phase-A: 5.0 mM ammonium formate pH 3.3: CH3CN (98:02), mobile phase-B: CH3CN: 5.0 mM ammonium formate pH 3.3 (98:02), gradient: initial 80% mobile phase A and 20% mobile phase B linear gradient to 100% mobile phase B in 4.0 minutes. MSD positive.

[0502] LCMS method 2. Aquity UPLC BEH C18, 50 × 3.0 mm, 1.7 μm, temperature: room temperature, flow rate: 1.0 mL / min, run time: 5 min, mobile phase conditions: mobile phase-A: 0.1% TFA / H2O, mobile phase-B: 0.1% TFA / ACN, gradient: initial 80% mobile phase A and 20% mobile phase B linear gradient to 100% mobile phase B over 3.0 min. MSD positive.

[0503] Step-1'. Preparation of (R)-tert-butyl 4-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate 3': A suspension of (R)-3-(4-bromophenyl)-3-methylpiperidine-2,6-dione 1' (1.0 g, 3.54 mmol), tert-butyl piperazine-1-carboxylate 2' (0.996 g, 5.32 mmol) and sodium tert-butoxide (1.022 g, 10.63 mmol) in toluene (10.0 mL, 0.089 M) was purged with nitrogen for 5 min. Pd2(dba)3 (0.26 g, 0.284 mmol) and Xantphos (0.328 g, 0.567 mmol) were added to the RM under nitrogen. The RM was then heated to 110 °C in a sealed vial for 16 h. After the reaction is complete, the RM is slowly poured into a 10.0% aqueous acetic acid solution. The RM is then extracted with ethyl acetate (2×25 mL). The separated organic layer is washed with water and then with a saline solution (10.0 mL). The combined organic layers are then dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product is purified by column chromatography using silica gel (100-200 mesh) with 30-50% ethyl acetate / petroleum ether to give pure (R)-4-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 3′ (225 mg, 13.75% yield) as a light yellow solid.

[0504] LCMS method 1: retention time: 2.181 min, 83.19% purity at 220 nm, [M+H] + =388.2

[0505] Step 2'. Preparation of (R)-3-methyl-3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione C-73: To a stirred solution of (R)-tert-butyl 4-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate 3' (220 mg, 0.476 mmol) in 1,4-dioxane (3.0 mL) was added 4.0 M HCl in dioxane (0.184 mL, 2.38 mmol) at room temperature. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was then concentrated under reduced pressure to afford the crude product (R)-3-methyl-3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione C-73 (231 mg) as a light yellow solid, which was used in the next step without further purification.

[0506] LCMS method 2: retention time: 0.456-0.643 min, 66.24% purity at 220 nm, [M+H] + =288.2. Example S17. (R)-3-Methyl-3-(4-((S)-2-methylpiperazin-1-yl)phenyl)piperidine-2,6-dione (C-80)

[0507] LCMS method 1. Kinetex XB-C18, 50 × 4.6 mm, 5.0 μm. Temperature: Room temperature, flow rate: 1.0 mL / min, run time: 5.5 min. Mobile phase conditions: Mobile phase A: 0.1% TFA / H2O, Mobile phase B: 0.1% TFA / ACN, Gradient: Initially 95% mobile phase A and 5% mobile phase B, linearly gradient to 95% mobile phase B over 2.5 min.

[0508] UPLC method 2. Aquity BEH-C18, 50 × 2.1 mm, 1.7 μm. Temperature: Room temperature, flow rate: 0.7 mL / min, run time: 2.5 min. Mobile phase conditions: Mobile phase A: 0.1% TFA / H2O, Mobile phase B: 0.1% TFA / ACN, Gradient: Initially 95% mobile phase A and 5% mobile phase B, linearly gradient to 98% mobile phase B over 1.5 min.

[0509] LCMS method 3.Kinetex XB-C18, 75 × 3.0 mm, 2.6 μm. Temperature: Room temperature, flow rate: 1.0 mL / min, run time: 5.0 min. Mobile phase conditions: Mobile phase-A: 5.0 mM ammonium formate pH 3.3: CH3CN (98:02), Mobile phase-B: CH3CN: 5.0 mM ammonium formate pH 3.3 (98:02), Gradient: Initially 98% mobile phase A and 2% mobile phase B, linear gradient to 100% mobile phase B over 4 min.

[0510] Step 1'. Preparation of 2-(4-bromophenyl)propionitrile 2': To a solution of 2-(4-bromophenyl)acetonitrile 1' (5.0 g, 25.5 mmol) in DMF (50 mL) was added sodium tert-butoxide (3.68 g, 38.3 mmol) followed by BH3.NHMe2 (1.878 mL, 25.5 mmol). The resulting reaction mixture was stirred at 80°C for 1 h. The reaction mixture was cooled to room temperature, treated with ice-cold water and extracted with EtOAc (2 x 150 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography using silica gel (230-400 mesh) with 6% ethyl acetate / petroleum ether to give 2-(4-bromophenyl)propionitrile 2' (2.6 g, 12.38 mmol, 48.5% yield) as a light yellow oil.

[0511] 1 H NMR (400MHz, CDCl3): δppm 1.65 (d, J=7.2Hz, 3H), 3.89 (q, J=7.2Hz, 1H), 7.24-7.27 (m, 2H), 7.53-7.56 (m, 2H).

[0512] Step 2'. Preparation of (R)-4-(4-bromophenyl)-4-cyanopentanoate 4a' and (S)-4-(4-bromophenyl)-4-cyanopentanoate 4b': To a solution of 2-(4-bromophenyl)propionitrile 2' (3.8 g, 18.09 mmol) in toluene (40 mL) was added tert-butyl acrylate 3' (4.64 g, 36.2 mmol), K2CO3 (5.00 g, 36.2 mmol) and benzyltriethylammonium chloride (0.824 g, 3.62 mmol). The resulting reaction mixture was heated to 90 ° C and stirred for 16 h. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography using silica gel (230-400 mesh) with 5% ethyl acetate in petroleum ether to afford a racemic mixture of tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate (5.5 g, 16.26 mmol, 90% yield) as a light yellow liquid. 4.5 g of this material was purified by chiral SFC to afford (R)-tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate 4a' (1.8 g) and (S)-tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate 4b' (1.76 g).

[0513] SFC method: CHIRALPAKAD-H, 250×4.6 mm, 5.0 μm. Flow rate: 3.0 mL / min. Co-solvent: 10.0% IPA.

[0514] Characterization of (R)-tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate 4a': rt 2.25; ee 97%; 1 H NMR (400MHz, CDCl3): δppm 1.42 (s, 9H), 1.74 (s, 3H), 2.10-2.27 (m, 3H), 2.39-2.45 (m, 1H), 7.32-7.36 (m, 2H), 7.53-7.56 (m, 2H).

[0515] Characterization of (S)-tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate 4b': rt 1.941; ee 99.9%; 1 H NMR (400MHz, CDCl3): δppm 1.43 (s, 9H), 1.74 (s, 3H), 2.09-2.28 (m, 3H), 2.39-2.44 (m, 1H), 7.32-7.36 (m, 2H), 7.53-7.57 (m, 2H).

[0516] Step 3'. Preparation of (S)-tert-butyl 4-(4-((R)-5-(tert-butoxy)-2-cyano-5-oxopentan-2-yl)phenyl)-3-methylpiperazine-1-carboxylate 6': To a stirred solution of (R)-tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate 4a' (2.0 g, 5.91 mmol, 1.0 eq.) in 1,4-dioxane (20.0 mL) was added (S)-tert-butyl 3-methylpiperazine-1-carboxylate 5' (1.303 g, 6.50 mmol, 1.1 eq.) followed by Cs2CO3 (5.78 g, 17.74 mmol, 3.0 eq.). The resulting reaction mixture was degassed with nitrogen for 10 min, and then RuPhos-Pd-G4 (0.101 g, 0.118 mmol, 0.02 eq.) was added. The reaction mixture was heated to 90° C. and stirred for 16 h. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography using silica gel (230-400 mesh) with 25% ethyl acetate / petroleum ether to give (S)-tert-butyl 4-(4-((R)-5-(tert-butoxy)-2-cyano-5-oxopentan-2-yl)phenyl)-3-methylpiperazine-1-carboxylate 6′ (2.2 g, 78% yield) as a colorless colloidal liquid.

