Heteroaryl compounds as ligand-directed degraders of IRAK4

Abstract

Provided herein are compounds and compositions thereof for modulating IRAK4. In some embodiments, the compounds and compositions are provided for treating inflammation or autoimmune diseases.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 390,888, filed July 8, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0002] FIELD OF THE INVENTION FIELD OF THE DISCLOSURE The present disclosure relates generally to compounds, compositions, and uses of compounds and compositions for treating inflammatory or autoimmune diseases. [Background technology]

[0003] The recruitment of immune cells to the site of injury involves the coordinated interaction of a large number of soluble mediators. Several cytokines appear to play important roles in these processes, including interleukin-1 (IL-1). IL-1 triggers the inflammatory response and is involved in the tissue degeneration observed in chronic inflammatory conditions. IL-1 is also involved in the process of bone resorption and in regulating tissue death. Thus, IL-1 plays an important role in a large number of pathological conditions, including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, cancer, and sepsis.

[0004] Treatment of cells with IL-1 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 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 MyD88-family adaptor proteins and a centrally located kinase domain. Of the four members of the mammalian IRAK family, IRAK-4 is considered the "master IRAK." IRAK-4 is a serine / threonine kinase that plays an essential role in Toll / IL-1 receptor (TIR)-mediated signal transduction. Under overexpression conditions, all IRAKs can mediate activation of nuclear factor-kappa B and stress-induced mitogen-activated protein kinase (MARK) signaling cascades. Studies have shown that IRAK4 kinase activity is essential for cytokine production, MARK activation, and induction of NF-kappa B-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 immunological protection, compounds that modulate IRAK4 function may be useful in the treatment of inflammatory, cell proliferative, and immune-related conditions, as well as 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 that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of nearly all intracellular processes. Protein ubiquitination is achieved by E3 ubiquitin ligases, which bind to proteins and attach ubiquitin molecules to them, thus marking them for proteasomal degradation.

[0006] There has been significant interest in harnessing UPP for therapeutic use (Zhou et al., Mol. Cell 2000, 6, 751-756). One promising therapeutic approach is the use of proteolysis-directed chimeras (commonly referred to as PROTACs) to remove unwanted proteins by proteolysis (Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160-176). PROTACs are ligand-directed degraders that link E3 ligases to target proteins for degradation. These bivalent molecules typically consist of a linker moiety between an E3 ligase ligand and a small molecule that binds to the target protein. PROTACs position the E3 ligase at the appropriate distance and orientation to the target protein, allowing it to be ubiquitinated. The ubiquitinated target protein is then recognized by the proteasome and degraded there.

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

[0008] In certain embodiments, compounds and compositions thereof for degrading IRAK4 are described herein. In various embodiments, the compounds and compositions thereof can be used for the treatment of inflammatory or autoimmune diseases.

[0009] The present embodiments may be more fully understood by reference to the following detailed description and examples, which are intended to exemplify non-limiting embodiments.

[0010] Embodiment A1 is a compound of formula (I'): [ka] [In formula: Ring A is phenyl, monocyclic 5- or 6-membered, or fused bicyclic 9- or 10-membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from 1 to 3 R 0 optionally substituted with groups; Each R 0 is independently selected from halo, -CN, -NH, -NH(C-C alkyl), C-C alkyl, C-C cycloalkyl, -(6- to 10-membered bridged heterocyclylene)-, and C-C alkoxy, wherein the heterocyclylene contains 1 to 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 said heteroarylene contains 1 to 3 heteroatoms selected from N, O and S; L 3 is -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 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 optionally substituted with a group; L 4 teeth [ka] 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 selected from the group consisting of 1 to 4 R 10 groups, wherein the heteroarylene and heterocyclylene contain 1 to 3 heteroatoms selected from N, S and O; R1a and R 1b are each H or together form an oxo group; R 2 and R 3 are independently H, C-C alkyl, or halo, or R 2 and R 3 together form an oxo group; Or R 3 and R 11 together 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 to 3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl, or heteroaryl is selected from 1 to 5 R 8 optionally substituted with a group; W, O, -NR 5 - or a conjugated hand; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halo, or -OH, or two R 6 the groups together form a bridging C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, or —OH, or two R 7 The groups together form an oxo group; Each R 8are independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halo, -CN, or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halo, or -OH, or two R 10 groups, taken together, form an oxo group; Each R 11 and R 12 is independently H, halo, C3-C6 cycloalkyl, —OH, —NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; Or R 11 and R 3 taken together 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 and; R 13 is H, halo, -OH, or C1-C6 alkyl; Z 1 is CH or N; and Z 2 is CH or N: However, Z 1 and Z 2 are never both N] or a pharmaceutically acceptable salt thereof.

[0011] Embodiment A2 is a compound of formula (I): [ka] [In formula: 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 contain 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from 1 to 3 R 0 optionally substituted with groups; Each R 0 are independently selected from halo, -CN, -NH, -NH(C-C alkyl), C-C alkyl, C-C cycloalkyl, and C-C 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—, —SONH—, —NHSO—, or a 5-membered heteroarylene containing 1 to 3 heteroatoms selected from N, O, and S; L 3 is -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 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 optionally substituted with a group; L 4 teeth [ka] phenylene, 5- or 6-membered heteroarylene, or 5- or 6-membered heterocyclylene, wherein the phenylene, heteroarylene, or heterocyclylene is selected from the group consisting of 1 to 4 R 10 groups, wherein the heteroarylene and heterocyclylene contain 1 to 3 heteroatoms selected from N and O; R 1a and R 1b are each H or together form an oxo group; R 2 and R 3 are independently H, C-C alkyl, or halo, or R 2 and R 3 together form an oxo group; Or R 3 and R 11 together 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 to 3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl, or heteroaryl is selected from 1 to 5 R 8 optionally substituted with a group; W, O, -NR 5 - or a conjugated hand; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halo, or -OH, or two R 6 the groups together form a bridging C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, or —OH, or two R 7 The groups together form an oxo group; Each R 8 are independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halo, -CN, or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halo, or -OH, or two R 10 The groups together form an oxo group; R 11 and R 12 are each independently H, halo, C3-C6 cycloalkyl, —OH, —NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; Or R 11 and R 3 taken together 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 and; R 13 is H, halo, or C1-C6 alkyl; Z 1 is CH or N; Z 2 is CH or N: However, Z 1 and Z 2 and N cannot both be N] or a pharmaceutically acceptable salt thereof.

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

[0013] Embodiment A4 is a compound or pharmaceutically acceptable salt of embodiment A3, wherein ring A is: [ka] 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 to 3 heteroatoms selected from N and O.

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

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

[0017] Embodiment A8 is a compound of any one of embodiments A1-A7, or a pharmaceutically acceptable salt thereof, wherein: [ka] teeth [ka] and; W is O, -NR 5 - or a bond; 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, halo, —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 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 the cycloalkyl, heterocyclyl, or heteroaryl is selected from 1 to 2 R 8 optionally substituted with a group; Each R 8 are independently —SO2(C1-C3 alkyl), —C(O)(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, halo, —CN, or —OH.

[0021] Embodiment A12 is a compound of any one of embodiments A1-A11, 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, [ka] is.

[0022] Embodiment A13 is a compound of any one of embodiments A1-A12, or a pharmaceutically acceptable salt thereof, wherein: L 3 is -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 to 3 heteroatoms selected from N and O, and optionally 1 or 2 R 7 may be substituted with a group; 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, halo, C1-C3 haloalkyl, or -OH, or two R 7 groups taken together to form an oxo group; and R 11 and R 12 are each independently H or —CH3.

[0023] Embodiment A14 is a compound or a pharmaceutically acceptable salt of embodiment A13, Here, L 3 teeth [ka] is.

[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'): [ka] [ka] [In formula: Ring A is a fused bicyclic 9- to 10-membered heteroaryl (containing 2-4 heteroatoms independently selected from N, O, and S, and 1-3 R 0 (optionally substituted with a 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; provided that Z 3 and Z 4 at least one of which is N] This is shown by:

[0025] Embodiment A16 is a compound of embodiment A15, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (If) or (If'): [ka] [ka] This is shown by:

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

[0027] Embodiment A18 is a pharmaceutical composition comprising a compound according to 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 the pharmaceutical composition of embodiment A18.

[0029] Embodiment A20 is a method of treating an inflammatory or 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 the pharmaceutical composition of Embodiment A18, wherein optionally the inflammatory or autoimmune disease is atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoprin-associated periodic syndrome, hidradenitis pustularis, Beckett's syndrome, or familial cold autoinflammatory syndrome. DETAILED DESCRIPTION OF THE INVENTION

[0030] definition As used herein, the words "comprising" and "including" can be used interchangeably. The words "comprising" and "including" should be interpreted as specifying the presence of the stated features or components as referred to, but do not exclude the presence or addition of one or more features or components, or groups thereof. In addition, the words "comprising" and "including" are intended to encompass examples encompassed by the word "consisting of." As a result, the word "consisting of" can be used in place of the words "comprising" and "including" to provide more specific embodiments of the present invention.

[0031] The term "consisting of" means that the object has at least 90%, 95%, 97%, 98% or 99% of the recited features or components that it consists of. In another embodiment, the term "consisting of" excludes from the scope of any succeeding recitation any other features or components, except those that are not essential to the technical effect to be achieved.

[0032] As used herein, the word "or" should be interpreted as an inclusive "or," meaning any one or any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition will occur only where combinations of elements, features, steps, or operations are inherently mutually exclusive in some way.

[0033] Any concentration range, percentage range, ratio range, or integer range herein should be understood to include any integer within the stated range, and fractions thereof (such as tenths and hundredths of an integer), where appropriate, unless otherwise specified. Also, any numerical range recited herein for any physical characteristic, such as polymer subunits, size, or thickness, should be understood to include any integer within the stated range, unless otherwise specified. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the stated range, value, or composition, unless otherwise specified.

[0034] An "alkyl" group is a saturated, partially saturated, or unsaturated, straight- or branched-chain acyclic hydrocarbon having from 1 to 10 carbon atoms (C1-C 10alkyl), 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 alkyls include -isopropyl, -sec-butyl, -isoisobutyl, tert-butyl, -isopentyl, -neopentyl, tertpentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also referred to as alkenyl or alkynyl. An "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group 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 can be substituted or unsubstituted.When alkyl groups described herein are referred to as "substituted," they include any of the optional substituents found in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, cycloalkyl and optionally substituted with arylalkylamino, aralkylamino, heterocyclylalkylamino, heteroaralkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea; nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2.In certain embodiments, when alkyl groups described herein are referred to as "substituted," they may be substituted with any of the substituents found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; 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 shown above, in which one or more hydrogen atoms are replaced with -OH. For example, "C1-C6 alkyl-OH" refers to a C1-C6 alkyl substituted with one or more -OH groups. The alkyl-OH may contain multiple hydroxy groups attached to the same carbon atom or to multiple carbon atoms.

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

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

[0038] A "cycloalkyl" group is a saturated or partially saturated cyclic alkyl group of 3 to 10 carbon atoms (C3-C6) having a single cyclic ring or multiple fused or bridged rings, which may be optionally substituted. 10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), while in other embodiments, the number of ring carbon atoms ranges from 3 to 5 (C3-C5 cycloalkyl), 3 to 6 (C3-C6 cycloalkyl), or 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl group is a saturated cycloalkyl group. Such saturated cycloalkyl groups include, by way of example only, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple 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 cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, and the like. The cycloalkyl groups can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example only, cyclohexanol, and the like.

[0039] An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms (C6-C8) having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). 14 In some embodiments, an aryl group has 6 to 14 carbons (C6-C7) in the ring portion of the group. 14 aryl), and others 6 to 12 (C6-C 12 aryl), or further 6 to 10 carbon atoms (C6-C 10Aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The term "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" means fluorine, chlorine, bromine or iodine.

[0041] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo groups, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms and is substituted with one or more halo groups (C-C haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted with one or more halo groups (C-C haloalkyl). The halo groups may all be the same, or the halo groups may be different. Unless otherwise specified, the haloalkyl group may be optionally substituted.

[0042] A "heteroaryl" group is an aromatic ring system having 1 to 4 heteroatoms as ring atoms, with the remaining atoms being carbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in other embodiments, 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 a monocyclic or bicyclic ring. Non-limiting examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl), Heteroaryl groups include, but are not limited to, groups such as benzo[d][1,2,3]triazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinaxalinyl and quinazolinyl groups. Heteroaryl groups can be substituted or unsubstituted.

[0043] A "heterocyclyl" is a non-aromatic cycloalkyl in which 1 to 4 ring carbon atoms are independently replaced with heteroatoms selected from O, S, and N. In some embodiments, heterocyclyl groups contain 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. A heterocyclyl can also be attached to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). Heterocycloalkyl groups can be substituted or unsubstituted. Heterocyclyl groups include saturated or partially saturated ring systems. Furthermore, the term "heterocyclyl" is intended to include any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of attachment to the rest of the molecule. The term also includes bridged polycyclic ring systems containing heteroatoms. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups may be mono- or more than twice substituted, such as pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted with various substituents, including, but not limited to, those set forth below.

[0044] When groups described herein, except for alkyl groups, are said to be "substituted," they may be substituted with any suitable substituent. Illustrative examples of substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH), O(alkyl)aminocarbonyl; cycloalkyl (monocyclic or fused rings). heterocyclyl (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., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, 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 disclosure are meant to encompass pharmaceutically acceptable salts, tautomers, isotopes, and stereoisomers of the compounds described herein, such as compounds of formula (I') or (I).

[0047] As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids and bases, and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of Formula (I') or (I) include, but are not limited to, metallic salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine), and procaine. Suitable non-toxic acids include, but are not limited to, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic 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, sulfanilic acid, sulfuric acid, tartaric acid, and butylenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Thus, examples of specific salts include hydrochloride, formate, and mesylate. Others are well known in the art, see, e.g., 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 herein, unless otherwise specified, the terms "stereoisomer" or "stereoisomerically pure" refer to one stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be 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. Typical stereoisomerically pure compounds contain 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 contain chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included within the scope of the embodiments disclosed herein.

[0049] The use of stereomerically pure forms of the compounds disclosed herein, as well as mixtures of these forms, are encompassed by the presently disclosed embodiments. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard methods, such as chiral columns or chiral resolving agents. See, for example, Jacques, J. et al., Enantiomers, Racemates and Resolutions (WileyInterscience, 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. p.268 (ed. EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation of 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 See 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, and cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are a mixture of E and Z isomers.

[0051] "Tautomer" refers to an isomer of a compound that is in equilibrium with one another. The concentration of isomers will depend on the environment in which the compound is found and may vary, for example, depending on whether the compound is a solid or an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomers, referred to as tautomers of one another: [ka]

[0052] As will be readily understood by one of ordinary skill in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of formula (I') or (I) are within the scope of the present disclosure.

[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 contain, for example, tritium ( 3 H), iodine-125( 125 I), sulfur 35( 35 S) or carbon-14 ( 14 It may be radiolabeled with a radioisotope such as deuterium ( 2 H), carbon-13( 13 C) or nitrogen-15( 15The compound may be enriched in an isotope, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 113, 120, 121, 130, 131, 142, 143, 144, 150, 151, 162, 170, 171, 182, 192, 193, 194, 195, 196, As used herein, "deuterated" means that at least one hydrogen (H) is replaced with a deuterium (D or 2 H), i.e., a compound enriched in deuterium at at least one position.

[0054] Regardless of stereoisomeric or isotopic composition, it is understood that each compound disclosed herein can be provided in the form of any of the pharmaceutically acceptable salts disclosed herein. Similarly, it is understood that the isotopic composition can vary independently of the stereoisomeric composition of each compound referred to herein. Furthermore, the isotopic composition is limited to those elements present in each compound disclosed herein or its salt, but may otherwise vary independently of the choice of pharmaceutically acceptable salt of each compound.

[0055] It should be noted that if there is a discrepancy between a displayed structure and the name of that structure, the displayed structure shall take precedence.