[0517] LCMS method 1: retention time: 2.859 min, 96.2% purity at 220 nm, [M+H] + =458.3

[0518] Step 4'. Preparation of (R)-3-methyl-3-(4-((S)-2-methylpiperazin-1-yl)phenyl)piperidine-2,6-dione 7': To a stirred solution of (S)-tert-butyl 4-(4-((R)-5-(tert-butoxy)-2-cyano-5-oxopentan-2-yl)phenyl)-3-methylpiperazine-1-carboxylate 6' (2.0 g, 4.37 mmol, 1.0 eq.) in AcOH (20.0 mL) was added HSO (0.466 mL, 8.74 mmol, 2.0 eq.). The resulting reaction mixture was heated to 120° C. and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to afford (R)-3-methyl-3-(4-((S)-2-methylpiperazin-1-yl)phenyl)piperidine-2,6-dione 7' (3.5 g) as a brown gum which was used in the next step without further purification.

[0519] UPLC method 2: retention time: 0.809 min, [M+H] + =302.2

[0520] Step 5'. Preparation of tert-butyl (S)-3-methyl-4-(4-((R)-3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate 8': To a stirred solution of (R)-3-methyl-3-(4-((S)-2-methylpiperazin-1-yl)phenyl)piperidine-2,6-dione 7' (3.5 g, 4.18 mmol, 1.0 eq.) in acetonitrile (20 mL) at 0°C was added DIPEA (5.84 mL, 33.4 mmol, 8.0 eq.) and stirred for 5 min. Di-tert-butyl decarbonate (1.941 mL, 8.36 mmol, 2.0 eq.) was then added to the reaction mixture and stirred at room temperature for 6 h. The reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography using silica gel (230-400 mesh) with 40% ethyl acetate / petroleum ether to afford (S)-tert-butyl 3-methyl-4-(4-((R)-3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate 8' (1.45 g, 84% yield) as an off-white solid.

[0521] LCMS method 1: retention time: 2.150 min, 97.3% purity at 220 nm, [M+H] + =402.3.

[0522] Step 6'. Preparation of (R)-3-methyl-3-(4-((S)-2-methylpiperazin-1-yl)phenyl)piperidine-2,6-dione C-80: To a stirred solution of (S)-tert-butyl 3-methyl-4-(4-((R)-3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate 8' (1.45 g, 3.61 mmol, 1.0 eq.) in DCM (4 mL, 0.903 M) at 0° C. was added 4.0 N HCl / 1,4-dioxane (4.51 mL, 18.06 mmol, 5.0 eq.). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give crude (R)-3-methyl-3-(4-((S)-2-methylpiperazin-1-yl)phenyl)piperidine-2,6-dione 2HCl C-80 (1.2 g), which was used in the next step without further purification.

[0523] LCMS method 3: retention time: 1.565 min, 95.17% purity at 220 nm, [M+H] + =302.1.

[0524] CBM intermediates prepared using General Procedure CBM-11 are summarized in Table 12. Table 12. CBM intermediates prepared via general procedure CBM-11. Common Procedure CBM-12 Example S18. (R)-3-Methyl-3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione hydrochloride (C-76)

[0525] LCMS method 1. Kinetex XB-C 18, 75×3.0 mm, 2.6 μm, temperature: room temperature, flow rate: 1.0 mL / min, run time: 5 minutes, mobile phase conditions: mobile phase-A: 5.0 mM ammonium formate pH 3.3: CH3CN (98:02), mobile phase-B: CH3CN: 5.0 mM ammonium formate pH 3.3 (98:02), gradient: initial 80% mobile phase A and 20% mobile phase B linear gradient to 100% mobile phase B in 4.0 minutes. MSD positive.

[0526] Step 1'. Synthesis of (R)-tert-butyl 4-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate 4': To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate 1' (174.7 mg, 0.868 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium.BF43' (314 mg, 0.794 mmol) in a 20 mL vial was added anhydrous tert-butyl methyl ether (4.0 mL) and the reaction mixture was stirred at room temperature for 5 min. Subsequently, 1.0 mL of anhydrous tert-butyl methyl ether containing pyridine (0.064 mL, 0.794 mmol) was added dropwise at room temperature. The resulting solution was stirred at room temperature for 10 min. During this time, a white solid precipitated. To another 40.0 mL vial was charged [Ir(dtbbpy)(ppy)2]PF6 (6.80 mg, 7.44 μmol), NiBr2(dtbbpy) (12.08 mg, 0.025 mmol), quinuclidine (97 mg, 0.868 mmol), (R)-3-(4-bromophenyl)-3-methylpiperidine-2,6-dione 2' (140 mg, 0.496 mmol) and phthalimide (16.79 mg, 0.114 mmol). N,N-dimethylacetamide (5.0 mL) was added to the vial under a nitrogen atmosphere.

[0527] The tert-butyl methyl ether suspension was transferred to a syringe. A syringe filter was then installed on the syringe and the tert-butyl methyl ether solution was injected into the dimethylacetamide solution. The reactants were degassed with nitrogen for 15 min and sealed with a screw cap. The vial of the reaction mixture was irradiated with a blue LED light for 2 h under constant stirring. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic layer was concentrated under reduced pressure and purified by column chromatography on silica gel with 30% ethyl acetate / petroleum ether to obtain compound (R)-4-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester 4' (90 mg, 47.0% yield) as an off-white solid.

[0528] LCMS method 1: retention time 2.82 min, 99.09% purity at 220 nm, [M+H-Boc] + =287.2

[0529] Step 2'. Preparation of (R)-3-methyl-3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione hydrochloride C-76: To a stirred solution of (R)-tert-butyl 4-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate 4' (140 mg, 0.362 mmol) in DCM (1.5 mL) was added 4.0 N HCl / dioxane (1.5 mL) at room temperature. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was then concentrated under reduced pressure to give the crude product (R)-3-methyl-3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione hydrochloride C-76 (120 mg), which was used in the next step without further purification.

[0530] LCMS method 1: retention time 1.647 min, 98.14% purity at 220 nm, [M+H] + =287.2.

[0531] CBM intermediates prepared using General Procedure CBM-12 are summarized in Table 13. Table 13. CBM intermediates prepared via general procedure CBM-12. Synthetic TBM molecules

[0532] The numbers of the intermediate compounds mentioned in this section are specific to each section. For example, Intermediate 3 in General Procedure TBM-1 and Intermediate 3 in General Procedure TBM-3 are not the same compound because they are derived from different sections. General Program TBM-1 wherein Ring B is a heteroaryl group; R 4 is a C3-C6 cycloalkyl group; and R 0 As defined in formula (I') or (I).

[0533] Step 1: To a solution of ethyl 4,6-dichloropyridine-3-carboxylate 1 (1 eq.) in MeCN (0.45 M) was added amine 2 (3 eq.). The reaction was stirred at room temperature. After completion according to LCMS, the reaction mixture was cooled to room temperature and the reaction was purified to give 3.

[0534] Step 2 (Option 1): To the reaction vessel was added ethyl 6-chloro-4-(amino)pyridine-3-carboxylate 3 (1 eq.), heterocyclic aniline 4 (1.2 eq.), Xantphos (0.05 eq.), Cs2CO3 (1.4 eq.) and Pd2(dba)3 (0.05 eq.) in 1,4-dioxane (0.2 M). The solution was sparged with nitrogen for 5 min, the tube was sealed and stirred at 150°C. After LCMS indicated conversion, the reaction mixture was cooled to room temperature and then purified by reverse phase column chromatography to give product 5.

[0535] Step 2 (Option 2): To the reaction vessel was added ethyl 6-chloro-4-(amino)pyridine-3-carboxylate 3 (1 eq.), heterocyclic aniline 4 (1.5 eq.), p-toluenesulfonic acid monohydrate (0.3 eq.) and ethanol (3 mL). The tube was purged with nitrogen, sealed and stirred at 105° C. After LCMS indicated conversion, EtOH was removed under vacuum and the residue was purified by reverse phase flash chromatography to give product 5.

[0536] Step 3: In a round-bottom flask, ethyl 4-(amino)-6-[heterocyclic]pyridine-3-carboxylate 5 (1 eq.), lithium hydroxide monohydrate (5 eq.), THF (1 mL), MeOH (1 mL) and water (1 mL) were added. The reaction was stirred at 60°C. After LCMS indicated conversion, the volatiles were removed under vacuum and the residue was taken up with water (5 mL). 6M aqueous HCl was added to reach pH 3. The precipitate was filtered off and dried in vacuo to give the product TBM-1. Example S19. 6-(1,3-Benzothiazol-6-ylamino)-4-(cyclopentylamino)pyridine-3-carboxylic acid (A-1)

[0537] Step 1'. Preparation of ethyl 6-chloro-4-(cyclopentylamino)pyridine-3-carboxylate (3'): Ethyl 4,6-dichloropyridine-3-carboxylate (1') (10 g, 45.4 mmol, 1.0 equiv) was added to a solution of cyclopentylamine (2') (17.9 mL, 182 mmol, 4.0 equiv) in MeCN (100 mL), and the reaction mixture was stirred at 65 ° C overnight. The reaction mixture was cooled to room temperature and water (400 mL) was added. The suspension was sonicated and then stirred at 0 ° C for 1 hour. The solid was filtered, rinsed with water, and dried under high vacuum to give 3' (11.9 g, 44.1 mmol, 97% yield) as a brown solid.

[0538] LCMS method 1: 96.5% purity at 215 nm, [M+H] + =269.2.

[0539] 1 H NMR (400MHz, DMSO-d6) δppm 1.30 (t, J=7.1Hz, 3H), 1.40-1.51 (m, 2H), 1.56-1.73 (m, 4H), 2.02 (dq, J=12.2, 6 .0Hz, 2H), 3.97 (sxt, J=6.3Hz, 1H), 4.29 (q, J=7.1Hz, 2H), 6.82 (s, 1H), 8.08 (br d, J=7.0Hz, 1H), 8.52 (s, 1H).

[0540] Step 2'. Preparation of ethyl 6-(1,3-benzothiazol-6-ylamino)-4-(cyclopentylamino)pyridine-3-carboxylate (5'): 1,3-Benzothiazol-6-amine (4') (4.19 g, 27.9 mmol, 1.5 equiv), ethyl 6-chloro-4-(cyclopentylamino)pyridine-3-carboxylate (3') (5 g, 18.6 mmol, 1.0 equiv) and PTSA.HO (1.42 g, 7.44 mmol, 0.4 equiv) were combined in ethanol (37.2 mL) in a sealed tube and the reaction mixture was stirred at 105° C. for 40 h. The organic solvent was evaporated under reduced pressure, and the crude mixture was taken up in a minimum amount of EtOAc and basified with saturated NaHCO (aq) until the product precipitated. The precipitate was filtered and triturated with 1:1 MeCN / H2O, then filtered again and rinsed with water to afford 5' (4.72 g, 12.34 mmol, 66% yield) as a green solid.

[0541] LCMS method 1: 98.5% purity at 215 nm, [M+H] + =383.2.

[0542] 1 H NMR (400MHz, DMSO-d6) δppm 1.29 (t, J=7.1Hz, 3H), 1.49 (br dd, J=11.9, 5.9Hz, 2H), 1.56-1.78 (m, 4H), 1.97-2.05 (m, 2H), 3.39-3.43 (m, 1H), 3.78 (dq, J =12.0, 6.0Hz, 1H), 4.23 (q, J = 7.1Hz, 2H), 6.06 (s, 1H), 7.56 (dd, J = 8.8, 1.7Hz, 1H), 7.78 (br d, J=6.2Hz, 1H), 7.95 (d, J=8.8Hz, 1H), 8.57 (s, 1H), 8.62 (d, J=1.3Hz, 1H), 9.16 (s, 1H), 9.42 (s, 1H).

[0543] Step 3. Preparation of 6-(1,3-benzothiazol-6-ylamino)-4-(cyclopentylamino)pyridine-3-carboxylic acid (A-1): A solution of LiOH·H2O (2.59 g, 61.7 mmol, 5.0 equiv) in water (15 mL) was added to a solution of ethyl 6-(1,3-benzothiazol-6-ylamino)-4-(cyclopentylamino)pyridine-3-carboxylate (5') (4.72 g, 12.3 mmol, 1.0 equiv) in THF (15 mL) and methanol (15 mL), and the reaction mixture was stirred at 80°C for 1 hour. The organic solvent was evaporated under reduced pressure, and the crude mixture was diluted with water (75 mL) and acidified to pH = 1 with 3.0 M HCl (aq). The precipitate was filtered, rinsed thoroughly with water, and dried under high vacuum to afford A-1 (4.03 g, 11.2 mmol, 91% yield) as a tan solid.

[0544] LCMS method 2: 98.7% purity at 215 nm, [M+H] + =355.1.

[0545] 1 H NMR (400MHz, DMSO-d6) δppm 1.41-1.55(m, 2H), 1.55-1.72(m, 4H), 1.92-2.10(m, 2H), 3.75-3.87(m, 1H), 6.11(s, 1H), 7.55(br d, J=8.2Hz, 1H), 8.05 (br d, J=8.8Hz, 1H), 8.38 (br d, J=3.3Hz, 1H), 8.43 (br s, 2H), 9.27 (s, 1H), 10.02 (br s, 1H), 12.95 (brs, 1H). Example S20. 6-(2-Chloro-4-cyano-anilino)-4-(isopropylamino)pyridine-3-carboxylic acid (A-53)

[0546] LCMS method 1. Column: Luna C18(2) 50×3 mm, 3 μm. Temperature: 45°C, flow rate: 1.5 mL / min, run time: 2.5 min. Mobile phase conditions: initial 95% H2O 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.3 min, followed by a 1.2 min hold at 95% MeCN 0.1% FA. MSD: ESI positive

[0547] LCMS method 3. Kinntex Polar C18 2.6 μm, 50 × 3.0 mm. Temperature: 45°C, flow rate: 1.2 mL / min, run time: 3 min. Mobile phase conditions: initial 95% H2O + 0.1% FA / 5% MeCN + 0.1% FA, followed by a linear gradient to 95% MeCN over 1.5 min, followed by a 1.5 min hold at 95% MeCN. MSD: positive

[0548] Step 1". Preparation of ethyl 6-chloro-4-(isopropylamino)pyridine-3-carboxylate (3"): To a solution of ethyl 4,6-dichloropyridine-3-carboxylate 1" (5 g, 22.72 mmol, 1 eq.) in MeCN (50 mL, 0.45 M) was added propan-2-amine 2" (5.86 mL, 68.17 mmol, 3 eq.). The reaction was stirred at 65°C. After overnight, LCMS showed complete conversion to compound 3". The reaction mixture was cooled to room temperature, water was added, the solution was sonicated for 1 minute and stirred at 0°C for 1 hour. The precipitate was filtered and dried in vacuo to give 3" (5.35 g, 97% yield) as a light pink solid.

[0549] LCMS method 1: 99.9% purity at 215 nm [M+H] + =243.2.

[0550] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J = 6.4 Hz, 6H), 1.40 (t, J = 7.1 Hz, 3H), 3.69 (dq, J = 13.3, 6.7 Hz, 1H), 4.34 (q, J = 7.3 Hz, 2H), 6.55 (s, 1H), 8.11 (br s, 1H), 8.67 (s, 1H).