[0056] As used herein, "treating" means alleviating, in whole or in part, a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or slowing or halting further progression or worsening of those symptoms, or alleviating or eradicating the cause of the disorder, disease, or condition itself. In one embodiment, the disorder is a neurodegenerative disease or symptom thereof, as described herein.

[0057] As used herein, "preventing" refers to a method of, in whole or in part, slowing and / or preventing the onset, recurrence, or spread of a disorder, disease, or condition; inhibiting a subject from acquiring a disorder, disease, or condition; or reducing the risk of a subject acquiring a disorder, disease, or condition. In one embodiment, the disorder is a neurodegenerative disease or symptom thereof, as described herein.

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

[0059] The term "subject" or patient as used herein 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, in one embodiment mammals, and in another embodiment humans. In one embodiment, the subject is a human having or at risk for having an S1P5-mediated disorder or a symptom thereof.

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

[0061] compound In one aspect, provided herein is a compound of formula (I'): [ka] [In formula: 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 contain 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from 1 to 3 R 0 optionally substituted with groups; Each R 0 are independently selected from halo, -CN, -NH, -NH(C-C alkyl), C-C alkyl, C-C cycloalkyl, -(6- to 10-membered bridged heterocyclylene)- and C-C alkoxy, wherein the heterocyclylene contains 1 to 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 to 3 heteroatoms selected from N, O, and S; L 3 is -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 to 3 heteroatoms selected from N and O and 1 to 5 R 7 optionally substituted with a group; L 4 teeth [ka] 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 selected from the group consisting of 1 to 4 R 10 groups, wherein the heteroarylene and heterocyclylene contain 1 to 3 heteroatoms selected from N, S and O; R 1a and R 1b are each H or together form an oxo group; R 2 and R 3are independently H, C-C alkyl, or halo, or R 2 and R 3 together form an oxo group; Or R 3 and R 11 together 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 to 3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl, or heteroaryl is selected from 1 to 5 R 8 optionally substituted with a group; W, O, -NR 5 - or a conjugated hand; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halo, or -OH, or two R 6 the groups together form a bridging C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, or —OH, or two R 7 The groups together form an oxo group; Each R 8 are independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halo, -CN, or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R10 are independently C1-C6 alkoxy, C1-C6 alkyl, halo, or -OH, or two R 10 The groups together form an oxo group; R 11 and R 12 are each independently H, halo, C3-C6 cycloalkyl, —OH, —NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; Or R 11 and R 3 taken together 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 and; R 13 is H, halo, -OH, or C1-C6 alkyl; Z 1 is CH or N; Z 2 is CH or N: However, Z 1 and Z 2 are never both N] or a pharmaceutically acceptable salt thereof.

[0062] In a further aspect, provided herein is a compound of formula (I): [ka] [In formula: 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 contain 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from 1 to 3 R 0 optionally substituted with groups; Each R 0are independently selected from halo, -CN, -NH, -NH(C-C alkyl), C-C alkyl, C-C cycloalkyl, and C-C 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—, —SONH—, —NHSO—, or a 5-membered heteroarylene containing 1 to 3 heteroatoms selected from N, O, and S; L 3 is -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 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 optionally substituted with a group; L 4 teeth [ka] phenylene, 5- or 6-membered heteroarylene, or 5- or 6-membered heterocyclylene, wherein the phenylene, heteroarylene, or heterocyclylene is selected from the group consisting of 1 to 4 R 10 groups, wherein the heteroarylene and heterocyclylene contain 1 to 3 heteroatoms selected from N and O; R 1a and R 1b are each H or together form an oxo group; R 2 and R 3 are independently H, C-C alkyl, or halo, or R 2 and R 3 together form an oxo group; Or R 3 and R 11 together 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 to 3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl, or heteroaryl is selected from 1 to 5 R 8 optionally substituted with a group; W, O, -NR 5- or a conjugated hand; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halo, or -OH, or two R 6 the groups together form a bridging C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, or —OH, or two R 7 The groups together form an oxo group; Each R 8 are independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halo, -CN, or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halo, or -OH, or two R 10 The groups together form an oxo group; R 11 and R 12 are each independently H, halo, C3-C6 cycloalkyl, —OH, —NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; Or R 11 and R 3 taken together 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 and; R 13 is H, halo, or C1-C6 alkyl; Z 1 is CH or N; Z 2 is CH or N: However, Z 1 and Z 2 are never both N] or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, Z 1 is CH or N; Z 2 is CH or N; provided that Z 1 and Z 2 and Z cannot both be N. In some embodiments, Z 1 and Z 2 are each CH. In some embodiments, Z 1 is CH and Z 2 is N. In some embodiments, Z 1 is N and Z 2 is 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 contain 1-4 heteroatoms independently selected from N, O, and S, each of which is selected from 1-3 R 0 The group may be optionally substituted with a group.

[0065] In some embodiments, ring A is 1 to 3 R 0 In some embodiments, ring A is phenyl optionally substituted with 1 to 2 R 0 In some embodiments, ring A is phenyl optionally substituted with one R 0 In some embodiments, ring A is phenyl optionally substituted with two R 0 In some embodiments, ring A is phenyl optionally substituted with three R groups. 0In some embodiments, Ring A is an unsubstituted phenyl, optionally substituted with a group.

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

[0067] In some embodiments, ring A is 1 to 3 R 0 In some embodiments, ring A is a monocyclic 5-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains 1 to 4 heteroatoms independently selected from N, O, and S. ...3 R 0In some embodiments, ring A is a monocyclic 5-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains 1-2 heteroatoms independently selected from N and O. In some embodiments, ring A is a 5-membered monocyclic heteroaryl optionally substituted with a group, wherein the heteroaryl contains 1-3 R 0 In some embodiments, ring A is a monocyclic 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains 1 to 4 heteroatoms independently selected from N, O, and S. In some embodiments, ring A is a 6-membered monocyclic ...3 R 0 In some embodiments, ring A is a monocyclic 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains 1 to 3 heteroatoms independently selected from N and O. ... 0 In some embodiments, ring A is a monocyclic 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains 1-2 heteroatoms independently selected from N and O. In some embodiments, ring A is a 6-membered monocyclic heteroaryl optionally substituted with a group, wherein the heteroaryl contains 1-3 R 0 In some embodiments, ring A is a monocyclic 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains 1 to 3 nitrogen atoms. 0 In some embodiments, ring A is a monocyclic 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains 1 to 2 nitrogen atoms. 0 In some embodiments, ring A is a monocyclic 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains one nitrogen atom. In some embodiments, ring A is a 6-membered monocyclic ... 0 In some embodiments, ring A, one R 0 In some embodiments, ring A is a monocyclic 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains one nitrogen atom. In some embodiments, ring A is a ... two R 0In some embodiments, ring A is a monocyclic 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains 1 nitrogen atom. In some embodiments, ring A is a 6-membered monocyclic ... 0 In some embodiments, ring A is a monocyclic 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains 2 nitrogen atoms. In some embodiments, ring A is a 6-membered monocyclic heteroaryl optionally substituted with a group, wherein the heteroaryl contains 1 to 2 R 0 In some embodiments, ring A is a monocyclic 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains two nitrogen atoms. In some embodiments, ring A is a 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains one R 0 In some embodiments, ring A is a monocyclic 6-membered heteroaryl optionally substituted with a group, wherein the heteroaryl contains two nitrogen atoms. 0 In some embodiments, ring A is a pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl, each of which is selected from the group consisting of 1 to 3 R 0 In some embodiments, ring A is pyridinyl or pyrimidinyl, each of which may be optionally substituted with 1 to 3 R groups. 0 In some embodiments, ring A is optionally substituted with 1 to 3 R 0 In some embodiments, ring A is a pyridinyl optionally substituted with 1 to 3 R 0 and pyrimidinyl optionally substituted by a group.

[0068] In some embodiments, ring A is [ka] is.

[0069] In some embodiments, Ring A is a fused bicyclic 9-10 membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 1-4 heteroatoms independently selected from N, O, and S, each of which is selected from 1-3 R 0 In some embodiments, ring A is a fused bicyclic 9-10 membered heteroaryl or heterocyclyl, wherein the heteroaryl and heterocyclyl contain 2-4 heteroatoms independently selected from N, O, and S, each of which is selected from 1-3 R 0 In some embodiments, ring A contains 2-4 heteroatoms independently selected from N, O, and S, and 1-3 R 0 In some embodiments, ring A contains 2-4 heteroatoms independently selected from N, O, and S, and one R 0 In some embodiments, ring A contains 2-4 heteroatoms independently selected from N, O, and S, and two R 0 In some embodiments, ring A contains 2 to 4 heteroatoms independently selected from N, O, and S, and 3 R 0 In some embodiments, ring A contains 2 to 4 heteroatoms independently selected from N, O, and S, and 4 R 0In some embodiments, ring A is a fused bicyclic 9-membered heteroaryl or heterocyclyl optionally substituted with a group. 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. 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 1-3 R 0 In some embodiments, ring A contains 2-4 heteroatoms independently selected from N, O, and S, and 1-3 R 0 is a fused bicyclic 9-membered heterocyclyl optionally substituted by a group.

[0070] In some embodiments, ring A is: [ka] -(R 0 ) 0-3 When is shown across a fused bicyclic heteroaryl or heterocyclyl, then one or both of the fused rings may be R 0 It is understood that the ring may be substituted with an R group. In some embodiments, only one ring of the fused bicyclic ring may be substituted with an R group. 0 In some embodiments, both rings of a fused bicyclic ring are substituted with an R group that substitutes the bicyclic ring. 0 R so that the total number of groups is 0 to 3 0 The group is substituted.

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

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

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

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

[0075] In some embodiments, R 0 is —NH(C1-C6 alkyl). In some embodiments, R 0 is -NH(C1-C3 alkyl). In some embodiments, R 0 is -NH(CH), -NH(CHCH), -NH(CHCHCH), or -NH(CH(CH)). In some embodiments, R 0 is -NH(CH3).

[0076] In some embodiments, R 0 is C1-C6 alkyl. In some embodiments, R 0 is C1-C3 alkyl. In some embodiments, R0 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 0 is methyl. In some embodiments, R 0 is ethyl. In some embodiments, R 0 is n-propyl. In some embodiments, R 0 is isopropyl.

[0077] In some embodiments, R 0 is C-C cycloalkyl. In some embodiments, R 0 is C-C cycloalkyl. In some embodiments, R 0 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 0 is cyclopropyl.

[0078] In some embodiments, R 0 is C1-C6 alkoxy. In some embodiments, R 0 is C1-C3 alkoxy. In some embodiments, R 0 is —OCH3, —OCH2CH3, —OCH2CH2CH3, or —OCH(CH3)2. In some embodiments, R 0 is —OCH. In some embodiments, R 0 is -OCH2CH3.

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

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

[0081] In some embodiments, ring A is selected from 1 to 3 R 0 phenyl optionally substituted by a group; Each R 0 is independently selected from halo, —CN, —NH2, —NH(C1-C3 alkyl), C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C3 alkoxy.

[0082] In some embodiments, ring A is [ka] is.

[0083] In some embodiments, ring A contains 1-2 heteroatoms independently selected from N and O and 1-3 R 0 a monocyclic 6-membered heteroaryl optionally substituted by a group; 0is independently selected from halo, —CN, —NH, —NH(C-C alkyl), C-C alkyl, C-C cycloalkyl, and C-C alkoxy.

[0084] In some embodiments, ring A is: [ka] is.

[0085] In some embodiments, ring A contains 2-4 heteroatoms independently selected from N, O, and S, and 1-3 R 0 a fused bicyclic 9-membered heteroaryl or heterocyclyl optionally substituted by a group; each R 0 are independently selected from halo, -CN, -NH, -NH(C-C alkyl), C-C alkyl, C-C cycloalkyl, -(6- or 8-membered bridged heterocyclylene)-, and C-C alkoxy, wherein the heterocyclylene contains 1 to 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: [ka] is.

[0087] In some embodiments, L 1 is —NH— or a bond. In some embodiments, L 1 In some embodiments, L 1 is a bond.

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

[0089] In some embodiments, L 2 is -NHC(O)-. In some embodiments, L 2 is —C(O)NH—. In some embodiments, L 2 In some embodiments, L 2 is -NHSO2-.

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

[0091] In some embodiments, L2 Ha-(C1-C6 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, L 2 Ha-(C1-C3 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, L 2 Ha-(C1-C3 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1 to 3 heteroatoms selected from N and O. In some embodiments, the 5-membered heteroarylene contains 1 to 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 triazolylene, imidazolylene, pyrazolylene, oxazolylene, isoxazolylene, or pyrrolylene. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, -(C1-C6 alkylene) z - is -CH-. In some embodiments, -(C1-C6 alkylene) z - is -CH2CH2-. In some embodiments, -(C1-C6 alkylene) z - is -CH2CH2CH2-. In some embodiments, L 2 teeth [ka] is.

[0092] In some embodiments, L 2 teeth [ka] is.

[0093] In some embodiments, L 2 teeth [ka] is.

[0094] In some embodiments, L 3 is -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 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 The group may be optionally substituted with a group.

[0095] In some embodiments, L 3 is -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 to 3 heteroatoms selected from N and O, and 1 or 2 R 7 The group may be optionally substituted with a group.

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

[0097] In some embodiments, L 3 Ha-NR 9 C(O)(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 Ha-NR 9 C(O)(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 Ha-NR 9 C(O)(C1-C3 alkylene) z(4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 3 R 7 In some embodiments, L 3 Ha-NR 9 C(O)(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 3 R 7 In some embodiments, L 3 Ha-NR 9 C(O)(C1-C3 alkylene) z (5- to 6-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 3 R 7 In some embodiments, L 3 Ha-NR 9 C(O)(C1-C3 alkylene) z (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 3 R 7 In some embodiments, L 3 Ha-NR 9 C(O)(6-membered heterocyclylene)-, where the heterocyclylene contains 1-2 nitrogen atoms and 1-3 R 7 In some embodiments, L 3 Ha-NR 9 C(O)CH2(6-membered heterocyclylene)-, where the heterocyclylene contains 1-2 nitrogen atoms and 1-3 R 7 The group may be optionally substituted with a group.

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

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

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

[0101] In some embodiments, L 3 Ha-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 Ha-(NR 9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O and 1-5 R 7 In some embodiments, L 3 Ha-(NR9 ) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-(NR 9 ) z (5- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-(NR 9 ) z (6- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-(NR 9 ) z (6- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-(NR 9 ) z (6- or 7-membered heterocyclylene)(CH2) z -, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-(NR 9 ) z (6- to 7-membered heterocyclylene)(CH2)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-(NR9 ) z (6- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 is -(6- to 7-membered heterocyclylene)(CH2)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 is -(6- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 The group may be optionally substituted with a group.

[0102] In some embodiments, L 3 Ha-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 Ha-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O, and 1-5 R 7 In some embodiments, L 3 Ha-NR 9 (C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-NR 9 (C1-C6 alkylene) z (5- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R7 In some embodiments, L 3 Ha-NR 9 (C1-C6 alkylene) z (6- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-NR 9 (C1-C6 alkylene) z (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-NR 9 (C1-C3 alkylene) z (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-NR 9 (CH2) z (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-NR 9 (CH2)(6-membered heterocyclylene)-, where the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-NR 9 (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 The group may be optionally substituted with a group.

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

[0104] In some embodiments, L 3 Ha-(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 Ha-(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O, and 1-5 R 7 In some embodiments, L 3 Ha-(C1-C6 alkylene) z (5- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 Ha-(C1-C6 alkylene) z (5- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-(C1-C3 alkylene) z (5- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 Ha-(C1-C3 alkylene) z (6-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 is -(CH2)(6-membered heterocyclylene)-, where the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R7 In some embodiments, L 3 is -(CH2CH2)(6-membered heterocyclylene)-, where the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 is -(6-membered heterocyclylene)-, where the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 The group may be optionally substituted with a group.