[0551] Step 2'. Preparation of 6-(2-chloro-4-cyano-anilino)-4-(isopropylamino)pyridine-3-carboxylic acid ethyl ester (5"): To a flame-dried sealed tube was added 6-chloro-4-(isopropylamino)pyridine-3-carboxylic acid ethyl ester 3' (100 mg, 0.41 mmol, 1 eq.), 4-amino-3-chloro-benzonitrile 4" (75.44 mg, 0.49 mmol, 1.2 eq.), Xantphos (11.92 mg, 0.02 mmol, 0.05 eq.), Cs2CO3 (187.9 mg, 0.58 mmol, 1.4 eq.) and Pd2(dba)3 (18.86 mg, 0.02 mmol, 0.05 eq.) in 1,4-dioxane (2 mL, 0.2 M). The solution was sparged with nitrogen for 5 min, the tube was sealed and stirred at 150°C. After spending the night, LCMS showed 77% conversion to compound 5 '. The reactant was cooled to room temperature, the mixture was passed through diatomaceous earth and the plate was washed with EtOAc. The solvent was evaporated under reduced pressure and purified by reverse phase FC (50g C18 column, liquid sediment (DMSO), 5% MeOH / 0.1% HCOOH over 4CV, then 5 to 95% MeOH / 0.1% HCOOH over 15CV, the product was washed out at about 70% MeOH) residue. The pure tubes were merged and concentrated to dryness to obtain 5 (105mg, 55% yield) as a red oil.

[0552] LCMS method 3: 77.5% purity at 215 nm [M+H] + =359.1.

[0553] 1 H NMR (400MHz, DMSO-d6) δppm 1.24 (d, J=6.4Hz, 6H), 1.30 (t, J=6.8Hz, 3H), 3.61-3.71 (m, 1H), 4.25 (q, J=7.1Hz, 2H), 6.58 (s, 1H), 7.6 6-7.72 (m, 1H), 7.74-7.78 (m, 1H), 8.00 (d, J=1.7Hz, 1H), 8.43 (d, J=8.8Hz, 1H), 8.54 (s, 1H), 8.84 (s, 1H)

[0554] Step 3'. Preparation of 6-(2-chloro-4-cyano-anilino)-4-(isopropylamino)pyridine-3-carboxylic acid (A-53): To a round-bottom flask was added 6-(2-chloro-4-cyano-anilino)-4-(isopropylamino)pyridine-3-carboxylic acid ethyl ester 5' (105 mg, 0.29 mmol, 1 eq.) and LiOH·H2O (61.39 mg, 1.46 mmol, 5 equiv) in H2O:THF:MeOH (0.49 mL:0.49 mL:0.49 mL, 0.2 M), and the reaction mixture was stirred at room temperature. After 1 hour, LCMS showed complete conversion to compound 6. The organic solvent was evaporated under reduced pressure and the crude mixture was purified by reverse phase FC (50 g C18 column, liquid sediment (DMSO), 5% MeCN / 0.1% HCOOH over 4CV, then 5 to 95% MeCN / 0.1% HCOOH over 15CV, the product eluted at about 35% MeCN). The pure tubes were combined and concentrated to dryness to give A-53 (40 mg, 38% yield) as a white solid.

[0555] LCMS method 3: 91.5% purity at 215 nm, [M+H] + =331.1.

[0556] 1 H NMR (400MHz, DMSO-d6) δppm 1.23 (d, J=6.4Hz, 6H), 3.60-3.70 (m, 1H), 6.57 (s, 1H), 7.69 (dd, J=8.7, 2.1Hz, 1 H), 7.94-8.02 (m, 2H), 8.45 (d, J=8.8Hz, 1H), 8.50 (s, 1H), 8.77 (s, 1H), 12.70 (br s, 1H). Example S21. 4-(Cyclopropylamino)-6-[(2-oxo-3H-1,3-benzothiazol-6-yl)amino]pyridine-3-carboxylic acid (A-59)

[0557] LCMS method 1 Column: Luna C18(2) 50×3 mm, 3 μm. Temperature: 45°C, flow rate: 1.5 mL / min, run time: 2.5 min. Mobile phase conditions: initial 95% H2O 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.3 min, followed by a 1.2 min hold at 95% MeCN 0.1% FA. MSD: ESI positive.

[0558] Step 1"'. Preparation of ethyl 6-chloro-4-(cyclopropylamino)pyridine-3-carboxylate (3"'): A 250 mL round-bottom flask was charged with tert-butyl 4,6-dichloropyridine-3-carboxylate 1"' (1.5 g, 6.82 mmol, 1 eq.), MeCN (50 mL) and cyclopropylamine 2"' (1.26 mL, 20.45 mmol, 3 eq.) and the mixture was stirred at 70°C. After 18 h, LCMS showed complete conversion. The volatiles were removed in vacuo and the residue was purified by normal phase flash chromatography (40 g silica gel column; elution: 0% EtOAc / heptane over 3CV, 0% to 20% EtOAc / heptane over 13CV). The fractions were collected and concentrated to give 3"' (1.5 g, 6.232 mmol, 92% yield) as a white solid.

[0559] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =241.2.

[0560] 1 H NMR (400MHz, CDCl3) δppm 0.61-0.66 (m, 2H), 0.88-0.94 (m, 2H), 1.39-1.42 (t, J=7.2Hz, 3H), 2.47-2.55 (m, 1H), 4.35 (q, J=7.1Hz, 2H), 6.98 (s, 1H), 8.23 ​​(br s, 1H), 8.68 (s, 1H).

[0561] Step 2"'. Preparation of ethyl 4-(cyclopropylamino)-6-[(2-oxo-3H-1,3-benzothiazol-6-yl)amino]pyridine-3-carboxylate (5"'): To a sealed tube was added ethyl 6-chloro-4-(cyclopropylamino)pyridine-3-carboxylate 3"' (100 mg, 0.42 mmol, 1 eq.), 6-aminobenzo[d]thiazol-2(3H)-one 4" (104 mg, 0.62 mmol, 1.5 eq.), p-toluenesulfonic acid monohydrate (24 mg, 0.12 mmol, 0.3 eq.) and ethanol (3 mL). The tube was purged with nitrogen, sealed and stirred at 105°C. After 2 days, LCMS showed 70% conversion. The EtOH was removed in vacuo and the residue was purified by reverse phase flash chromatography (liquid deposit (DMSO), elution: 5% MeCN / water over 10CV, 5%-40% MeCN / water over 10CV, and 40%-100% MeCN / water over 10CV). The product eluted from the column at approximately 98% MeCN. The fractions were combined and concentrated to give 5' (100 mg, 0.2457 mmol, 60% yield) as an off-white solid.

[0562] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =371.1.

[0563] 1 H NMR (400MHz, DMSO-d6) δppm 0.53-0.61 (m, 2H), 0.76-0.84 (m, 2H), 1.29 (t, J=7.1Hz, 3H), 4.24 (q, J=7.1Hz, 2H), 6.33 (s, 1H ), 7.05-7.14 (m, J=8.6Hz, 1H), 7.30-7.37 (m, 1H), 7.48 (d, J=8.1Hz, 1H), 7.87 (s, 1H), 7.98 (br s, 1H), 8.44 (s, 1H), 9.47 (br s, 1H), 11.81 (br s, 1H).

[0564] Step 3"'. Preparation of 4-(cyclopropylamino)-6-[(2-oxo-3H-1,3-benzothiazol-6-yl)amino]pyridine-3-carboxylic acid (A-59): In a round-bottom flask was added ethyl 4-(cyclopropylamino)-6-[(2-oxo-3H-1,3-benzothiazol-6-yl)amino]pyridine-3-carboxylate 5"' (100 mg, 0.27 mmol, 1 eq.), lithium hydroxide monohydrate (32 mg, 1.35 mmol, 5 eq.), THF (1 mL), MeOH (1 mL) and water (1 mL). The reaction was stirred at 60 ° C. After 6 h, LCMS showed complete conversion. The volatiles were removed under vacuum and the residue was taken up in water (5 mL). 6M HCl aqueous solution was added to reach pH 3. The precipitate was filtered off and dried in vacuo to afford A-59 (73 mg, 0.213 mmol, 79% yield) as a brown solid.

[0565] LCMS method 1: 85.2% purity at 215 nm, [M+H] + =343.1.

[0566] 1 H NMR (400MHz, DMSO-d6) δppm 0.56-0.65(m, 2H), 0.76-0.85(m, 2H), 2.54-2.59(m, 1H), 6.34(s, 1H), 7.18(d, J=8 .6Hz, 1H), 7.26-7.36(m, 1H), 7.76(s, 1H), 8.32(s, 1H), 8.41-8.58(m, 1H), 9.95(br s, 1H), 11.99 (s, 1H), 13.22 (br s, 1H).

[0567] TBM intermediates prepared using general procedure TBM-1 are summarized in Table 14. Table 14. TBM intermediates prepared via general procedure TBM-1 General Program TBM-2 Example S22. 1-(4-(Cyclopentylamino)-5-ethynylpyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (A-9)

[0568] Step 1 '. Preparation of 2-chloro-N-cyclopentyl-5-iodopyridine-4-amine (3 '): To a stirred solution of 2-chloro-5-iodo-pyridine-4-amine (1.25 g, 4.91 mmol) (1 ') in DMF (6.7293 mL) at 0 ° C, NaH (654.98 mg, 9.82 mmol) was added in small portions and the reactant was stirred at room temperature for 1 hour. The reaction mixture was heated to 80 ° C and stirred at this temperature for 30 minutes. Bromocyclopentane (1.05 mL, 9.82 mmol) (2 ') was added dropwise at this temperature, and the reactant was stirred at 80 ° C overnight. The reactant was quenched with NH4Cl (saturated) solution and extracted with EtOAc. The organic phase was washed with brine (× 3). The aqueous phase was extracted with EtOAc (× 3). The combined organic phase was washed with brine and dried (MgSO4), then concentrated to dryness. Purification was performed by normal phase flash chromatography, pre-adsorbed onto SiO2 on an 80 g SNAP column, and eluted with 1 to 50% EtOAc / heptane over 10 CV. The desired product eluted in the first UV-active peak (18% EA), and the fractions were combined and concentrated under reduced pressure to give 1.2 g (28% yield) of the desired product (3') and 1.69 g of the starting material.

[0569] LCMS (3.0 min run, low pH): rt = 1.9670 min; [M+H] + =323.0m / z

[0570] Step 2'. Preparation of 5-((tert-butyldimethylsilyl)ethynyl)-2-chloro-N-cyclopentylpyridin-4-amine (4'): 2-chloro-N-cyclopentyl-5-iodo-pyridin-4-amine (2.6 g, 8.06 mmol) (3'), tert-butyl-ethynyl-dimethyl-silane (1.43 mL, 7.66 mmol), CuI (383.77 mg, 2.02 mmol), NEt (22.47 mL, 161.21 mmol) in DMF (37.201 mL) were degassed with N. Then, PdCl(PPh) (565.75 mg, 0.8100 mmol) was added to the mixture, which was sparged with N for 10 minutes. The reaction was stirred at room temperature until complete conversion was observed by LCMS. The crude mixture was diluted with H2O and extracted with MTBE (2x), MeTHF (2x), and the organic layers were combined. The organic layers were washed with 1M HCl, NaHCO3 (saturated), and brine, dried over MgSO4, filtered, and concentrated under reduced pressure for purification. Purification was performed via normal phase chromatography, pre-adsorbed onto SiO2, and eluted on an 80 g SNAP column from 2% to 20% EtOAc / heptane over 15 CV, with the product eluting at 8% EA. Fractions from the main peak were combined and concentrated under reduced pressure to give 2.75 g (66% yield) of the desired product (4') as a white solid.

[0571] LCMS (3.5 min run, low pH): pdt rt = 2.499 min; [M+H] + =335.4m / z.

[0572] Step 3'. Preparation of 1-(5-((tert-butyldimethylsilyl)ethynyl)-4-(cyclopentylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (6'): 5-[2-[tert-butyl(dimethyl)silyl]ethynyl]-2-chloro-N-cyclopentyl-pyridin-4-amine (2.75 g, 8.21 mmol) (4'), 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (0.66 mL, 9.85 mmol) (5'), Xantphos (1520.14 mg, 2.63 mmol), and Zn(OAc)2 (1506.36 mg, 8.21 mmol) in 1,4-dioxane (50 mL) were degassed with N2. Next, Pd2(dba)3.CHCl3 (1127.7 mg, 1.23 mmol) was added to the mixture, which was bubbled with N2 for 10 minutes. The reaction mixture was stirred at 105 ° C for 10 hours, showing incomplete conversion (about 50%). At room temperature, additional Zn(OAc)2 (753.18 mg, 4.1 mmol), Xantphos (1425.13 mg, 2.46 mmol), Pd2(dba)3 (751.8 mg, 0.8200 mmol) were added to the mixture and bubbled with N2 for 10 minutes. The reaction mixture was stirred at 105 ° C for another 10 hours, where LCMS showed complete conversion. The reaction mixture was passed through celite, washed with MeTHF, and the solvent was concentrated under reduced pressure. It was then purified via normal phase flash chromatography, pre-adsorbed on SiO2, and eluted from 1 to 65% EtOAc / heptane on an 80 g SNAP column over 15CV. Fractions from the last peak (about 58% EtOAc / heptane) were combined and concentrated under reduced pressure to give the final product (6') 1.5 g (41% yield).

[0573] LCMS (2.5 min run, low pH): rt = 2.278 min; [M+H] + =443.2m / z.

[0574] Step 4'. Preparation of 1-(4-(cyclopentylamino)-5-ethynylpyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (A-9): To a stirred solution of 1-[5-[2-[tert-butyl(dimethyl)silyl]ethynyl]-4-(cyclopentylamino)-2-pyridinyl]pyrazolo[3,4-b]pyridine-5-carbonitrile (265. mg, 0.6000 mmol) in THF (5.9869 mL) was added TBAF (2.39 mL, 2.39 mmol) 1M in THF at 0°C. The mixture was stirred while warming to room temperature until LCMS showed complete conversion. The crude mixture was concentrated to dryness. It was then quenched with NH4Cl and diluted in EtOAc. The organic layer was washed with NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure, then purified via reverse phase FC (MeOH / 0.1% aqueous FA, 5% to 100% MeOH over 17CV, product exited at 41% MeOH) to give A-9, M = 80 mg, 95% purity at 215 nm.

[0575] LCMS (2.5 min run, low pH): 1.677 min; [M+H] + =329.1m / z.

[0576] TBM intermediates prepared using general procedure TBM-2 are summarized in Table 15. Table 15. TBM intermediates prepared via general procedure TBM-2 General Procedure TBM-3 R 4 As defined in formula (I') or (I), and X', Y' and Z' are selected from C, N, O and S.

[0577] Step 1. Preparation of tert-butyl 4,6-dichloropyridine-3-carboxylate (2): To a solution of 4,6-dichloropyridine-3-carboxylic acid 1 (1 eq.) and DMAP (0.2 eq.) in THF (0.52 M) at 70° C. was added dropwise over 2 hours using an addition funnel. The reaction mixture was then stirred at 70° C. for another hour. The THF was evaporated under reduced pressure and the residue was purified by normal phase flash chromatography to give the product 2.

[0578] Step 2. Preparation of tert-butyl 6-chloro-4-(amino)pyridine-3-carboxylate (4): To a solution of tert-butyl 4,6-dichloropyridine-3-carboxylate 2 (1 eq.) in MeCN (0.45 M) was added amine 3 (3 eq.). The reactants were stirred at 70 ° C. After LCMS indicated conversion, the reaction mixture was cooled to room temperature and water (350 mL) was added to form a white semi-solid. The resulting slurry was stirred at 0 ° C for 1 h. The aqueous solution was extracted with 2 × DCM and 2 × MeTHF. The solvent was evaporated under reduced pressure and the residue was purified by normal phase flash chromatography to give product 4.