[0105] In some embodiments, L 3 Ha-(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 Ha-(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)(C1-C6 alkylene) z wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O and 1-5 R 7 In some embodiments, L 3 Ha-(C1-C3 alkylene) z (5- to 7-membered heterocyclylene)(C1-C3 alkylene) z wherein the heterocyclylene contains 1-2 heteroatoms selected from N and O and 1-5 R 7 In some embodiments, L 3 Ha-(C1-C3 alkylene) z (5- to 7-membered heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7In some embodiments, L 3 Ha-(C1-C3 alkylene) z (6-membered heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 is —(CH)(6-membered heterocyclylene)CH—, where the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 is -(5- to 6-membered heterocyclylene)CH-, where the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 is -(7-membered heterocyclylene)CH-, where the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 The group may be optionally substituted with a group.

[0106] In some embodiments, L 3 -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 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 1-5 R 7 In some embodiments, L 3 -O(C1-C6 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7In some embodiments, L 3 -O(C1-C3 alkylene) z (4- to 7-membered heterocyclylene)-, wherein the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 is —O(C1-C3 alkylene)(4- to 7-membered heterocyclylene)-, where the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 is —O(CH)(4- to 7-membered heterocyclylene)-, where the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 is —O(4- to 7-membered heterocyclylene)-, where the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 In some embodiments, L 3 is —O(4- to 6-membered heterocyclylene)-, where the heterocyclylene contains 1 to 2 nitrogen atoms and 1 to 5 R 7 The group may be optionally substituted with a group.

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

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

[0109] In some embodiments, L 3 -(7- to 10-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 -(7- to 10-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 -(7-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 -(7-membered fused bicyclic heterocyclylene)(C1-C3 alkylene)z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 -(7-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z wherein the heterocyclylene contains 3 heteroatoms selected from N and O and 1 to 5 R 7 In some embodiments, L 3 is -(7-membered fused bicyclic heterocyclylene)(CH)-, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 is -(7-membered fused bicyclic heterocyclylene)-, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 -(8-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 -(8-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 -(8-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z wherein the heterocyclylene contains 3 heteroatoms selected from N and O and 1 to 5 R 7 In some embodiments, L3 is -(8-membered fused bicyclic heterocyclylene)(CH)-, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 is -(8-membered fused bicyclic heterocyclylene)-, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 -(9-membered fused bicyclic heterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 -(9-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 -(9-membered fused bicyclic heterocyclylene)(C1-C3 alkylene) z wherein the heterocyclylene contains 3 heteroatoms selected from N and O and 1 to 5 R 7 In some embodiments, L 3 is -(9-membered fused bicyclic heterocyclylene)(CH)-, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 is -(9-membered fused bicyclic heterocyclylene)-, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 The group may be optionally substituted with a group.

[0110] In some embodiments, L 3 Ha-(O) z (6- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 Ha-(O) z (7- to 10-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 Ha-(O) z (7- to 9-membered spiroheterocyclylene)(C1-C6 alkylene) z -, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 is -O(7- to 9-membered spiroheterocyclylene)(C1-C6 alkylene)-, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 is —O(7- to 9-membered spiroheterocyclylene)(CH)—, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 is —O(6- to 10-membered spiroheterocyclylene)-, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3is -(6- to 10-membered spiroheterocyclylene)(C-C alkylene)-, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 is -(6- to 10-membered spiroheterocyclylene)(CH)-, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 In some embodiments, L 3 is -(6- to 10-membered spiroheterocyclylene)-, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 The group may be optionally substituted with a group.

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

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

[0113] In some embodiments, R 9 is C1-C6 alkyl. In some embodiments, R 9 is C1-C3 alkyl. In some embodiments, R 9 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 9 is methyl. In some embodiments, R 9 is ethyl. In some embodiments, R 9 is n-propyl. In some embodiments, R 9 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, halo, C1-C6 haloalkyl, or —OH, or two R 7 The groups taken together form an oxo group. In some embodiments, each R 7 are independently C1-C3 alkyl, halo, C1-C3 haloalkyl, or -OH, or two R 7 The groups taken together form an oxo group. 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, R 7 is C1-C6 alkyl. In some embodiments, R 7 is C1-C3 alkyl. In some embodiments, R 7 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is ethyl. In some embodiments, R 7 is n-propyl. In some embodiments, R 7 is isopropyl.

[0117] In some embodiments, R 7 is halo. In some embodiments, R 7 is Cl, F, or Br. In some embodiments, R 7 is Cl. In some embodiments, R 7 is F. In some embodiments, R7 is Br.

[0118] In some embodiments, R 7 is C1-C6 haloalkyl. In some embodiments, R 7 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 7 is C1-C3 haloalkyl. In some embodiments, R 7 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 7 is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. In some embodiments, R 7 is —CF. In some embodiments, R 7 is -CHF2.

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

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

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

[0122] In some embodiments, R 11 is H. In some embodiments, R11 is halo. In some embodiments, R 11 is Cl, F, or Br. In some embodiments, R 11 is Cl. In some embodiments, R 11 is F. In some embodiments, R 11 is Br.

[0123] In some embodiments, R 11 is C-C cycloalkyl. In some embodiments, R 11 is C-C cycloalkyl. In some embodiments, R 11 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 11 is cyclopropyl. In some embodiments, R 11 is cyclobutyl.

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

[0125] In some embodiments, R 11 is —NH(C1-C6 alkyl). In some embodiments, R 11 is -NH(C1-C3 alkyl). In some embodiments, R 11 is -NH(CH), -NH(CHCH), -NH(CHCHCH), or -NH(CH(CH)). In some embodiments, R 11 is -NH(CH3).

[0126] In some embodiments, R 11 is C1-C6 haloalkyl. In some embodiments, R 11 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 11 is C1-C3 haloalkyl. In some embodiments, R 11is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 11 is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. In some embodiments, R 11 is —CF. In some embodiments, R 11 is -CHF2.

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

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

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

[0130] In some embodiments, R 12 is C-C cycloalkyl. In some embodiments, R 12 is C-C cycloalkyl. In some embodiments, R 12is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 12 is cyclopropyl. In some embodiments, R 12 is cyclobutyl.

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

[0132] In some embodiments, R 12 is —NH(C1-C6 alkyl). In some embodiments, R 12 is -NH(C1-C3 alkyl). In some embodiments, R 12 is -NH(CH), -NH(CHCH), -NH(CHCHCH), or -NH(CH(CH)). In some embodiments, R 12 is -NH(CH3).

[0133] In some embodiments, R 12 is C1-C6 haloalkyl. In some embodiments, R 12 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 12 is C1-C3 haloalkyl. In some embodiments, R 12 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 12 is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. In some embodiments, R 12 is —CF. In some embodiments, R 12 is -CHF2.

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

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

[0136] In some embodiments, R 11 and R 3 and together form a C-C cycloalkylene group. In some embodiments, R 11 and R 3 and together form a C-C cycloalkylene group. In some embodiments, R 11 and R 3 and together form a C4-C6 cycloalkylene group. In some embodiments, R 11 and R 3 and together form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene. In some embodiments, R 11 and R 3 together form cyclopropylene.

[0137] In some embodiments, L 3 teeth: [ka] is.

[0138] In some embodiments, L 4 teeth [ka] 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 selected from the group consisting of 1 to 4 R 10 groups, wherein the heteroarylene and heterocyclylene contain 1 to 3 heteroatoms selected from N, S and O.

[0139] In some embodiments, L 4 teeth [ka] In some embodiments, R 1a and R 1b are each H or together form an oxo group. In some embodiments, R 1a and R 1b are each H. In some embodiments, R 1a and R 1b and together form an oxo group. In some embodiments, L 4 teeth [ka] In some embodiments, L 4 teeth [ka] is.

[0140] In some embodiments, L 4is 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 selected from 1 to 4 R 10 groups, wherein the heteroarylene or heterocyclylene contains 1 to 3 heteroatoms selected from N, S and O.

[0141] In some embodiments, L 4 is 1 to 4 R 10 In some embodiments, L is phenylene optionally substituted with a group. 4 is 1 to 3 R 10 In some embodiments, L is phenylene optionally substituted with a group. 4 is 1 to 2 R 10 In some embodiments, L is phenylene optionally substituted with a group. 4 is one R 10 In some embodiments, L is phenylene optionally substituted with a group. 4 is unsubstituted phenylene.

[0142] In some embodiments, L 4 is 1 to 4 R 10 In some embodiments, L is an —N(H)phenylene optionally substituted with a group. 4 is 1 to 3 R 10 In some embodiments, L is an —N(H)phenylene optionally substituted with a group. 4 is 1 to 2 R 10 In some embodiments, L is an —N(H)phenylene optionally substituted with a group. 4 is one R 10 In some embodiments, L is an —N(H)phenylene optionally substituted with a group. 4 is unsubstituted -N(H)phenylene.

[0143] In some embodiments, L 4 is 1 to 4 R 10 and a 5- to 6-membered heteroarylene optionally substituted with a group, wherein the heteroarylene contains 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, L 4 is 1 to 4 R 10 and a 5- to 6-membered heteroarylene optionally substituted with a group, wherein the heteroarylene contains 1 to 3 nitrogen atoms. 4 is 1 to 4 R 10 and a 5-membered heteroarylene optionally substituted with a group, wherein the heteroarylene contains 1 to 3 nitrogen atoms. 4 is 1 to 4 R 10 and a 6-membered heteroarylene optionally substituted with a group, wherein the heteroarylene contains 1 to 3 nitrogen atoms. 4 is 1 to 4 R 10 and a 5- to 6-membered heteroarylene optionally substituted with a group, wherein the heteroarylene contains two heteroatoms selected from N and S. In some embodiments, L 4 is 1 to 4 R 10 In some embodiments, the 5- to 6-membered heteroarylene is pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, triazolylene, imidazolylene, thiazolylene, pyrazolylene, or pyrrolylene, each of which is selected from the group consisting of 1 to 4 R 10 The group may be optionally substituted with a group.

[0144] In some embodiments, L 4 is 1 to 4 R 10and an 8- to 10-membered fused bicyclic heteroarylene optionally substituted with a group, wherein the fused heteroarylene contains 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, L 4 is 1 to 4 R 10 In some embodiments, L is an 8- to 10-membered fused bicyclic heteroarylene optionally substituted with a group, wherein the fused heteroarylene contains 1 to 3 nitrogen atoms. 4 is 1 to 4 R 10 and an 8- to 10-membered fused bicyclic heteroarylene optionally substituted with a group, wherein the fused heteroarylene contains 1 to 3 nitrogen atoms. In some embodiments, L 4 is 1 to 4 R 10 and an 8-membered fused heteroarylene optionally substituted with a group, wherein the heteroarylene contains 1 to 3 nitrogen atoms. In some embodiments, L 4 is 1 to 4 R 10 and a 9-membered fused heteroarylene optionally substituted with a group, wherein the heteroarylene contains 1 to 3 nitrogen atoms. In some embodiments, L 4 is 1 to 4 R 10 and a 10-membered fused heteroarylene optionally substituted with a group, wherein the heteroarylene contains 1 to 3 nitrogen atoms.

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

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

[0147] In some embodiments, each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halo, or -OH, or two R 10 The groups taken together form an oxo group. In some embodiments, each R 10 are independently C1-C3 alkoxy, C1-C3 alkyl, halo, or -OH, or two R 10 The groups taken together form an oxo group. 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 is C1-C6 alkoxy. In some embodiments, R 10 is C1-C3 alkoxy. In some embodiments, R 10 is —OCH, —OCHCH, —OCHCHCH, or —OCH(CH). In some embodiments, R 10 is —OCH. In some embodiments, R 10 is -OCH2CH3.

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

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

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

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

[0153] In some embodiments, L 4 teeth: [ka] is.

[0154] In some embodiments, R 2 and R 3 are independently H, C-C alkyl, or halo, or R 2 and R 3 taken together form an oxo group. In some embodiments, R 2 and R 3 is independently H, C-C alkyl, or halo. In some embodiments, R 2 and R 3is independently H, —CH, or F. In some embodiments, R 2 and R 3 together form an oxo group.

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

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

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

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

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

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

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

[0162] In some embodiments, R 3 and R 11 taken together form a C-C cycloalkylene group. In some embodiments, R 3 and R 11 taken together form a C-C cycloalkylene group. In some embodiments, R 3 and R 11 taken together form a C-C cycloalkylene group. In some embodiments, R 3 and R 11 taken together form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene. In some embodiments, R 3 and R 11 together to 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 to 3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl, or heteroaryl is selected from 1 to 5 R 8 In some embodiments, 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 selected from 1 to 2 R 8 The group may be optionally substituted with a group.

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

[0167] In some embodiments, R 4 is C1-C6 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl is 1 to 5 R 8 In some embodiments, R 4 is C1-C3 alkylene-(C3-C6 cycloalkyl), wherein the cycloalkyl is one to five R 8 The group may be optionally substituted with a group.

[0168] In some embodiments, R 4 is a C1-C3 alkylene-(cyclopropyl), wherein the cyclopropyl is one to five R 8 In some embodiments, R 4is a C1-C3 alkylene-(cyclobutyl), wherein the cyclobutyl is one to five R 8 In some embodiments, R 4 is a C1-C3 alkylene-(cyclopentyl), wherein the cyclopentyl is one to five R 8 In some embodiments, R 4 is a C1-C3 alkylene-(cyclohexyl), wherein the cyclohexyl is one to five R 8 In some embodiments, R 4 is —CH—(C-C cycloalkyl), where the cycloalkyl is 1 to 5 R 8 In some embodiments, R 4 is —CH2CH2—(C3-C6 cycloalkyl), where the cycloalkyl is 1 to 5 R 8 The group may be optionally substituted with a group.

[0169] In some embodiments, R 4 is 1 to 5 R 8 A 4- to 6-membered heterocyclyl optionally substituted with a group, wherein the heterocyclyl contains 1 to 3 heteroatoms selected from N and O. In some embodiments, R 4 is 1 to 5 R 8 A 4- to 6-membered heterocyclyl optionally substituted with a group, wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O. In some embodiments, R 4 is 1 to 5 R 8 and a 4- to 6-membered heterocyclyl optionally substituted with a group, wherein the heterocyclyl contains 1 nitrogen atom. In some embodiments, R 4 is 1 to 5 R 8 In some variations, R is a 4- to 6-membered heterocyclyl optionally substituted with a group, wherein the heterocyclyl contains 1 oxygen atom.4 is 1 to 3 R 8 and optionally substituted 4- to 6-membered heterocyclyl groups, wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O. In some variations, R 4 is one R 8 A 4- to 6-membered heterocyclyl substituted with a group, 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, wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O. In some embodiments, the 4- to 6-membered heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, azetidinyl, or piperazinyl, each of which is selected from 1-5 R 8 The group may be optionally substituted with a group.

[0170] In some embodiments, R 4 is C1-C6 alkylene-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is selected from 1 to 5 R 8 group, wherein the heterocyclyl contains 1 to 3 heteroatoms selected from N and O. In some embodiments, R 4 is C1-C3 alkylene-(4- to 6-membered heterocyclyl), wherein the heterocyclyl is selected from 1 to 5 R 8 group, wherein the heterocyclyl contains 1 to 3 heteroatoms selected from N and O. In some embodiments, R 4 is —CH2(4- to 6-membered heterocyclyl), wherein the heterocyclyl is selected from 1 to 5 R 8 group, wherein the heterocyclyl contains 1 to 3 heteroatoms selected from N and O. In some embodiments, R 4 is —CH2CH2(4- to 6-membered heterocyclyl), wherein the heterocyclyl is selected from 1 to 5 R8 In some embodiments, the 4- to 6-membered heterocyclyl contains 1-3 heteroatoms selected from N and O. 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 1 nitrogen atom. In some embodiments, the 4- to 6-membered heterocyclyl contains 1 oxygen atom. In some variations, the 4- to 6-membered heterocyclyl contains 1-3 R 8 In some variations, the 4- to 6-membered heterocyclyl is substituted with 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 substituted with 1-5 R 8 The group may be optionally substituted with a group.