[0579] In some cases, DIPEA was added to help promote S N Ar reaction, especially when the salt form of the amine is used.

[0580] Step 3. Preparation of tert-butyl 6-(heterobicyclo)-4-(amino)pyridine-3-carboxylate (6): A round-bottom flask was charged with 4 (1.0 eq.), 5 (1.1 eq.), XantPhos (0.3 eq.), Zn(OAc)2 (0.6 eq.), and Pd2(dba)3·CHCl3 (0.15 eq.). 1,4-Dioxane (0.2 M) was added, the mixture was sonicated, and nitrogen was sparged through the mixture for 5 min. The mixture was stirred at 110°C for 16 h. The mixture was passed through celite, which was washed with DCM. The solution was dry packed on silica. Purification by normal phase flash chromatography (heptane / EtOAc) gave 6.

[0581] Step 4. Preparation of TBM-3: TFA (30 eq.) was added to a solution of 6 (1.0 eq.) in DCM (0.9 M) at room temperature. The solution was stirred at 45 ° C for 2 h. The solvent was removed in vacuo. The remaining TFA was co-evaporated with toluene (2×) and then co-evaporated with MeCN. The residue was dried under high vacuum to obtain a yellow solid. MTBE was added to the solid and the mixture was sonicated and stirred at room temperature for 16 h. The suspension was filtered through a Buchner funnel and rinsed with MTBE to obtain TBM-3.

[0582] Similar acidic conditions can be used in ester hydrolysis. Example S23. 6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopentylamino)pyridine-3-carboxylic acid (A-7)

[0583] LCMS method 1. Column: Luna C18(2) 50×3 mm, 3 μm. Temperature: 45°C, flow rate: 1.5 mL / min, run time: 2.5 min. Mobile phase conditions: initial 95% H2O 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.3 min, followed by a 1.2 min hold at 95% MeCN 0.1% FA. MSD: ESI positive

[0584] Step 1'. Preparation of tert-butyl 4,6-dichloropyridine-3-carboxylate (2'): To a solution of 4,6-dichloropyridine-3-carboxylic acid 1' (20.0 g, 104.2 mmol, 1 eq.) and DMAP (2.5 g, 20.8 mmol, 0.2 eq.) in THF (150 mL, 0.52 M) at 70 ° C. was added dropwise with an addition funnel over 2 hours containing tert-butyl tert-butoxycarbonyl carbonate (45.4 g, 208.3 mmol, 2 eq.) in THF (50 mL, 0.52 M). The reaction mixture was then stirred at 70 ° C. for another hour. THF was evaporated under reduced pressure and the residue was purified by normal phase flash chromatography (380 g column, solid deposit, elution 0 to 15% heptane / EtOAc over 15 CV). The fractions were combined and concentrated to give 2' (22 g, 85% yield) as a light yellow oil.

[0585] LCMS method 1: 99.9% purity at 215 nm [M+H] + =248.2.

[0586] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.63 (s, 9H), 7.45 (s, 1H), 8.77 (s, 1H).

[0587] Step 2'. Preparation of tert-butyl 6-chloro-4-(cyclopentylamino)pyridine-3-carboxylate (4'): To a solution of tert-butyl 4,6-dichloropyridine-3-carboxylate 2' (2.02 g, 8.13 mmol, 1 eq.) in MeCN (18 mL, 0.45 M) was added cyclopentylamine 3' (2.41 mL, 24.38 mmol, 3 eq.). The reactants were stirred at 70 ° C. After 2.5 h, LCMS showed complete conversion to compound 4'. The reaction mixture was cooled to room temperature, water (350 mL) was added to form a white semi-solid. The resulting slurry was stirred at 0 ° C for 1 h. No precipitate was formed. The aqueous solution was extracted with 2 × DCM and 2 × MeTHF. The solvent was evaporated under reduced pressure and the residue was purified by normal phase flash chromatography (40 g column, solid deposit, eluted 0% to 30% EtOAc / heptane over 15 CV). The fractions were combined and concentrated to afford 4' (2.4 g, 99% yield) as a colorless oil.

[0588] LCMS method 1: 99.9% purity at 215 nm [M+H] + =297.2.

[0589] 1 H NMR (400 MHz, chloroform-d) δ ppm 1.45-1.54 (m, 11H), 1.55-1.64 (m, 2H), 1.66-1.76 (m, 2H), 1.94-2.05 (m, 2H), 3.67-3.78 (m, 1H), 6.46 (s, 1H), 8.12 (br. d, J=5.1 Hz, 1H), 8.50 (s, 1H).

[0590] Step 3 '. Preparation of 6- (5-cyanopyrazolo [3, 4-b] pyridin-1-yl) -4- (cyclopentylamino) pyridine-3-carboxylic acid tert-butyl ester (6 '): To a flame-dried sealed tube was added 6-chloro-4- (cyclopentylamino) pyridine-3-carboxylic acid tert-butyl ester 4 ' (1.0 g, 3.37 mmol, 1 eq.), 1H-pyrazolo [3, 4-b] pyridine-5-carbonitrile 5 ' (631.3 mg, 4 .38mmol, 1.3eq.), Xantphos (623.8mg, 1.08mmol, 0.3eq.), Zn(OAc) 2 (197.8mg, 1.08mmol, 0.3eq.) and Pd 2 (dba) 3 · CHCl 3 (523.1mg, 0.51mmol, 0.15eq.) in 1,4-dioxane (13.5mL, 0.25M). The solution was sparged with nitrogen for 35min, sealed and stirred at 110°C. After spending the night, LCMS showed complete conversion to compound 6 '. The mixture was passed through diatomaceous earth and the plate was washed with DCM. The solvent was evaporated under reduced pressure and the residue was purified by normal phase flash chromatography (40g gold columns, solid deposit, eluted 20 to 100% EtOAc / heptane, over 15CV). Each fraction was combined and concentrated to obtain 6 ' (1.29g, 87% yield) as a yellow solid.

[0591] LCMS method 1: 92.3% purity at 215 nm [M+H] + =405.2.

[0592] 1H NMR (400MHz, chloroform-d) δppm 1.55(s, 9H), 1.60-1.72(m, 4H), 1.75-1.84(m, 2H), 2.10-2.18(m, 2H), 3.92-4.03(m, 1H), 7.82(b r.s, 1H), 8.56 (s, 1H), 8.68 (d, J=1.7Hz, 1H), 8.74 (s, 1H), 8.93 (br.s, 1H), 8.98 (d, J=2.0Hz, 1H).

[0593] Step 4'. Preparation of 6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopentylamino)pyridine-3-carboxylic acid (A-7): To a solution of tert-butyl 6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopentylamino)pyridine-3-carboxylate 6' (0.8 g, 1.98 mmol, 1 eq.) in anhydrous DCM (11.6 mL, 0.17 M) was added TFA (4.8 mL, 59.3 mmol, 30 eq.) under nitrogen atmosphere and the reaction was stirred at room temperature. After stirring overnight, LCMS showed complete conversion to compound 7'. The solvent was removed under reduced pressure and the residue was co-evaporated with toluene (3x) and then with MeCN (2x) to give a yellow semisolid, to which was added H2O (50 mL) / MeCN (10 mL) and the mixture was sonicated for 3-5 min. The solid was stirred at room temperature for 10 min, filtered and washed with water and MeCN (until white solid) to afford A-7 (0.9 g, 99% yield) as a white solid.

[0594] LCMS method 1: 93.2% purity at 215 nm [M+H] + =349.2.