[0171] In some embodiments, R 4 is a 5- or 6-membered heteroaryl, wherein the heteroaryl is 1 to 5 R 8 In some embodiments, R 4 is a 5-membered heteroaryl, wherein the heteroaryl is a group consisting of 1 to 5 R 8 In some embodiments, R 4 is a 6-membered heteroaryl, wherein the heteroaryl is a group consisting of 1 to 5 R 8 In some embodiments, R 4 is a 5- or 6-membered heteroaryl, wherein the heteroaryl is 1 to 5 R 8In some embodiments, R 4 is a 5- or 6-membered heteroaryl, wherein the heteroaryl is 1 to 5 R 8 In some variations, the 5- or 6-membered heteroaryl is optionally substituted with 1-3 R groups, where the heteroaryl contains 1-2 nitrogen atoms. 8 In some variations, the 5- or 6-membered heteroaryl is substituted with 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 substituted with 1-5 R 8 The group may be optionally substituted with a group.

[0172] In some embodiments, R 4 is C1-C6 alkylene-(5- to 6-membered heteroaryl), wherein the heteroaryl is one to five R 8 In some embodiments, R 4 is C1-C6 alkylene-(5-membered heteroaryl), wherein the heteroaryl is selected from 1 to 5 R 8 In some embodiments, R 4 is C1-C6 alkylene-(6-membered heteroaryl), wherein the heteroaryl is selected from 1 to 5 R 8 In some embodiments, R 4 is C1-C3 alkylene-(5- or 6-membered heteroaryl), wherein the heteroaryl is selected from 1 to 5 R8 In some embodiments, R 4 is —CH—(5- or 6-membered heteroaryl), wherein the heteroaryl is selected from 1 to 5 R 8 In some embodiments, R 4 is —CH2CH2—(5- or 6-membered heteroaryl), wherein the heteroaryl is selected from 1 to 5 R 8 In some embodiments, R 4 is C1-C3 alkylene-(5- or 6-membered heteroaryl), wherein the heteroaryl is selected from 1 to 5 R 8 In some embodiments, R 4 is C1-C3 alkylene-(5- or 6-membered heteroaryl), wherein the heteroaryl is selected from 1 to 5 R 8 In some variations, the 5- or 6-membered heteroaryl is optionally substituted with 1-3 R groups, where the heteroaryl contains 1-2 nitrogen atoms. 8 In some variations, the 5- or 6-membered heteroaryl is substituted with 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 substituted with 1-5 R 8 The group may be optionally substituted with a group.

[0173] In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R4 is C1-C3 alkyl. In some embodiments, R 4 is C1-C4 alkyl. In some embodiments, R 4 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, or —CHCH(CH). In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is tert-butyl. In some embodiments, R 4 is -CH2CH(CH3)2.

[0174] In some embodiments, R 4 is C1-C6 haloalkyl. In some embodiments, R 4 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 4 is C1-C3 haloalkyl. In some embodiments, R 4 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 4 is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. In some embodiments, R 4 is —CF. In some embodiments, R 4 is -CHF2. In some embodiments, R 4 is a C2-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 4 is -CH2CF3, -CH2CH2F, -CH2CF2CH3, -CH(CH3)CF3, or -CH2CH2CF3.

[0175] In some embodiments, R 4 is C1-C6 alkyl-OH. In some embodiments, R 4 is C1-C3 alkyl-OH. In some embodiments, R 4 is -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(OH)CH, -CH(OH)CHOH, or -CHCH(OH)CH. In some embodiments, R 4 is —CHOH. In some embodiments, R 4 is —CHCHOH. In some embodiments, R 4 is C-C alkyl-OH. In some embodiments, R 4 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 is -CHCN, -CHCHCN, -CHCHCHCN, -CH(CH)CN, -C(CH)CN, or -CHCH(CN)CH. In some embodiments, R 4 is —CHCN. In some embodiments, R 4 is —CHCHCN. In some embodiments, R 4 is —CH(CH)CN. In some embodiments, R 4 is —C(CH)CN. In some embodiments, R 4 is -CH(CH2CH3)CN or -CH2CH(CH3)CN.

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

[0178] In some embodiments, R 8 is —SO2(C1-C6 alkyl). In some embodiments, R 8 is —SO2(C1-C3 alkyl). In some embodiments, R 8 is —SO2CH3. In some embodiments, R 8 is —SO2CH2CH3. In some embodiments, R 8 is -SO2CH2CH2CH3.

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

[0180] In some embodiments, R 8 is C1-C6 alkyl. In some embodiments, R 8 is C1-C3 alkyl. In some embodiments, R 8 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is n-propyl. In some embodiments, R 8 is isopropyl.

[0181] In some embodiments, R 8 is C1-C6 haloalkyl. In some embodiments, R 8 is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. 8 is C1-C3 haloalkyl. In some embodiments, R 8 is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 8 is —CF, —CHF, —CHF, CHCF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. In some embodiments, R 8 is —CF. In some embodiments, R 8 is -CH2CF3.

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

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

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

[0185] In some embodiments, R 4 are 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, [ka] is.

[0186] In some embodiments, W is O, —NR 5 In some embodiments, W is O, —N(H)—, —N(CH 3 )—, 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 -It is.

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

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

[0192] In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is C1-C3 alkyl. In some embodiments, R 5is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is n-propyl. In some embodiments, R 5 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, halo, or -OH, or two R 6 The groups together form a bridging C-C alkylene group. In some embodiments, each R 6 are independently C1-C3 alkyl, halo, or -OH, or two R 6 The groups, taken together, form a bridging C-C alkylene group. In some embodiments, each R 6 are independently -CH3, Cl, or -OH, or two R 6 The groups together form a bridging C1-C2 alkylene group.

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

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

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

[0198] In some embodiments, two R 6 The groups together form a bridging C-C alkylene group. In some embodiments, two R 6 The groups together form a bridging C-C alkylene group. In some embodiments, two R 6 The groups together form a bridging methylene group. In some embodiments, two R 6 The groups together form a bridging ethylene group. In some embodiments, two R 6 The groups together form a cross-linking 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, [ka] teeth: [ka] is.

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

[0202] In some embodiments, X is N.

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

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

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

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

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

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

[0209] In some embodiments, the compound of Formula (I') or (I) has Formula (IA), (IB), (IC), (ID), or (IE): [ka] [In the formula: 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 the same as described for formula (I') or (I). It is a compound represented by the formula:

[0210] In some embodiments, the compound of Formula (I') or (I) has Formula (IIa), (IIb), (IIIa), (IIIb), (IVa), or (IVb): [ka] [In the formula: 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 the same as described for formula (I') or (I). It is a compound represented by the formula:

[0211] In some embodiments, the compound of Formula (I') or (I) has the formula (Ia): [ka] [In the formula: Ring A, R 2 , R 3 , R 4 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , L 2 and y is as described for formula (I') or (I); Z 3 and Z 4 are independently N or CH; provided that Z 3 and Z 4 at least one of which is N] In some embodiments, ring A is a fused bicyclic 9- to 10-membered heteroaryl (containing 2-4 heteroatoms independently selected from N, O, and S, and 1-3 R 0 group), wherein R 0 has the same meaning as in formula (I') or (I).

[0212] In some embodiments, the compound of Formula (I') or (I) has Formula (Ib) or (Ic): [ka] [ka] [In the formula: Ring A, R 2 , R 3 , R 4 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13and y is as described for formula (I') or (I); Z 3 and Z 4 are independently N or CH; provided that Z 3 and Z 4 at least one of which is N] It is a compound represented by the formula:

[0213] In some embodiments, the compound of Formula (I') or (I) has Formula (Id) or (Ie): [ka] [ka] [In the formula: R 0 , R 2 , R 3 , R 4 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 and y is as described for formula (I') or (I); Z 3 and Z 4 are independently N or CH; provided that Z 3 and Z 4 at least one of which is N] It is a compound represented by the formula:

[0214] In some embodiments, the compound of Formula (I') or (I) has the formula (If) or (Ig): [ka] [ka] [In the formula: R 0 , R 4 , and R 7 is the same as described for formula (I') or (I); Z 3 and Z 4are independently N or CH; provided that Z 3 and Z 4 at least one of which is N] In some embodiments, each R 0 are independently -CN or -NH; R 4 is C1-C3 alkyl-CN, or C3-C6 cycloalkyl (optionally substituted with C1-C3 alkyl); R 7 is C1-C3 alkyl.

[0215] In some embodiments, the compound of Formula (I') or (I) has the formula (Ia'): [ka] [In the formula: Ring A, R 2 , R 3 , R 4 , R 6 , R 7 , R 10 , R 11 , R 12 , L 2 and y is as described for formula (I') or (I); Z 3 and Z 4 are independently N or CH; provided that Z 3 and Z 4 at least one of which is N] In some embodiments, ring A is a fused bicyclic 9- to 10-membered heteroaryl (containing 2-4 heteroatoms independently selected from N, O, and S, and 1-3 R 0 groups), where R 0 has the same meaning as in formula (I') or (I).

[0216] In some embodiments, the compound of Formula (I') or (I) has Formula (Ib') or (Ic'): [ka] [ka] [In the formula: Ring A, R 2 , R 3 , R 4 , R 6 , R 7 , R 10 , R 11 , R 12 and y is as described for formula (I') or (I); Z 3 and Z 4 are independently N or CH; provided that Z 3 and Z 4 at least one of which is N] It is a compound represented by the formula:

[0217] In some embodiments, the compound of Formula (I') or (I) has the formula (Id') or (Ie'): [ka] [ka] [In the formula: R 0 , R 2 , R 3 , R 4 , R 6 , R 7 , R 10 , R 11 , R 12 and y is as described for formula (I') or (I); Z 3 and Z 4 are independently N or CH; provided that Z 3 and Z 4 at least one of which is N] It is a compound represented by the formula:

[0218] In some embodiments, the compound of formula (I') or (I) has formula (If') or (Ig'): [ka] [ka] [In the formula: R 0 , R 4 , and R 7 is the same as described for formula (I') or (I); Z 3 and Z 4 are independently N or CH; provided that Z 3 and Z 4 at least one of which is N] In some embodiments, each R 0 are independently -CN or -NH; R 4 is C1-C3 alkyl-CN or C3-C6 cycloalkyl (optionally substituted with C1-C3 alkyl); R 7 is C1-C3 alkyl] It is a compound represented by the formula:

[0219] In some embodiments, the compound of Formula (I') or (I) has Formula (Va) or (Vb): [ka] [ka] [In the formula: R 0 , R 2 , R 3 , R 4 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , X, and y are the same as described for formula (I') or (I); ring C is phenylene or pyridylene; Z 3 and Z 4 are independently N or CH; provided that Z 3 and Z 4 at least one of which is N] It is a compound represented by the formula:

[0220] In the description herein, any description, variation, embodiment, or aspect of one part may be combined with any description, variation, embodiment, or aspect of another part, and it is understood that any and all combinations described are the same as if specifically and individually listed. For example, any description, variation, embodiment, or aspect provided herein with respect to ring A of formula (I') or (I) may be combined with L 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 2, x, and y may be combined with any description, variation, embodiment, or aspect of the formula (I') or (I), and any and all combinations are the same as if specifically and individually listed. It is also understood that any description, variation, embodiment, or aspect of formula (I') or (I), where applicable, applies equally to other formulas detailed herein, and that any and all descriptions, variations, embodiments, or aspects are equally described for all formulas as if listed separately and individually. For example, any description, variation, embodiment or aspect of formula (I') or (I), where applicable, applies equally to any formula detailed herein, such as 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), and it is also understood that each and every description, variation, embodiment or aspect is equally described for all formulas as if listed separately and individually.

[0221] In some embodiments, provided is a compound selected from the compounds set forth in Table 1 or a pharmaceutically acceptable salt thereof. Although certain compounds described in this disclosure, including those set forth in Table 1, are depicted as particular stereoisomers and / or in non-stereoisomeric forms, it is understood that any and all stereoisomeric forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms, of any compounds described in this disclosure, including those set forth in Table 1, are also described herein. Table 1

[0222] [Table 1] [Table 2] [Table 3]

Table 4

Table 5

[0223]

Table 6

Table 7

Table 8

Table 9

Table 10

[0224]

Table 11

Table 12

Table 13

Table 14

Table 15

[0225] Table 16 Table 17 Table 18 Table 19 Table 20

[0226] Table 21 Table 22 Table 23 Table 24 Table 25

[0227] Table 26 Table 27 Table 28 Table 29

Table 30

[0228] Table 31 Table 32 Table 33 Table 34 Table 35

[0229] Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42

[0230] Table 43 Table 44 Table 45 Table 46

[0231] Table 47 Table 48 Table 49

Table 50

[0232] Table 51 Table 52 Table 53 Table 54 Table 55

[0233] Table 56 Table 57 Table 58 Table 59 Table 60

[0234] Table 61 Table 62 Table 63 Table 64 Table 65

[0235] Table 66 Table 67 Table 68 Table 69 Table 70 Table 71

[0236] Table 72 Table 73 Table 74 Table 75

[0237] Table 76 Table 77 Table 78 Table 79 Table 80

[0238] [Table 81] [Table 82] [Table 83] [Table 84] "or1" and "or2" indicate that the absolute stereochemistry has not been determined; the stereochemistry may be as drawn or the stereochemistry may be reversed.

[0239] It is understood that, in this description, combinations of substituents and / or variables of the depicted formula are permissible only if such combinations result in stable compounds.

[0240] Furthermore, all compounds of formula (I') or (I) that exist in free base or acid form can be converted into their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid 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 acid by standard techniques.

[0241] Synthesis method The compounds described herein can be prepared using conventional organic synthesis methods and commercially available starting materials, or the methods provided herein. By way of example, and not limitation, compounds of formula (I') or (I) can be prepared as outlined in Scheme 1 and in the Examples described herein. It should be noted that one of ordinary skill in the art would know how to modify the procedures shown in the illustrated Schemes and Examples to obtain the desired products.

[0242] Compounds of formula (X-1) can be prepared as outlined in Scheme 1. Cereblon Binding Moiety (CBM) intermediate (CX) is coupled with intermediate a under basic conditions using HATU to form intermediate b, which is then deprotected under acidic conditions to form intermediate c. Intermediate c is then coupled with target binding moiety (TBM) intermediate (AX) to yield compounds of formula (X-1).

[0243] Scheme 1 [ka]

[0244] 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 give intermediate e, which is then deprotected under acidic conditions to form intermediate f. Intermediate f is then coupled with TBM intermediate (AX) to give compounds of formula (X-2).

[0245] Scheme 2 [ka]

[0246] Compounds of formula (X-3) can be prepared as outlined in Scheme 3. The alcohol of intermediate g is activated to form mesylated intermediate h, which is subsequently subjected to deoxyazidation using NaN to give intermediate i. Intermediate i is then coupled with TBM intermediate (AX) to form intermediate j, which is then subjected to deprotection to form intermediate k. Intermediate k is then coupled with CBM intermediate (CX) to give compounds of formula (X-3).

[0247] Scheme 3 [ka]

[0248] The synthetic route to compounds of formula (X-4) is outlined in the scheme below. Intermediate l can be coupled with intermediate m under basic conditions using HATU to form intermediate n, which can then be activated with mesyl chloride to form intermediate o. This is followed by deoxyazidation using NaN to give intermediate p. The ester of intermediate p is deprotected to give intermediate q, which is then coupled with CBM intermediate (CX) to form intermediate f. Intermediate f is then coupled with TBM intermediate (AX) via a copper-catalyzed azide-alkyne cycloaddition reaction to form compounds of formula (X-4).

[0249] Scheme 4 [ka]

[0250] Compounds of formula (X-7) can be prepared as outlined in Scheme 5. The intermediate alcohol is activated with mesyl chloride to form intermediate t, which undergoes a deoxyazidation reaction with NaN to give intermediate u. The intermediate ester is reduced to give intermediate v, which is subsequently activated with tosyl chloride to form intermediate w. Intermediate w is then coupled with CBM intermediate (CX) under basic conditions to give intermediate x, which is then coupled with TBM intermediate (AX) via a copper-catalyzed azide-alkyne cycloaddition reaction to form compounds of formula (X-7).

[0251] Scheme 5 [ka]

[0252] The synthetic route to compounds of formula (X-8) is outlined in Scheme 6. The carboxylic acid of intermediate y is reduced to form 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 a copper-catalyzed azide-alkyne cycloaddition reaction to give compounds of formula (X-8).

[0253] Scheme 6 [ka]

[0254] Compounds of formula (X-11) can be prepared as outlined in Scheme 7. The alcohol group of intermediate c' can be protected with TBDPS to form intermediate d', which can then be activated with mesyl chloride to form intermediate e'. The activated alcohol of intermediate e' can be displaced with cyano to form intermediate f', which can then be reduced to an aldehyde to form intermediate g'. Further reduction affords intermediate h'. The alcohol group of intermediate h' can be protected with THP to form intermediate i', which can then be deprotected under acidic conditions to form intermediate j'. Intermediate j' can then be oxidized to form intermediate k'. The aldehyde of intermediate k' can be converted to an alkyne via a Seyfarth-Gilbert polymerization reaction to form intermediate L-1, which can then be deprotected to form intermediate L-2. Intermediate L-2 is then coupled with TBM intermediate (AX) via a copper-catalyzed azide-alkyne cycloaddition reaction to form intermediate l', which is then coupled with CBM intermediate (CX) to form a compound of formula (X-11).

[0255] Scheme 7 [ka]

[0256] Compounds of formula (X-15) can be prepared as outlined in Scheme 8. The alcohol group of intermediate m' is oxidized to an aldehyde to give intermediate n', which is then coupled with intermediate o' via reductive amination to form compounds of formula (X-15).

[0257] Scheme 8 [ka]

[0258] How to use Embodiments of the present disclosure provide a method for modulating IRAK4 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I') or (I). Modulation (e.g., inhibition or activation) of IRAK4 can be assessed and demonstrated by a variety of methods known in the art. Kits and commercially available assays are available to determine whether and to what extent IRAK4 is modulated (e.g., inhibited or activated).

[0259] In one aspect, provided herein are methods for modulating 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, a compound of Formula (I') or (I) inhibits IRAK4. In other embodiments, a compound of Formula (I') or (I) activates IRAK4. In some embodiments, a compound of Formula (I') or (I) is an agonist of IRAK4. In some embodiments, a compound of Formula (I') or (I) is an antagonist of IRAK4.

[0260] In some embodiments, provided herein are methods 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.

[0261] In some embodiments, a 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, a compound of Formula (I') or (I) may increase 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%, 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%, 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%, 410-100%, 420-100%, 430-100%, 440-100%, 450-100%, 460-100%, 470-100%, 4 Adjust to: 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%.

[0262] Also provided in certain embodiments of the present disclosure is a method for degrading IRAK4 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I') or (I). Degradation of IRAK4 can be assessed and demonstrated by a variety of methods known in the art. Kits and commercially available assays (cell-based assays) are available to determine whether and to what extent IRAK4 has been degraded.

[0263] In one aspect, provided herein are methods 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.

[0264] In some embodiments, a 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, a compound of Formula (F) or (F) inhibits 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%, 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%, 410-100%, 420-100%, 430-100%, 440-100%, 450-100%, 460-100%, 470-100%, 480-1 Decompose by 0%, 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%.

[0265] In another aspect, provided herein is a method for treating an inflammatory 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, provided herein is 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, provided herein is 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, provided herein is a method for preventing an inflammatory 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, provided herein is a method for preventing an inflammatory 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, provided herein is 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 syndrome, hidradenitis pustularis, Beckett's syndrome, or familial cold autoinflammatory syndrome.

[0266] In some embodiments, administering a compound of Formula (I') or (I) to a subject predisposed to inflammation or an autoimmune disease prevents the subject from developing any symptoms of inflammation or an autoimmune disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject who does not yet exhibit symptoms of inflammation or an autoimmune disease prevents the subject from developing any symptoms of inflammation or an autoimmune disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof reduces the severity of inflammation or an autoimmune disease in the subject. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof stabilizes inflammation or an autoimmune disease (prevents or slows the worsening of inflammation or an autoimmune disease). In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof delays the onset or recurrence of inflammation or an autoimmune disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof slows the progression of inflammation or an autoimmune disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof provides partial remission of inflammation or an autoimmune disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof provides complete remission of inflammation or an autoimmune disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof reduces the dose of one or more other medications required to treat inflammation or an autoimmune disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof enhances the effect of another medication used to treat inflammation or an autoimmune disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof slows the progression of inflammation or an autoimmune disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof improves the quality of life of a subject with inflammation or an autoimmune disease.In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof prolongs survival of the subject with an inflammatory or autoimmune disease.

[0267] In one aspect, provided herein is a method of preventing a subject predisposed to inflammation or an autoimmune disease from developing any symptoms of inflammation or an autoimmune disease, the method comprising administering to the subject a compound of Formula (I') or (I). In some embodiments, provided herein is a method of preventing a subject who does not already exhibit symptoms of inflammation or an autoimmune disease from developing symptoms of inflammation or an autoimmune disease, the method comprising administering to the subject a compound of Formula (I') or (I).

[0268] In some aspects, provided herein are methods for reducing the level of inflammation or autoimmune disease in a subject, comprising administering a compound of Formula (I') or (I) to the subject. In some embodiments, provided herein are methods for stabilizing inflammation or autoimmune disease in a subject, comprising administering a compound of Formula (I') or (I) to the subject. In some embodiments, the method prevents the inflammation or autoimmune disease from worsening. In some embodiments, the method delays the worsening of the inflammation or autoimmune disease.

[0269] In another aspect, provided herein is a method for delaying the onset or recurrence of an inflammatory or autoimmune disease in a subject, comprising administering to the subject a compound of Formula (I') or (I).

[0270] In some embodiments, provided herein are methods for slowing the progression of an inflammatory or autoimmune disease in a subject, comprising administering to the subject a compound of Formula (I') or (I). In some embodiments, the method provides partial remission of the inflammatory or autoimmune disease. In some embodiments, the method provides complete remission of the inflammatory or autoimmune disease.

[0271] In a further aspect, provided herein are methods for reducing the dose of one or more medications required to treat inflammation or an autoimmune disease in a subject, comprising administering to the subject a compound of Formula (I') or (I). In some embodiments, provided herein are methods for improving the effectiveness of another medication used to treat inflammation or an autoimmune disease in a subject, comprising administering to the subject a compound of Formula (I') or (I).

[0272] Also provided herein are methods for slowing the progression of an inflammatory or autoimmune disease in a subject, comprising administering a compound of Formula (I') or (I) to the subject. In some embodiments, the methods improve the quality of life of a subject with an inflammatory or autoimmune disease. In some embodiments, the methods prolong the survival of a subject with an inflammatory or autoimmune disease.

[0273] In another aspect, provided herein are methods for treating symptoms of inflammation or autoimmune disease caused by a disease in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound of Formula (I') or (I). In some embodiments, provided herein are methods for preventing symptoms of inflammation or autoimmune disease caused by a disease in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound of Formula (I') or (I). In some embodiments, administering a compound of Formula (I') or (I) to a subject predisposed to a disease that causes symptoms of inflammation or autoimmune disease prevents the subject from developing any symptoms of inflammation or autoimmune disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject who does not yet show symptoms of inflammation or autoimmune disease caused by a disease that causes symptoms of inflammation or autoimmune disease prevents the subject from developing any symptoms of inflammation or autoimmune disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof reduces the level of inflammation or autoimmune disease 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 stabilizes inflammation or autoimmune disease symptoms of the disease (prevents or delays the worsening of inflammation or autoimmune disease symptoms). In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof delays the onset or recurrence of inflammation or autoimmune disease symptoms caused by the disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof slows the progression of inflammation or autoimmune disease symptoms caused by the disease. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof provides partial remission of the disease causing inflammation or autoimmune disease symptoms.In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof provides complete remission of a disease causing inflammation or autoimmune disease symptoms. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof reduces the dose of one or more other medications required to treat a disease causing inflammation or autoimmune disease symptoms. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof enhances the effectiveness of another medication used to treat inflammation or autoimmune disease symptoms. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof slows the progression of a disease causing inflammation or autoimmune disease symptoms. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof improves the quality of life of a subject with a disease causing inflammation or autoimmune disease symptoms. In some embodiments, administering a compound of Formula (I') or (I) to a subject in need thereof prolongs the survival of a subject with a disease causing inflammation or autoimmune disease symptoms. In some embodiments, the disease is atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoprin-associated periodic syndrome, hidradenitis pustularis, Beckett's syndrome, or familial cold autoinflammatory syndrome.

[0274] In some embodiments, the compounds of Formula (I') or (I) are useful for treating a disorder selected from atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoprin-associated periodic syndrome, hidradenitis pustularis, Beckett's syndrome, and familial cold autoinflammatory syndrome.

[0275] In some embodiments, compounds of Formula (I') or (I) are useful for treating cancer. In some embodiments, the cancer is a solid tumor, skin cancer, or lymphoma. In some embodiments, the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder, intestinal, breast, cervical, colon, esophageal, head, kidney, liver, lung, neck, ovarian, pancreatic, prostate, or stomach cancer, leukemia, benign and malignant lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, benign and malignant melanoma, myeloproliferative disorders, sarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, glioma, and glioma. Meningeal sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, posterior mediastinal ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, schwannoma, intestinal cancer, breast cancer, prostate cancer, cervical cancer, glomerular cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytic carcinoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colorectal cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, or teratocarcinoma. Additional cancers that may be treated using the compounds of Formula (I') or (I) include, for example, T-acute lymphoblastic leukemia (T-ALL), T-lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0276] 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, colon cancer, pancreatic cancer, mesothelioma, carcinoma (e.g., adenocarcinoma, including esophageal adenocarcinoma), sarcoma (e.g., spindle cell sarcoma, liposarcoma, leiomyosarcoma, abdominal leiomyosarcoma, sclerosarcoma), and melanoma (e.g., metastatic malignant melanoma).

[0277] In some embodiments, compounds of Formula (I') or (I) are useful for treating fibrosis, such as interstitial pulmonary fibrosis, cystic fibrosis, progressive pulmonary fibrosis, and idiopathic pulmonary fibrosis.

[0278] Pharmaceutical Compositions and Routes of Administration The compounds provided herein can be administered to a subject orally, topically, or parenterally in conventional formulations such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0279] The compounds disclosed herein can be administered to a subject orally, topically, or parenterally in conventional formulations such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations may contain 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 calcium citrate), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc, etc.), and / or soluble or soluble ... or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersants (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolactam, or polyethylene glycol). The effective amount of the compound of formula (I') or (I) in the pharmaceutical composition can be a level that will produce the desired effect; for example, for both oral and parenteral administration, the unit dose can be from about 0.005 mg per kg of subject's body weight to about 10 mg per kg of subject's body weight.

[0280] The dosage of a compound of Formula (I') or (I) administered to a subject is rather widely variable and subject to the judgment of a medical professional. Generally, the compounds disclosed herein can be administered at a dosage of about 0.001 mg / kg to about 10 mg / kg of subject body weight once to four times a day, although the dosage can be appropriately varied depending on the subject's age, body weight, and health condition, as well as the type of administration. In one embodiment, the dosage is about 0.001 mg / kg to about 5 mg / kg of subject body weight, about 0.01 mg / kg to about 5 mg / kg of subject body weight, about 0.05 mg / kg to about 1 mg / kg of subject body weight, about 0.1 mg / kg to about 0.75 mg / kg of subject body weight, or about 0.25 mg / kg to about 0.5 mg / kg of subject body weight. In one embodiment, it is administered in a single dose per day. In any given case, the amount of a 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.

[0281] 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.

[0282] In another embodiment, provided herein is a unit dosage form comprising between about 0.1 mg and 500 mg, between about 1 mg and 250 mg, between about 1 mg and about 100 mg, between about 1 mg and about 50 mg, between about 1 mg and about 25 mg, or between about 1 mg and about 10 mg of a compound of Formula (I') or (I).

[0283] In certain embodiments, provided herein are unit dosage forms comprising about 0.1 mg or 100 mg of a compound of Formula (I') or (I).

[0284] In another embodiment, provided herein is a unit dosage form 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 (F) or (F).

[0285] Compounds of Formula (I') or (I) may be administered once, twice, three times, four or more times daily, hi certain embodiments, doses of 100 mg or less are administered in a single dose daily, and doses of more than 100 mg are administered twice daily in an amount equal to one-half of the total daily dose.

[0286] The compound of formula (I') or (I) can be administered orally for convenience. In one embodiment, when administered orally, the compound of formula (I') or (I) is administered with food and water. In another embodiment, the compound of formula (I') or (I) is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0287] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, orally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is left to the discretion of the healthcare professional, and may depend in part on the site of the condition.

[0288] In one embodiment, provided herein is a capsule containing a compound of Formula (I') or (I) without additional carriers, excipients, or vehicles.

[0289] In another embodiment, provided herein is a composition comprising an effective amount of a compound of Formula (I') or (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may include an excipient, diluent, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0290] The compositions may be in the form of tablets, chewable tablets, capsules, liquids, parenteral solutions, troches, suppositories, suspensions, and the like. The compositions may be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule, or a convenient liquid volume. In one embodiment, the liquid is prepared from a water-soluble salt, such as the hydrochloride salt. Generally, all compositions are prepared according to known methods in pharmaceutical chemistry. Capsules may be prepared by mixing a compound of Formula (I') or (I) with a suitable carrier or diluent and filling the appropriate amount of the mixture into capsules. Useful 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, grain flours, and similar edible powders.

[0291] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These preparations usually contain diluents, binders, lubricants, disintegrants, and the compound of the present invention. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sucrose. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin, and sucrose such as lactose, fructose, glucose, etc. Natural and synthetic gums, including acacia, alginates, methylcellulose, polyvinylpyrrolidine, etc., are also useful. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0292] Lubricants may be necessary in tablet formulations to prevent tablets and punches from sticking in 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 expand when wet, breaking up the tablet and releasing the compound. Such substances include starch, clay, cellulose, algin, and gum. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose, as well as sodium lauryl sulfate, can be used. Tablets can be coated with sucrose as a flavoring and sealant, or with a film-forming protective agent to modify the dissolution properties of the tablet. The composition can also be formulated as a chewable tablet, for example, by using substances such as mannitol in the formulation.

[0293] When it is desired to administer the compound of formula (I') or (I) as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base, and can be modified by adding waxes to slightly raise its melting point. In particular, water-miscible suppository bases, including polyethylene glycols of various molecular weights, are widely used.

[0294] The effect of the compound of formula (I') or (I) can be delayed or prolonged by appropriate formulation.For example, slowly dissolving pellets of the compound of formula (I') or (I) can be prepared and incorporated into tablets or capsules, or prepared and incorporated into sustained-release implantable devices.This technique also includes preparing pellets with different dissolution rates and filling capsules with a mixture of the pellets.Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time.Even in parenteral preparations, the compound of formula (I') or (I) can be made long-acting by dissolving or suspending it in an oily or emulsified vehicle that slowly disperses in serum.

[0295] Illustrative Embodiments The present disclosure is further illustrated by the following embodiments, the features of each embodiment may be combined with any features of the other embodiments where appropriate and practical.

[0296] Embodiment 1. Formula (I'): [ka] [In formula: 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 contain 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from 1 to 3 R 0 optionally substituted with groups; Each R 0 are independently selected from halo, -CN, -NH, -NH(C-C alkyl), C-C alkyl, C-C cycloalkyl, -(6- to 10-membered bridged heterocyclylene)-, and C-C alkoxy, wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, or two R 0 The groups together form an oxo group; L 1is -NH- or a bond; L 2 is -NHC(O)-, -C(O)NH-, -SO2NH-, -NHSO2-, or -(C1-C6 alkylene) z (5-membered heteroarylene)-, wherein said heteroarylene contains 1 to 3 heteroatoms selected from N, O, and S; L 3 is -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 to 3 heteroatoms selected from N and O, and 1 to 5 R 7optionally substituted with a group; L 4 teeth [ka] 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 selected from the group consisting of 1 to 4 R 10 groups, wherein the heteroarylene and heterocyclylene contain 1 to 3 heteroatoms selected from N, S and O; R 1a and R 1b are each H or together form an oxo group; R 2 and R 3 are independently H, C-C alkyl, or halo, or R 2 and R 3 together form an oxo group; Or R 3 and R 11 together 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 to 3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl, or heteroaryl is selected from 1 to 5 R 8 optionally substituted with a group; W, O, -NR 5- or a conjugated hand; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halo, or -OH, or two R 6 the groups together form a bridging C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, or —OH, or two R 7 The groups together form an oxo group; Each R 8 are independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halo, -CN, or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halo, or -OH, or two R 10 The groups together form an oxo group; R 11 and R 12 are each independently H, halo, C3-C6 cycloalkyl, —OH, —NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; Or R 11 and R 3 taken together 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 and; R 13 is H, halo, -OH, or C1-C6 alkyl; Z 1 is CH or N; Z 2 is CH or N: However, Z 1 and Z 2 are never both N] or a pharmaceutically acceptable salt thereof.