[0595] 1 H NMR (400MHz, chloroform-d) δppm 1.50-1.61 (m, 2H), 1.62-1.76 (m, 4H), 2.04-2.17 (m, 2H), 3.95-4.04 (m, 1H), 7.46 (s, 1H), 8.40 (b rd, J=6.4Hz, 1H), 8.67 (s, 1H), 8.77 (s, 1H), 9.03 (d, J=2.0Hz, 1H), 9.09 (d, J=2.0Hz, 1H), 13.25 (br.s, 1H). Example S24. 6-(6-Amino-5-cyano-pyrazolo[3,4-b]pyridin-1-yl)-4-[(1-methylsulfonyl-4-piperidinyl)amino]pyridine-3-carboxylic acid (A52)

[0596] LCMS method 1. Column: Luna C18(2) 50×3 mm, 3 μm. Temperature: 45°C, flow rate: 1.5 mL / min, run time: 2.5 min. Mobile phase conditions: initial 95% H2O 0.1% FA / 5% MeCN + 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.3 min, followed by a 1.2 min hold at 95% MeCN 0.1% FA. MSD: ESI positive.

[0597] Step 1". Preparation of tert-butyl 6-chloro-4-[(1-methylsulfonyl-4-piperidinyl)amino]pyridine-3-carboxylate (4"): To a solution of 3" (3.46 g, 19.41 mmol) and 2' (1.26 g, 5.08 mmol) in MeCN (19 mL) was added DIPEA (5.3 mL, 30.47 mmol) at room temperature and the resulting mixture was stirred at 65°C. After 4 days, the volatiles were evaporated and the residue was partitioned between EtOAc and water. The aqueous phase was extracted into EtOAc (2x). The combined organic phases were washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc / heptane) to give 4" (1.9 g, 94% yield) as a white solid.

[0598] LCMS method 1: 98.1% purity at 215 nm, [M+H] + =390.1.

[0599] 1 H NMR (400MHz, CDCl3) δppm 1.58 (s, 9H), 1.75 (dtd, J=13.4, 9.7, 3.8Hz, 2H), 2.10-2.19 (m, 2H), 2.84 (s, 3H), 2.99-3.09 (m, 2H) , 3.48-3.58 (m, 1H), 3.72 (dt, J=12.3, 4.1Hz, 2H), 6.51 (s, 1H), 8.38 (d, J=7.6Hz, 1H), 8.63 (s, 1H).

[0600] Step 2". Preparation of tert-butyl 6-(6-amino-5-cyano-pyrazolo[3,4-b]pyridin-1-yl)-4-[(1-methylsulfonyl-4-piperidinyl)amino]pyridine-3-carboxylate (6"): A sealed tube was charged with 4" (300 mg, 0.77 mmol), 5" (134 mg, 0.85 mmol), Xantphos (133 mg, 0.23 mmol), Pd2(dba)3·CHCl3 (119 mg, 0.12 mmol), Zn(OAc)2 (141 mg, 0.77 mmol) in 1,4-dioxane (3.8 mL). Nitrogen was then sparged through the mixture for 15 minutes. The tube was sealed and the reaction mixture was heated at 105°C for 16 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filter cake was washed with DCM and the filtrate was concentrated to dryness. The residue was purified by reverse phase C18 flash chromatography (MeOH / 0.1% aqueous formic acid) to afford tert-butyl 6 (127 mg, 32% yield) as a yellow solid.

[0601] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =513.2.

[0602] 1 H NMR (400MHz, DMSO-d6) δppm 1.58(s, 9H), 1.59-1.67(m, 2H), 2.08-2.19(m, 2H), 2.90(s, 3H), 2.98-3.11(m , 2H), 3.50-3.58(m, 2H), 3.70-3.85(m, 1H), 7.25(s, 2H), 7.46(s, 1H), 8.07(br d, J=7.3Hz, 1H), 8.20 (s, 1H), 8.54 (s, 1H), 8.71 (s, 1H).

[0603] Step 3". Preparation of 6-(6-amino-5-cyano-pyrazolo[3,4-b]pyridin-1-yl)-4-[(1-methylsulfonyl-4-piperidinyl)amino]pyridine-3-carboxylic acid (A-52): To a solution of 6" (127 mg, 0.25 mmol) in MeCN (1.0 mL) was added 4M HCl / 1,4-dioxane (3.1 mL, 12.39 mmol). The reaction mixture was stirred at room temperature. After 18 h, the volatiles were removed in vacuo and the residue was co-evaporated with MeCN (2x). The crude solid was triturated in MeCN to give A-52 (115 mg, quantitative) as a yellow solid.

[0604] LCMS method 1: 99.9% pure at 215 nm, [M+H]+ = 457.1.

[0605] 1 H NMR (400MHz, DMSO-d6) δppm 1.57-1.70(m, 2H), 2.09-2.20(m, 2H), 2.91(s, 3H), 3.04-3.14(m, 2H), 3.82-3.93(m, 2H), 4.14(dd, J=5.6, 3.4Hz, 1H), 7.44 (d, J=3.9Hz, 1H), 7.62-7.75 (m, 3H), 8.31 (s, 1H), 8.59 (s, 1H), 8.67 (s, 1H).

[0606] TBM intermediates prepared using general procedure TBM-3 are summarized in Table 16. Table 16. TBM intermediates prepared via general procedure TBM-3 General Program TBM-4 where R 4 As defined in formula (I') or (I).

[0607] Step 1. Preparation of 2-chloro-N-alkyl-5-nitropyridin-4-amine 3: To a solution of 2,4-dichloro-5-nitropyridine 1 (1.0 equiv.) in acetonitrile (1.0 M) was added alkylamine 2 (1.5 equiv.) and DIPEA (2 equiv.) at room temperature. The resulting solution was stirred at 40°C for 2 h. The solution was then cooled to room temperature and concentrated under reduced pressure (70% volume). Finally, ice water was added to the reaction mixture and stirred for 10 min to obtain a light yellow solid. The solid was filtered, washed with water, and dried to obtain compound 3.

[0608] Step 2. Preparation of 1-(4-(alkyl-amino)-5-nitropyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 5: To a solution of 2-chloro-N-alkyl-5-nitropyridin-4-amine 3 (1.0 equiv) in 1,4-dioxane was added 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 4 (1.2 equiv.), Xantphos (0.1 equi...