[0297] Embodiment 2. Formula (I): [ka] [In formula: 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 contain 1 to 4 heteroatoms independently selected from N, O, and S, each of which is selected from 1 to 3 R 0 optionally substituted with groups; Each R 0 are independently selected from halo, -CN, -NH, -NH(C-C alkyl), C-C alkyl, C-C cycloalkyl, and C-C 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—, —SONH—, —NHSO—, or a 5-membered heteroarylene containing 1 to 3 heteroatoms selected from N, O, and S; L 3 is -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 to 3 heteroatoms selected from N and O, and 1 to 5 R 7 optionally substituted with a group; L 4 teeth [ka] phenylene, 5- to 6-membered heteroarylene, or 5- to 6-membered heterocyclylene, wherein the phenylene, heteroarylene, or heterocyclylene is selected from the group consisting of 1 to 4 R 10 groups, wherein the heteroarylene and heterocyclylene contain 1 to 3 heteroatoms selected from N and O; R 1a and R 1b are each H or together form an oxo group; R 2 and R 3 are independently H, C-C alkyl, or halo, or R 2 and R 3 together form an oxo group; Or R 3 and R 11together 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 to 3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl, or heteroaryl is selected from 1 to 5 R 8 optionally substituted with a group; W, O, -NR 5 - or a conjugated hand; R 5 is H or C1-C6 alkyl; Each R 6 are independently C1-C6 alkyl, halo, or -OH, or two R 6 the groups together form a bridging C1-C3 alkylene group; Each R 7 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, or —OH, or two R 7 The groups together form an oxo group; Each R 8 are independently -SO2(C1-C6 alkyl), -C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halo, -CN, or -OH; Each R 9 are independently H or C1-C6 alkyl; Each R 10 are independently C1-C6 alkoxy, C1-C6 alkyl, halo, or -OH, or two R 10 The groups together form an oxo group; R 11 and R 12are each independently H, halo, C3-C6 cycloalkyl, —OH, —NH(C1-C6 alkyl), C1-C6 haloalkyl, or C1-C6 alkyl; Or R 11 and R 3 taken together 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 and; R 13 is H, halo, or C1-C6 alkyl; Z 1 is CH or N; Z 2 is CH or N: However, Z 1 and Z 2 are never both N] or a pharmaceutically acceptable salt thereof.

[0298] Embodiment 3. Z 1 and Z 2 are CH, respectively. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof.

[0299] Embodiment 4. Z 1 is CH; Z 2 is N, The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof.

[0300] Embodiment 5. Z 1 is N; Z 2 is CH, The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof.

[0301] Embodiment 6. Ring A is 1 to 3 R 0phenyl optionally substituted by a group; Each R 0 is independently selected from halo, —CN, —NH, —NH(C-C alkyl), C-C alkyl, C-C cycloalkyl, and C-C alkoxy; A compound according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof.

[0302] Embodiment 7. Ring A is [ka] That is, The compound of embodiment 6, or a pharmaceutically acceptable salt thereof.

[0303] Embodiment 8. Ring A contains 1-2 heteroatoms independently selected from N and O, and 1-3 R 0 a monocyclic 6-membered heteroaryl optionally substituted by a group; Each R 0 is independently selected from halo, —CN, —NH, —NH(C-C alkyl), C-C alkyl, C-C cycloalkyl, and C-C alkoxy; A compound according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof.

[0304] Embodiment 9. Ring A is [ka] is The compound of embodiment 8 or a pharmaceutically acceptable salt thereof.

[0305] Embodiment 10. Ring A contains 2-4 heteroatoms independently selected from N, O, and S, and 1-3 R 0 a fused bicyclic 9- to 10-membered heteroaryl or heterocyclyl optionally substituted by a group; Each R 0are independently prepared from halo, -CN, -NH, -NH(C-C alkyl), C-C alkyl, C-C cycloalkyl, -(6- to 8-membered bridged heterocyclylene)-, and C-C alkoxy, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, or two R 0 The groups together form an oxo group A compound according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof.

[0306] Embodiment 11. Ring A is [ka] is The compound of embodiment 10, or a pharmaceutically acceptable salt thereof.

[0307] Embodiment 12. L 1 is -NH- 12. A compound according to any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof.

[0308] Embodiment 13. L 1 is a bond 12. A compound according to any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof.

[0309] Embodiment 14. L 2 -(C1-C3 alkylene) z (5-membered heteroarylene)-, wherein the heteroarylene contains 1 to 3 heteroatoms selected from N and O. A compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof.

[0310] Embodiment 15. L 2 but [ka] is 15. The compound of embodiment 14, or a pharmaceutically acceptable salt thereof.

[0311] Embodiment 16. L 2 is -NHC(O)- or triazolylene A compound according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt thereof.

[0312] Embodiment 17. L 2 is -NHC(O)- 17. The compound of embodiment 16, or a pharmaceutically acceptable salt thereof.

[0313] Embodiment 18. L 2 but [ka] is 17. The compound of embodiment 16, or a pharmaceutically acceptable salt thereof.

[0314] Embodiment 19. L 4 but [ka] and; R 1a and R 1b are each H or together form an oxo group 19. A compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof.

[0315] Embodiment 20. L 4 but [ka] is 20. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof.

[0316] Embodiment 21. L 4 but [ka] is 20. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof.

[0317] Embodiment 22. 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 selected from 1 to 4 R 10 and optionally substituted with a group, wherein the heteroarylene or heterocyclylene contains 1 to 3 heteroatoms selected from N, S, and O. 19. A compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof.

[0318] Embodiment 23. Each R 10 are independently C1-C3 alkoxy, C1-C3 alkyl, halo, or -OH, or two R 10 The groups together form an oxo group 23. The compound of embodiment 22, or a pharmaceutically acceptable salt thereof.

[0319] Embodiment 24. Each R 10 are independently -OCH3, -CH3, Cl, F, or -OH, or two R 10 The groups together form an oxo group 24. The compound of embodiment 23, or a pharmaceutically acceptable salt thereof.

[0320] Embodiment 25. L 4 but [ka] is A compound according to any one of embodiments 22 to 24, or a pharmaceutically acceptable salt thereof.

[0321] Embodiment 26. x is 0 26. A compound according to any one of embodiments 1 to 25, or a pharmaceutically acceptable salt thereof.

[0322] Embodiment 27. x is 1 26. A compound according to any one of embodiments 1 to 25, or a pharmaceutically acceptable salt thereof.

[0323] Embodiment 28. R 2 and R 3 are independently H, C1-C3 alkyl, or halo A compound according to any one of embodiments 1 to 25 and 27, or a pharmaceutically acceptable salt thereof.

[0324] Embodiment 29. R 2 and R 3 are independently H, -CH3, or F 29. The compound of embodiment 28, or a pharmaceutically acceptable salt thereof.

[0325] Embodiment 30. R 2 and R 3 together form an oxo group A compound according to any one of embodiments 1 to 25 and 27, or a pharmaceutically acceptable salt thereof.

[0326] Embodiment 31. R 3 and R 11 together form a C3-C5 cycloalkylene group A compound according to any one of embodiments 1 to 25 and 27, or a pharmaceutically acceptable salt thereof.

[0327] Embodiment 32. R 3 and R 11 together form a cyclopropylene group The compound of embodiment 31, or a pharmaceutically acceptable salt thereof.

[0328] Embodiment 33. y is 0 or 1 A compound according to any one of embodiments 1 to 32, or a pharmaceutically acceptable salt thereof.

[0329] Embodiment 34. Each R6 are independently C1-C3 alkyl, halo, or -OH, or two R 6 The groups together form a C1-C2 alkylene group that is attached to the bridge. A compound according to any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof.

[0330] Embodiment 35. Each R 6 are independently -CH3, Cl, or -OH, or two R 6 The groups together form a C1-C2 alkylene group that is attached to the bridge. The compound of embodiment 34, or a pharmaceutically acceptable salt thereof.

[0331] Embodiment 36. [ka] but [ka] is A compound according to any one of embodiments 1 to 35, or a pharmaceutically acceptable salt thereof.

[0332] Embodiment 37. W is O, -NR 5 - or a bond; R 5 is H or C1-C3 alkyl A compound according to any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof.

[0333] Embodiment 38. W is O, —N(H)—, —N(CH3)—, or a bond. The compound of embodiment 37, or a pharmaceutically acceptable salt thereof.

[0334] Embodiment 39. X is N A compound according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof.

[0335] Embodiment 40. X is CR 13 and; R 13 is H, halo, -OH, or C1-C3 alkyl A compound according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof.

[0336] Embodiment 41. R 13 is H, CH3, -OH, or F 41. The compound of embodiment 40, or a pharmaceutically acceptable salt thereof.

[0337] Embodiment 42. Y is NH 42. A compound according to any one of embodiments 1 to 41, or a pharmaceutically acceptable salt thereof.

[0338] Embodiment 43. Y is O or a bond. 42. A compound according to any one of embodiments 1 to 41, or a pharmaceutically acceptable salt thereof.

[0339] Embodiment 44. 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 selected from 1 to 2 R 8 optionally substituted with a group 44. A compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof.

[0340] Embodiment 45 The compound of embodiment 44, wherein: Each R 8are independently -SO2(C1-C3 alkyl), -C(O)(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, halo, -CN, or -OH 45. The compound of embodiment 44, or a pharmaceutically acceptable salt thereof.

[0341] Embodiment 46. Each R 8 are independently -SO2CH3, -C(O)CH3, methyl, ethyl, -CH2CF3, F, -CN, or -OH 46. The compound of embodiment 45, or a pharmaceutically acceptable salt thereof.

[0342] Embodiment 47. R 4 are 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, [ka] is 47. A compound according to any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof.

[0343] Embodiment 48. L 3 But, -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 to 3 heteroatoms selected from N and O, and 1 or 2 R 7 optionally substituted with groups; each z is independently 0 or 1 48. A compound according to any one of embodiments 1 to 47, or a pharmaceutically acceptable salt thereof.

[0344] Embodiment 49. Each R 9 are independently H or C1-C3 alkyl A compound according to any one of embodiments 1 to 48, or a pharmaceutically acceptable salt thereof.

[0345] Embodiment 50. Each R 9 are independently H or -CH3 50. The compound of embodiment 49, or a pharmaceutically acceptable salt thereof.

[0346] Embodiment 51. Each R 7 are independently C1-C3 alkyl, halo, C1-C3 haloalkyl, or —OH, or two R7 The groups together form an oxo group 51. A compound according to any one of embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0347] Embodiment 52. Each R 7 are independently -CH3, -CF3, F, or -OH, or two R 7 The groups together form an oxo group 52. The compound of embodiment 51, or a pharmaceutically acceptable salt thereof.

[0348] Embodiment 53. R 11 and R 12 are each independently H or C1-C3 alkyl A compound according to any one of embodiments 1 to 52, or a pharmaceutically acceptable salt thereof.

[0349] Embodiment 54. R 11 and R 12 are each independently H or -CH3 54. The compound of embodiment 53, or a pharmaceutically acceptable salt thereof.

[0350] Embodiment 55. L 3 but [ka] [ka] is A compound according to any one of embodiments 1 to 48, or a pharmaceutically acceptable salt thereof.

[0351] Embodiment 56. The compound has the formula (Ia): [ka] [In formula: Ring A is a fused bicyclic 9- to 10-membered heteroaryl (containing 2-4 heteroatoms independently selected from N, O, and S, and 1-3 R0 (optionally substituted with a group); Z 3 and Z 4 are independently N or CH; provided that Z 3 and Z 4 at least one of which is N] is shown by The compound of any one of embodiments 1-3, 10, 11, 13-18, 22-25, 27-38, 40-42, 44-48, and 51-55, or a pharmaceutically acceptable salt thereof.

[0352] Embodiment 57. The compound has formula (Ib) or (Ic): [ka] [ka] is shown by 57. The compound of embodiment 56, or a pharmaceutically acceptable salt thereof.

[0353] Embodiment 58. The compound has the formula (Id) or (Ie): [ka] [ka] is shown by 58. The compound of embodiment 56 or 57, or a pharmaceutically acceptable salt thereof.

[0354] Embodiment 59. The compound has the formula (If) or (Ig): [ka] [ka] is shown by 59. A compound according to any one of embodiments 56 to 58, or a pharmaceutically acceptable salt thereof.

[0355] Embodiment 60. Each R 0 is independently -CN or -NH; R 4 is C1-C3 alkyl-CN, or C3-C6 cycloalkyl (optionally substituted with C1-C3 alkyl); R 7 is C1-C3 alkyl 60. The compound of embodiment 59, or a pharmaceutically acceptable salt thereof.

[0356] Embodiment 61. The compound has the formula (Ia'): [ka] [In formula: Ring A is a fused bicyclic 9- to 10-membered heteroaryl (containing 2-4 heteroatoms independently selected from N, O, and S, and 1-3 R 0 (optionally substituted with a group); Z 3 and Z 4 are independently N or CH; provided that Z 3 and Z 4 at least one of which is N] is shown by 54. A compound according to any one of embodiments 1, 2, 10, 11, 13-18, 22-25, 27-38, 39, 42, 44-48, and 51-54, or a pharmaceutically acceptable salt thereof.

[0357] Embodiment 62. The compound has formula (Ib') or (Ic'): [ka] [ka] is shown by 62. The compound of embodiment 61, or a pharmaceutically acceptable salt thereof.

[0358] Embodiment 63. The compound has the formula (Id') or (Ie'): [ka] [ka] is shown by 63. The compound of embodiment 61 or 62, or a pharmaceutically acceptable salt thereof.

[0359] Embodiment 64. The compound has the formula (If') or (Ig'): [ka] [ka] is shown by A compound according to any one of embodiments 61 to 63, or a pharmaceutically acceptable salt thereof.

[0360] Embodiment 65. Each R 0 is independently -CN or -NH; R 4 is C1-C3 alkyl-CN, or C3-C6 cycloalkyl (optionally substituted with C1-C3 alkyl); R 7 is C1-C3 alkyl 65. The compound of embodiment 64, or a pharmaceutically acceptable salt thereof.

[0361] Embodiment 66. A compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0362] 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.

[0363] Embodiment 68. A method for 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 1 to 66, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 67.

[0364] Embodiment 69. A method of treating a subject in need of treatment for an inflammatory or autoimmune disease, comprising administering to the subject an effective amount of a compound of any one of embodiments 1-66, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 67.

[0365] Embodiment 70. The method of embodiment 69, wherein the inflammatory or autoimmune disease is atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryopreserved periodic syndrome, hidradenitis pustularis, Beckett's syndrome, or familial cold autoinflammatory syndrome.

[0366] Example The following examples are offered for illustrative purposes, not for limiting purposes. Compounds are named using an automatic name generator provided by ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures while adhering to the Cahn-Ingold-Prelog rules of stereochemistry. Those skilled in the art can modify the procedures shown in the illustrative examples to arrive at the desired products.

[0367] 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 by stirring the product with a solution of an acid (e.g., aqueous HCl) after chromatographic purification.

[0368] As used in the particular structures of the chemical structures provided in the Examples below, the designation of a particular atom with "*," "or1," or "or2" indicates that the absolute stereochemistry of the indicated atom has not been determined.

[0369] The following abbreviations may be relevant to this application: Abbreviation [Table 85] [Table 86]

[0370] Synthesis Example Synthesis of CBM molecules The numbering of intermediate compounds referred to in this section, as well as other sections, is specific to each section. For example, Intermediate 3 of General Procedure CMB-1 and Intermediate 3 of General Procedure CMB-2 are listed in different sections and, as such, refer to different compounds.

[0371] General Operation CBM-1 [ka] where Z 3 is N or CH.

[0372] Step 1a: A sealed tube was charged with 1a, tert-butyl piperazine-1-carboxylate 2a (1.1 equivalents), DIPEA (3.0 equivalents), and DMSO (15 mL). The tube was sealed and heated at 90° C. for 72 hours. The progress of the reaction was monitored by HPLC. Upon completion, the reaction mixture was directly purified by reverse-phase chromatography. Pure fractions were combined and concentrated under reduced pressure to give the product.

[0373] Step 1b: To an oven-dried 40 mL vial equipped with a magnetic stir bar under ambient atmosphere 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)(dtbbpy)PF (1 mol %), followed by DMA (10 mL). Dibromonickel; 1,2-dimethoxyethane (5 mol %) was then added as a solution in DMA (0.5 mL) under a N atmosphere. The reaction was placed in front of one 30 W blue LED at 25 °C for 96 h. The material was added dropwise to water, and the solid that formed was filtered and concentrated. The residue was purified by preparative HPLC to give the product.

[0374] Step 1c: A solution of 3-(6-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (1b), potassium; (1-tert-butoxycarbonyl-4-piperidyl)-trifluoroboranide (2b) (3.0 equivalents), and 2,4,6-trimethylpyridine (1.8 equivalents) in 1,4-dioxane (0.15 M) was placed in a Schlenk flask, to which was added a solution of (Ir[dF(CF3)ppy]2(dtbpy))PF6 (2 mol%) in 1,4-dioxane (1 mL). Next, a solution of Ni-dtbbpy-Br2 (10 mol%) in 1,4-dioxane (1 mL) that had been sonicated for 1 minute was added. The reaction mixture was degassed three times using the 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 irradiation for 4 days. The solution was evaporated before being dissolved in DMSO for purification by reverse phase chromatography. Pure fractions were combined to give the product.

[0375] Step 2: TFA (20 equiv.) was added to a solution of (3) in CHCl (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 (3x) and MTBE (2x). The residue was purified by reverse-phase chromatography. Pure fractions were concentrated under reduced pressure to give the product CBM-1 as the TFA salt.

[0376] Example S1. 2-(2,6-Dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione trifluoroacetate (C-2) [ka]

[0377] Step 1'. Preparation of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate (2'): A sealed tube was charged with 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-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 hours. The reaction progress was monitored by HPLC. After completion, the reaction mixture was directly purified by reverse-phase chromatography (C18 RediSep Rf Gold, using 5-95% MeOH / 0.1% formic acid in HO as eluent). Pure fractions were combined and concentrated under reduced pressure to give 2' (2.86 g, 89% yield) as a yellow solid.

[0378] LCMS method 1: 99.9% purity at 215 nm, [M-tBu+H] + =387.2 m / z, [M+Na] + =466.2m / z

[0379] 1H NMR (400MHz, DMSO-d6) δ ppm 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)

[0380] Step 2'. Preparation of 2-(2,6-dioxo-3-piperidyl)-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-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate (2') (2.87 g, 6.48 mmol) in CHCl (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 (3x) and MTBE (2x). The residue was purified by C18 RediSep Rf Gold reverse-phase chromatography using 5-20% MeCN / 0.05% TFA in H2O as the eluent. Pure fractions were concentrated under reduced pressure to give (C-2) (2.52 g, 85% yield) as a yellow solid as the TFA salt.

[0381] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =343.2m / z

[0382] 1 H NMR (400MHz, DMSO-d6) δ ppm 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)

[0383] Example S2. 3-(1-oxo-6-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (C-7) [ka]

[0384] Step 1″. Preparation of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazine-1-carboxylate (3″): In an oven-dried 40 mL vial equipped with a magnetic stir bar, add 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)(dtbbpy)PF (14.2 mg, 15.47 μmol) were added, followed by DMA (10 mL). Dibromonickel; 1,2-dimethoxyethane (23.9 mg, 77.4 μmol) was then added as a solution in DMA (0.5 mL) under N. The reaction was placed 6 cm in front of one 30 W blue LED at 25 °C for 96 h. LCMS showed mostly product. Eight batches were combined and added dropwise to water (200 mL). The solid formed was filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250 mm x 100 mm x 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-piperidyl)-3-oxo-isoindolin-5-yl]piperazine-1-carboxylate (3″) (2.5 g, 47.1% yield) as a gray solid.

[0385] 1H 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)

[0386] 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-piperidyl)-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 formed solid was filtered, and the cake was dried to give 12 g of product. 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.

[0387] 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,2 H), 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)

[0388] CBM intermediates prepared using general procedure CBM-1 are summarized in Table 2. Table 2. CBM intermediates produced via general procedure CBM-1 [Table 87] [Table 88]

[0389] General Operation CBM-2 [ka]

[0390] Step 1: To a solution of amine (1) (1 equiv.) and carbonyl (2) (1.2 equiv.) in DCM (0.24 M) was added NaBH(OAc)3 (1.2 equiv.) and AcOH (1 equiv.). 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 give (3).

[0391] Step 2: To (3) (1 equivalent) in THF (0.1 M) was added 4 M HCl in dioxane (15 equivalents). The reaction mixture was stirred at room temperature. After 1 hour, LCMS showed complete conversion, the solvent was removed under reduced pressure, and the residue was co-evaporated with MeCN (3x). The residue was dried under high vacuum to give CBM-2.

[0392] Example S3. 3-[4-(4-piperidylmethylamino)phenyl]piperidine-2,6-dione (C-6) [ka]

[0393] Step 1'. Preparation of tert-butyl N-[4-[[1-[4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]oxymethyl]cyclohexyl]carbamate (3): To a solution of 3-(4-aminophenyl)piperidine-2,6-dione (1') (250 mg, 1.22 mmol, 1 equiv.) and tert-butyl 4-formylpiperidine-1-carboxylate (2') (310 mg, 1.45 mmol, 1.19 equiv.) in DCM (5 mL, 0.24 M) was added NaBH(OAc)3 (310 mg, 1.46 mmol, 1.19 equiv.) and AcOH (0.07 mL, 1.22 mmol, 1 equiv.). The mixture was stirred at room temperature. After an overnight period, LCMS indicated complete conversion to compound (3). The reaction mixture was quenched with water, extracted three 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 precipitate, elution with 0% to 100% heptane / EtOAc over 15 CV, product emerges at 100% EtOAc). The fractions were combined and concentrated to give 3' (440 g, 89% yield) as a white solid.

[0394] LCMS Method 1: 96.8% purity at 215 nm, [M-Boc+H] + =302.2

[0395] 1 H NMR (400MHz, DMSO-d6) δ ppm 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(brt,J=5.7Hz,2H), 3 .62(dd,J=10.5, 5.1Hz,1H), 3.94(brd,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)

[0396] Step 2'. Preparation of 3-[4-(4-piperidylmethylamino)phenyl]piperidine-2,6-dione (C-6): To a mixture of tert-butyl 4-[[4-(2,6-dioxo-3-piperidyl)anilino]methyl]piperidine-1-carboxylate (3') (419 mg, 1.04 mmol, 1 equiv.) in THF (10.4 mL, 0.1 M) was added 4 M HCl in dioxane (3.91 mL, 15.65 mmol, 15 equiv.). 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 give (C-6) (353 mg, quantitative yield) as a white solid.

[0397] LCMS Method 1: 97.8% purity at 215 nm, [M+H] + =302.2

[0398] 1 H NMR (400MHz, DMSO-d6) δ ppm 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(brd,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)

[0399] CBM intermediates prepared using general procedure CBM-2 are summarized in Table 3. Table 3. CBM intermediates prepared via general procedure CBM-2 [Table 89]

[0400] General Operation CBM-3 [ka] wherein X is N or CR as defined in formula (I') or (I). 13 is.

[0401] Step 1: To a flask under N2 was added amine (1) (1 equivalent), carboxylic acid (2) (1 equivalent), and DIPEA (5 equivalents) in DMF (0.12 M). The resulting solution was stirred at room temperature. PyAOP (1.3 equivalents) or other coupling reagent was then added in one portion. The reaction was stirred at room temperature. Upon completion, the reaction mixture was directly loaded onto a reverse-phase purification system, and the clean fractions were combined and concentrated to give product (3).

[0402] Step 2: To a solution of amide (3) (1 equiv.) in DCM (0.13 M) was added TFA (15 equiv.) or other deprotecting agent. 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 give (CBM-3).

[0403] Example S4. 4-Amino-N-[4-(2,6-dioxo-3-piperidyl)phenyl]benzamide (C-10) [ka]

[0404] Step 1'. Preparation of tert-butyl N-[4-[[4-(2,6-dioxo-3-piperidyl)phenyl]carbamoyl]phenyl]carbamate (3'): To a round-bottom flask were added 3-(4-aminophenyl)piperidine-2,6-dione (1') (300 mg, 1.47 mmol, 1 equiv.), 4-(tert-butoxycarbonylamino)benzoic acid (2') (348.5 mg, 1.47 mmol, 1 equiv.), and DIPEA (1.28 mL, 7.34 mmol, 5 equiv.) in DMF (12.2 mL, 0.12 M) under N2. The resulting solution was stirred at room temperature for 10 minutes. The resulting solution was stirred at room temperature for 10 minutes. Then, PyAOP (995.65 mg, 1.91 mmol, 1.3 equiv.) was added in one portion. The reaction was stirred at room temperature. After 16 hours, LCMS indicated complete conversion to compound 2. The reaction mixture was loaded directly onto a reverse-phase FC purification column (50 g C18 column, liquid precipitate (reaction mixture), 5% MeCN / 0.1% HCOOH over 3 CV, then 5–40% MeCN / 0.1% HCOOH over 2 CV, then 40–100% MeCN / 0.1% HCOOH over 15 CV, with product coming off at 60% MeCN). Fractions were combined and concentrated to give 3' (267 mg, 43% yield) as a tan solid.

[0405] LCMS Method 1: 99.9% purity at 215 nm, [M+H] + =424.2

[0406] 1 H NMR (400MHz, DMSO-d6) δ ppm 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)

[0407] Step 2'. Preparation of 4-amino-N-[4-(2,6-dioxo-3-piperidyl)phenyl]benzamide (C-10): To a solution of tert-butyl N-[4-[[4-(2,6-dioxo-3-piperidyl)phenyl]carbamoyl]phenyl]carbamate (3') (267 mg, 0.63 mmol, 1 equiv.) in DCM (5 mL, 0.13 M) was added TFA (1.03 mL, 12.61 mmol, 15 equiv.). The reaction mixture was stirred at room temperature. After 30 min, LCMS indicated 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 afford C-10 (207 mg, 69% yield) as a tan solid trifluoroacetate salt.

[0408] LCMS Method 1: 92.3% purity at 215 nm, [M-CF3COOH+H] + =324.2

[0409] 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); three protons were lost.

[0410] Example S5. N-[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]piperidine-4-carboxamide hydrochloride (C-16) [ka]

[0411] 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 sequential 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 hours. The reaction mixture was directly loaded onto a column for reverse-phase flash chromatography purification (MeCN in 0.1% HCOOH (aq), 5% (3 CV) → 100%, 100 g of RediSep Rf Gold® C18Aq, 10 CV, λ = 214-254 nm). Evaporation of the fractions gave 3″ (211 mg, 0.507 mmol, 60% yield) as a yellow solid.

[0412] LCMS Method 1: 99.9% purity at 215 nm, [M-tBu+H] + =317.2

[0413] 1 H NMR (400MHz, DMSO-d6) δ ppm 1.39-1.42(m,9H), 1.42-1.54(m,2H), 1.77(brd,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(brd,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)

[0414] 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 1 h. The solvent was evaporated under reduced pressure, and the residue was then 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 directly in the next step.

[0415] LCMS Method 1: 99.9% purity at 215 nm, [M-HCl+H] + =317.2

[0416] 1 H NMR (400MHz, DMSO-d6) δ ppm 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), 3.7 4(t,J=6.7Hz,2H), 7.25(d,J=8.8Hz,2H), 7.59(d,J=8.8Hz,2H), 8.41(brs,1H), 8.70(brs,1H), 10.11(s,1H), 10.33(s,1H)

[0417] CBM intermediates prepared using general procedure CBM-3 are summarized in Table 4. Table 4. CBM intermediates produced via general procedure CBM-3 [Table 90]

[0418] Typical Operation CBM-4 (CBM-4A and CBM-4B) General operation CBM-4A [ka] where R 7 and R 10 is as defined in formula (I') or (I).

[0419] LCMS Method 1. Column: Kinetex XB-C18, 75x3.0 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, Linear Gradient to 100% Mobile Phase B over 4.1 min, then hold for 0.5 min. MSD Positive

[0420] LCMS Method 2. Column: Kinetex XB-C18, 75x3.0 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, linear gradient to 100% Mobile phase B over 4.0 min, then hold for 0.5 min. MSD positive

[0421] LCMS Method 3. Column: Kinetex XB-C18, 50x4.6mm, 5.0μm; Temperature: 45°C; Flow rate: 1.5mL / min; Run time: 6.0 min; Mobile phase conditions: Mobile phase A: 0.1% TFA in HO, Mobile phase B: 0.1% TFA in ACN, Gradient: Initially 95% Mobile phase A and 5% Mobile phase B, Linear gradient to 95% Mobile phase B over 2.5 min, then hold for 1.5 min. MSD positive

[0422] Step A. Preparation of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (B) [ka] In a sealed tube, 2,6-dibenzyloxy-3-bromo-pyridine (A) (1.0 g, 2.701 mmol, 1.0 equiv.), bis(pinacolato)diboron (1.0 g, 4.051 mmol, 1.5 equiv.), KOAc (795.2 mg, 8.103 mmol, 3.0 equiv.), and Pd(dppf)Cl·DCM (220.57 mg, 0.270 mmol, 0.1 equiv.) were dissolved in 1,4-dioxane (4.0 mL, 0.6 M) and purged with nitrogen for 10 min. 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, elution with 0% EtOAc to 10% EtOAc in hexanes over 18 CV) to give 900 mg of (B) contaminated with bis(pinacolato). A second purification by normal-phase flash chromatography (80 g SNAP column; elution with 0% EtOAc in heptane over 2 CV, then 0 to 4.5% EtOAc in 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.

[0423] 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

[0424] 1 H NMR (400MHz, DMSO-d6) δ ppm 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)

[0425] Step 1: To a flame-dried sealed tube was added CsCO (2.0 equiv.), heterocycle 2 (1.1 equiv.), bromo-iodo 1 (1.0 equiv.), XantPhos (0.2 equiv.), and Pd(dba) (0.1 equiv.) 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. Upon complete conversion of the starting material, the reaction mixture was cooled to room temperature. Ethyl acetate and water were added, the phases were separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were then combined, washed once with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography, after which the fractions were combined and concentrated to give the bromide product 3.

[0426] Step 2: A sealed tube was charged with KPO (2.3 equiv.), bromide (3) (1.0 equiv.), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (B) (1.2 equiv.), and Pd(PPh) (0.1 equiv.). 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, and the mixture was then degassed by sparging with nitrogen for 10 minutes. The vial was sealed, and the reaction was heated at 90 °C overnight. Upon complete conversion of the starting material, the reaction was cooled to room temperature, filtered through Celite, washed with EtOAc, and the filtrate was evaporated. The residue was purified by normal phase flash chromatography, after which the fractions were combined and concentrated to give pyridine (5).

[0427] Step 3: A solution of pyridine (5) (1.0 equiv.) in THF / EtOH (0.05 M) was degassed for 15 minutes, followed by degassing with Pd(OH) (0.2 equiv.) by sparging with nitrogen for 5 minutes. Hydrogen was then bubbled through the reaction mixture for 5 minutes, and the mixture was stirred in a hot water bath under a hydrogen atmosphere at 50°C. The mixture was cooled to room temperature. Ethyl acetate and water were added, the phases were separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were then combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography, after which the fractions were combined and concentrated to give glutarimide (6).