Claims

1. A compound of formula (I'), or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, monocyclic 5- to 6-membered heteroaryl, or fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 1-4 heteroatoms independently selected from N, O and S, each of which is optionally substituted by 1-3 R 0 Group substitution; Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C6 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl, -(6- to 10-membered bridged heterocyclylene)-, and C1-C6 alkoxy, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O, or two R 0 The groups together form an oxo group; L 1 is -NH- or a bond; L 2 is -NHC(O)-, -C(O)NH-, -SO2NH-, -NHSO2- or -(C1-C6 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1-3 heteroatoms selected from N, O and S; L 3 For-NR 9 (C1-C6 alkylene)NR 9 -、-NR 9 C(O)(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene) (C1-C6 alkylene) z -、-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene) (C1-C6 alkylene) z -, -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene) (C1-C6 alkylene) z -, -(6- to 10-membered bridged heterocyclylene)(C1-C6 alkylene) z -, -(7- to 10-membered fused bicyclic heterocyclic group)(C1-C6 alkylene) z -or- (O) z (6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 Group substitution; L 4 for phenylene, -N(H)(phenylene), 5- to 6-membered heteroarylene, -N(H)(5- to 6-membered heteroarylene)-, 8- to 10-membered fused bicyclic heteroarylene, or 5- to 6-membered heterocyclylene, wherein the phenylene, heteroarylene or heterocyclylene is optionally substituted by 1-4 R 10 The heteroarylene and heterocyclylene groups contain 1 to 3 heteroatoms selected from N, S and O; R 1a and R 1b Each is H or together form an oxo group; R 2 and R 3 are independently H, C1-C6 alkyl or halogen, or R 2 and R 3 Together they form an oxo group; or R 3 and R 11 Together they form a C3-C6 cycloalkylene group; Y is NH, O or a bond; R 4 is C3-C6 cycloalkyl, C1-C6 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C6 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C6 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-5 R 8 Group substitution; W is O, -NR 5 - or key; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halogen or -OH, or two R 6 The groups together form a bridged C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halogen, C1-C6 haloalkyl or -OH, or two R 7 The groups together form an oxo group; Each R 8 is independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halogen or -OH, or two R 10 The groups together form an oxo group; Each R 11 and R 12 are independently H, halogen, C3-C6 cycloalkyl, -OH, -NH(C1-C6 alkyl), C1-C6 haloalkyl or C1-C6 alkyl; or R 11 and R 3 Together they form a C3-C6 cycloalkylene group; x is 0 or 1; y is 0, 1, 2, 3, 4, or 5; Each z is independently 0 or 1; X is N or CR 13 ; R 13 is H, halogen, -OH or C1-C6 alkyl; Z 1 is CH or N; and Z 2 is CH or N, The restriction condition is Z 1 and Z 2 Not all are N.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I): in: Ring A is phenyl, monocyclic 5- to 6-membered heteroaryl, or fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 1-4 heteroatoms independently selected from N, O and S, each of which is optionally substituted by 1-3 R 0 Group substitution; Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C6 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 alkoxy, or two R 0 The groups together form an oxo group; L 1 is -NH- or a bond; L 2 is -NHC(O)-, -C(O)NH-, -SO2NH-, -NHSO2-, or a 5-membered heteroarylene group containing 1 to 3 heteroatoms selected from N, O and S; L 3 For-NR 9 (C1-C6 alkylene)NR 9 -、-NR 9 C(O)(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene) (C1-C6 alkylene) z -、-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, -(6- to 10-membered bridged heterocyclylene)(C1-C6 alkylene) z -, -(9- to 10-membered fused bicyclic heterocyclic group)(C1-C6 alkylene) z -or- (O) z (6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O and is optionally substituted by 1-5 R 7 Group substitution; L 4 for phenylene, 5 to 6 membered heteroarylene or 5 to 6 membered heterocyclylene, wherein the phenylene, heteroarylene or heterocyclylene is optionally substituted by 1 to 4 R 10 The heteroarylene and heterocyclylene groups contain 1 to 3 heteroatoms selected from N and O; R 1a and R 1b Each is H or together form an oxo group; R 2 and R 3 are independently H, C1-C6 alkyl or halogen, or R 2 and R 3 Together they form an oxo group; or R 3 and R 11 Together they form a C3-C6 cycloalkylene group; Y is NH or O; R 4 is C3-C6 cycloalkyl, C1-C6 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C6 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C6 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-5 R 8 Group substitution; W is O, -NR 5 - or key; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halogen or -OH, or two R 6 The groups together form a bridged C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halogen, C1-C6 haloalkyl or -OH, or two R 7 The groups together form an oxo group; Each R 8 is independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halogen, -CN or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halogen or -OH, or two R 10 The groups together form an oxo group; Each R 11 and R 12 are independently H, halogen, C3-C6 cycloalkyl, -OH, -NH(C1-C6 alkyl), C1-C6 haloalkyl or C1-C6 alkyl; or R 11 and R 3 Together they form a C3-C6 cycloalkylene group; x is 0 or 1; y is 0, 1, 2, 3, 4, or 5; Each z is independently 0 or 1; X is N or CR 13 ; R 13 is H, halogen or C1-C6 alkyl; Z 1 is CH or N; and Z 2 is CH or N, The restriction condition is Z 1 and Z 2 Not all are N.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Ring A is: (i) optionally through 1-3 R 0 phenyl substituted with a group; and Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), C1-C3 alkyl, C3-C6 cycloalkyl and C1-C3 alkoxy; (ii) contains 1 to 2 heteroatoms independently selected from N and O and optionally 1 to 3 R 0 A monocyclic 6-membered heteroaryl group substituted with a group; and Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), C1-C3 alkyl, C3-C6 cycloalkyl and C1-C3 alkoxy; or (iii) contains 2 to 4 heteroatoms independently selected from N, O and S and optionally 1 to 3 R 0 A fused bicyclic 9-membered heteroaryl or heterocyclyl substituted with a radical; and Each R 0 independently selected from halogen, -CN, -NH2, -NH(C1-C3 alkyl), C1-C3 alkyl, C3-C6 cycloalkyl, -(6- to 8-membered bridged heterocyclylene)-, and C1-C3 alkoxy, wherein the heterocyclylene contains 1-3 heteroatoms selected from N and O, or two R 0 The groups are taken together to form an oxo group.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Ring A is:

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: L 2 is -NHC(O)- or -(C1-C3 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1-3 heteroatoms selected from N and O.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein: L 2 -NHC(O)-, 7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein: L 4 for 8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein: for W is O, -NR 5 - or key; and R 5 It is H or C1-C3 alkyl.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein: X is N.

10. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein: X is CR 13 ;and R 13 It is H, halogen, -OH or C1-C3 alkyl.

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein: Y is NH; R 4 is C3-C6 cycloalkyl, C1-C3 alkylene-(C3-C6 cycloalkyl), 4- to 6-membered heterocyclyl, C1-C3 alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C1-C3 alkylene-(5- to 6-membered heteroaryl), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted by 1-2 R 8 group substitution; and Each R 8 independently -SO2(C1-C3 alkyl), -C(O)(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, halogen, -CN or -OH.

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein: R 4 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CH2CH(CH3)2, -CH2CF3, -CH2CH2F, -CH2CF2CH3, -CH(CH3)CF3, -CH2CH2CF3, -CH(CH3)CH2OH, -CH2C(CH3)2OH, -CH2CN, -CH(CH3)CN, -C(CH3)2CN, -CH(CH2CH3)CN, -CH2CH(CH3)CN, 13. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein: L 3 For-NR 9 (C1-C3 alkylene)NR 9 -、-NR 9 C(O)(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, -(4- to 7-membered heterocyclylene)CR 11 R 12 -, -(4- to 7-membered heterocyclylene)(CO) z -, -(4 to 7 membered heterocyclylene) (NR 9 ) z -、-(NR 9 ) z (4- to 7-membered heterocyclylene) (C1-C3 alkylene) z -、-NR 9 (C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, -NR 9 C(O)(phenylene)NR 9 -, -(C1-C3 alkylene) z (4- to 7-membered heterocyclylene) (C1-C3 alkylene) z -, -O(C1-C3 alkylene) z (4- to 7-membered heterocyclylene) (C1-C3 alkylene) z -, -(6- to 10-membered bridged heterocyclylene)(C1-C3 alkylene) z -, -(7- to 10-membered fused bicyclic heterocyclic group)(C1-C6 alkylene) z -or- (O) z (6- to 10-membered spiroheterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene group contains 1 to 3 heteroatoms selected from N and O and is optionally substituted by 1 or 2 R 7 Group substitution; Each z is independently 0 or 1; Each R 9 are independently H or C1-C3 alkyl; Each R 7 are independently C1-C3 alkyl, halogen, C1-C3 haloalkyl or -OH, or two R 7 The groups together form an oxo group; and Each R 11 and R 12 are independently H or -CH3.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein: L 3 for 15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein the compound has formula (Ia) or (Ia'): in: Ring A is a ring containing 2-4 heteroatoms independently selected from N, O and S, optionally 1-3 R 0 a substituted fused bicyclic 9- to 10-membered heteroaryl; R 4 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH or C1-C6 alkyl-CN; and Z 3 and Z 4 is independently N or CH, with the proviso that Z 3 and Z 4 At least one of them is N.

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (If) or (If'):

17. A compound selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

19. A method for modulating interleukin-1 (IL1) receptor associated kinase 4 (IRAK4) activity, comprising contacting IRAK4 with an effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18.

20. A method for treating an inflammatory disease or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, optionally wherein the inflammatory disease or autoimmune disease is atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoprin protein-associated periodic syndrome, hidradenitis suppurativa, Behcet's syndrome, or familial cold autoinflammatory syndrome.

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