[0428] Step 4: To a solution of glutarimide (6) (1.0 equiv.) was added 4 M HCl in dioxane (54 equiv.). The reaction was stirred at room temperature. After an overnight period, LCMS showed complete conversion to the product. The reaction mixture was concentrated under reduced pressure and co-evaporated with acetonitrile three times to give the product (CBM-4A), which was used directly in the next step.

[0429] General operation CBM-4B [ka] where R 7 and R 10 is as defined in formula (I') or (I).

[0430] Step 1: A solution of bromide 1 (1.20 g, 6.09 mmol, 1 equiv.) and tert-butyl prop-2-enoate 2 (1.05 equiv.) in anhydrous THF (0.5 M) was cooled to 0 °C under nitrogen. tBuOK (0.1 equiv.) was added, and the reaction was stirred at 0 °C and allowed to warm slowly to room temperature. Upon completion, the reaction mixture was filtered through a pad of Celite, 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 saturated aqueous NaHCO and EtOAc. The layers were separated, and the aqueous layer was back-extracted with EtOAc. The organics were combined, dried over NaSO, filtered, and concentrated to dryness to give 3.

[0431] Step 2: To a sealed tube was added bromide 3 (1 equiv.), heterocycle 4 (1.2 equiv.), CsCO (2 equiv.), XPhos (0.2 equiv.), and 1,4-dioxane (0.1 M). The reaction mixture was sparged with nitrogen for 10 minutes, and Pd(dba) CHCl (0.1 equiv.) was added quickly. The reaction mixture was sparged with nitrogen for an additional 10 minutes, after which it was stirred at 90 °C. Upon completion, the reaction mixture was filtered through a pad of Celite, rinsed with EtOAc, and the filtrate concentrated to dryness. The residue was purified by reverse-phase flash chromatography, and the reactions 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 organics were combined, dried over NaSO, filtered, and concentrated to dryness to give 5.

[0432] Step 3: To a sealed tube was added (5) (1 equivalent), acetic acid (0.2 M), and concentrated sulfur (4 equivalents). The reaction mixture was allowed to stir 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 directly in the next step.

[0433] Example S6. 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (C-12) [ka]

[0434] Step 1'. Preparation of (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (2'): To a stirred solution of 2,6-bis(benzyloxy)-3-bromopyridine (1') (30.0 g, 81 mmol, 1.0 equiv.) in THF (300 mL) was added n-BuLi (48.6 mL, 122 mmol, 1.5 equiv.) at -78 °C and stirred at the same temperature for 30 min. Trimethylborate (10.86 mL, 97 mmol, 1.2 equiv.) was then added dropwise, and stirring at the same temperature was continued for another 30 min. The reaction was quenched with saturated aqueous ammonium chloride (300 mL) and acidified with 1.5 N HCl solution to maintain a pH of 3-4. The reaction mixture was extracted with ethyl acetate (3 x 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 give (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (2') (16 g, 50.1% yield) as an off-white solid.

[0435] LCMS Method 1: Retention time: 3.003 min, Purity at 220 nm: 85.56%, [M+H] + =336.0

[0436] 1 H NMR (400MHz, DMSO-d6): δ ppm 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)

[0437] 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 equiv.) 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 equiv.) followed by dibasic potassium phosphate (20.42 g, 117 mmol, 2.0 equiv.). The resulting reaction mixture was degassed with nitrogen for 15 minutes, and PdCl(dppf)·CHCl (4.79 g, 5.86 mmol, 0.1 equiv.) was added to the reaction mixture. The reaction mixture was then heated in a sealed tube at 85° C. for 3 hours. The reaction mixture was cooled to room temperature, poured into ice-cold water, and extracted with ethyl acetate (2×25 mL). The organic extracts were combined, 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 in petroleum ether to give 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.

[0438] LCMS Method 2: Retention time: 2.326 min, Purity at 220 nm: 92.15%, [M+H] + =552.2

[0439] 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 equiv.) in ethyl acetate (700 mL), Pd(OH) (5.98 g, 42.6 mmol, 0.5 equiv.) was added. The reaction mixture was stirred at room temperature under an H atmosphere for 12 hours. The reaction mixture was filtered through a bed of Celite, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (5') (24 g, 71.7% yield) as an off-white solid.

[0440] LCMS Method 3: Retention time: 1.781 min, Purity at 220 nm: 95.26%, [M+H] + =374.3

[0441] 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 equiv.) in DCM (20 mL, 0.208 M) at 0 °C was added dry HCl in 1,4-dioxane (10.42 mL, 41.7 mmol, 4.0 M in 1,4-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·2HCl (C-12) (1.9 g) as a brown solid. The material was used in the next step without further purification.

[0442] LCMS method 4: Retention time: 0.307 min, [M+H] + =274.2

[0443] Example S7. 3-(2-Methoxy-4-piperazin-4-ium-1-yl-phenyl)piperidine-2,6-dione hydrochloride (C-34) [ka]

[0444] Step 1'. Preparation of tert-butyl 4-(4-bromo-3-methoxyphenyl)piperazine-1-carboxylate (3'): To a flame-dried sealed tube was added CsCO (2.08 g, 6.39 mmol, 2 equiv.), tert-butyl piperazine-1-carboxylate (2') (654.7 mg, 3.52 mmol, 1.1 equiv.), 1-bromo-4-iodo-2-methoxybenzene (1') (1 g, 3.2 mmol, 1 equiv.), Xantphos (369.81 mg, 0.64 mmol, 0.2 equiv.), and Pd(dba) (292.63 mg, 0.32 mmol, 0.1 equiv.) and dissolved in dry 1,4-dioxane (16 mL, 0.2 M). The mixture was degassed by sparging with nitrogen for 10 min. The tube was sealed, and the mixture was stirred at 110 °C. After an overnight period, LCMS indicated complete conversion of the starting material to compound (3). The reaction mixture was cooled to room temperature. Ethyl acetate and water were added, the phases were separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were then combined, 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 column; elution: 0-10% MeOH / DCM over 10 CV, then 10% MeOH until the product came out). The fractions were combined and concentrated to give (3') (742 mg, 62% yield) as a light yellow solid.

[0445] LCMS Method 1: 98.5% purity at 215 nm, [M+H] + =373.2

[0446] 1H NMR (400MHz, chloroform-d) δ ppm 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)

[0447] Step 2'. Preparation of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)-3-methoxy-phenyl]piperazine-1-carboxylate (5'): A sealed tube was charged with KPO (194.91 mg, 0.92 mmol, 2.27 equiv.), tert-butyl 4-(4-bromo-3-methoxy-phenyl)piperazine-1-carboxylate (3') (150 mg, 0.40 mmol, 1 equiv.), 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 equiv.), and Pd(PPh) (46.69 mg, 0.04 mmol, 0.1 equiv.). The mixture was degassed by sparging with nitrogen for 10 minutes. A solution of 1,4-dioxane (4.04 mL, 0.08 M) and water (1.01 mL, 0.08 M) was added, and the mixture was then degassed by sparging with nitrogen for 10 minutes. The vial was sealed, and the reaction was heated at 90 °C overnight. After the overnight period, LCMS indicated complete conversion of starting material to material (5'). The mixture was cooled to room temperature, and the reaction was filtered through Celite, washed with EtOAc, and the filtrate was evaporated. The residue was purified by normal-phase flash chromatography (40 g silica column; elution: 5–50% EtOAc / heptane over 10 CV, 25% EtOAc to remove product). The fractions were combined and concentrated to give (5') (195.9 mg, 77% yield) as a yellow solid.

[0448] LCMS Method 1: 92.0% purity at 215 nm, [M+H] + =582.2

[0449] 1 H NMR (400MHz, chloroform-d) δ ppm 1.50(s,9H), 3.19(t,J=5.0Hz,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)

[0450] Step 3'. Preparation of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)-3-methoxy-phenyl]piperazine-1-carboxylate (6'): A solution of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)-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, and then Pd(OH) (33.8 mg, 0.05 mmol, 0.2 eq) was added by sparging with nitrogen for 5 minutes. Hydrogen was then bubbled through the reaction mixture for 5 minutes, and the mixture was stirred under a hydrogen atmosphere in a hot water bath at 50 °C for 4 hours. The mixture was cooled to room temperature. Ethyl acetate and water were added, the phases were separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were then combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase flash chromatography (40 g silica column; elution: 0 to 100% MeOH / DCM over 30 CV). The fractions were combined and concentrated to give 6' (30 mg, 23% yield) as a light blue solid.

[0451] LCMS Method 1: 99.9% purity at 215 nm, [M+H] + =404.2

[0452] 1H NMR (400 MHz, chloroform-d) δ ppm 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 = 5.2 Hz, 4H), 3.58 (t, J = 5.2 Hz, 4H), 3.80 (s, 3H), 6.46-6.52 (m, 2H), 6.97-7.04 (m, 1H), 7.86 (s, 1H).

[0453] 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-piperidyl)-3-methoxy-phenyl]piperazine-1-carboxylate (6') (30 mg, 0.07 mmol, 1 equiv.) was added 4 M HCl in dioxane (1 mL, 4 mmol, 54 equiv.). The reaction was stirred at room temperature. After an overnight period, LCMS indicated complete conversion to the product. The reaction mixture was concentrated under reduced pressure and coevaporated 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.

[0454] LCMS Method 1: 99.9% purity at 215 nm, [M-HCl+H] + =304.4

[0455] Example S8. 3-(2-Methoxy-4-piperazin-4-ium-1-yl-phenyl)piperidine-2,6-dione hydrochloride (C-29) [ka]

[0456] Step 1'. Preparation of tert-butyl 4-[4-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidyl]phenyl]-4-cyano-butanoate (3'): In a flame-dried sealed tube under a nitrogen atmosphere, add Cs2CO3 (1.01 g, 3.084 mmol, 2.0 equiv.), tert-butyl N-methyl-N-(4-piperidyl)carbamate (2') (396.6 mg, 1.850 mmol, 1.2 equiv.), tert-butyl 4-(4-Bromophenyl)-4-cyanobutanoate (1') (500.0 mg, 1.542 mmol, 1.0 equiv.), XPhos (110.28 mg, 0.231 mmol, 0.15 equiv.), Pd2(dba)3 (141.22 mg, 0.154 mmol, 0.1 equiv.), and dry 1,4-dioxane (7.7 mL, 0.2 M) were introduced. 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 column; elution: 0-50% heptane / EtOAc over 15 CV; the product was eluted at 45% EtOAc and was the only one absorbing at 254 nm). The fractions were combined and concentrated to give tert-butyl 4-[4-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidyl]phenyl]-4-cyano-butanoate (3′) (660 mg, 83% yield) as an orange oil.

[0457] LCMS Method 1: Retention time: 2.061 min, purity 88.3% at 215 nm, [M+H] + =458.2

[0458] 1H NMR (400MHz, DMSO-d6) δ ppm 0.79-0.88(m,1H), 1.21-1.28(m,1H), 1.36-1.41(m,18H), 1.60(brd,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(brd,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)

[0459] Step 2'. Preparation of 3-[4-[4-(methylamino)-1-piperidyl]phenyl]piperidine-2,6-dione sulfate (C-29): To an aqueous mixture of tert-butyl 4-[4-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidyl]phenyl]-4-cyanobutanoate (3') (866 mg, 1.892 mmol) in acetic acid (9.5 mL, 0.2 M) was added concentrated HSO (0.3 mL, 5.677 mmol, 3.0 equiv.). The reaction mixture was vigorously stirred at 120 °C for 1 h and then concentrated. The crude material was dissolved in a minimal amount of water and purified by reverse-phase flash 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, eluting with 5% MeCN to evaporate the product). Pure fractions were combined and concentrated to give 3-[4-[4-(methylamino)-1-piperidyl]phenyl]piperidine-2,6-dione sulfate (C-29) (265 mg, 34% yield) as a yellow oil.

[0460] LCMS Method 1: Retention time: 0.588 min, purity 97.7% at 215 nm, [M+H] + =302.2

[0461] 1H NMR (400MHz, DMSO-d6) δ ppm 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(brt,J=11.4Hz ,1H), 3.67-3.83(m,3H), 4.76(brd,J=15.9Hz,1H), 6.91(brd,J=8.6Hz,2H), 7.05(brd,J=8.3Hz,2H), 8.24(s,1H), 10.77(brs,1H)

[0462] Example S9. Anhydrous acid; 3-(5-ピペラジン-1-イル-2-ピリジル)ピペリジン-2,6-ジオン (C-37)

change

[0463] Step 1'. Preparation of tert-butyl 4-(5-bromo-2-pyridyl)-4-cyanobutanoate (3'): A solution of 2-(5-bromo-2-pyridyl)acetonitrile (1') (1.20 g, 6.09 mmol, 1 equiv.) and tert-butyl prop-2-enoate (2') (820 mg, 6.39 mmol, 1.05 equiv.) in anhydrous THF (12 mL) was cooled to 0 °C under nitrogen. tBuOK (74 mg, 0.61 mmol, 0.1 equiv.) was added, and the reaction was stirred at 0 °C (allowed to warm slowly to room temperature while maintaining the ice bath). After 16 h, LCMS indicated incomplete conversion. The reaction mixture was filtered through a pad of Celite, rinsing with EtOAc, and the filtrate was concentrated to dryness. The residue was purified by reverse-phase flash chromatography (100 g C18 column, liquid precipitate (DMSO), elution: 5% MeCN / 0.1% HCOOH over 3 CV, then 5–40% MeCN / 0.1% HCOOH over 2 CV, then 40–100% MeCN / 0.1% HCOOH over 14 CV). The fractions were combined and partially concentrated to dryness. The suspension was then partitioned between saturated aqueous NaHCO3 and EtOAc. The layers were separated, and the aqueous layer was back-extracted with EtOAc. The organics were combined, dried over Na2SO4, filtered, and concentrated to dryness to give 3' (466 mg, 24% yield) as a brown oil.

[0464] LCMS Method 1: 96.6% purity at 215 nm, [M-tBu+H] + =269.0

[0465] 1 H NMR (400MHz, CDCl3) δ ppm 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)

[0466] Step 2'. Preparation of tert-butyl 4-[6-(4-tert-butoxy-1-cyano-4-oxo-butyl)-3-pyridyl]piperazine-1-carboxylate (5'): To a sealed tube was added tert-butyl 4-(5-bromo-2-pyridyl)-4-cyano-butanoate (3') (336 mg, 1.03 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (4') (229 mg, 1.23 mmol, 1.2 equiv.), CsCO (664 mg, 2.04 mmol, 2 equiv.), XPhos (102 mg, 0.21 mmol, 0.2 equiv.), and 1,4-dioxane (10 mL). The reaction mixture was sparged with nitrogen for 10 minutes, and Pd2(dba)3·CHCl3 (98 mg, 0.09 mmol, 0.1 equiv.) was added quickly. The reaction mixture was sparged with nitrogen for another 10 minutes, and then it was stirred at 90 °C. After 14.5 hours, LCMS indicated complete conversion. The reaction mixture was filtered over a pad of Celite, rinsed with EtOAc, and the filtrate was concentrated to dryness. The residue was purified by reverse-phase flash chromatography (100 g C18 column, liquid precipitate (DMSO), elution: 5% MeCN / 0.1% HCOOH over 3 CV, then 5–30% MeCN / 0.1% HCOOH over 2 CV, then 30–80% MeCN / 0.1% HCOOH over 17 CV). The fractions were combined and partially concentrated to dryness. The suspension was then partitioned between saturated aqueous NaHCO3 and EtOAc. The layers were separated, and the aqueous layer was back-extracted with EtOAc. The organics were combined, dried over Na2SO4, filtered, and concentrated to dryness to give (5') (285 mg, 60% yield) as an orange oil.

[0467] LCMS Method 1: 99.9% purity at 215 nm, [M+H] + =431.3

[0468] 1H NMR (400MHz, CDCl3) δ ppm 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. 63(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)

[0469] Step 3'. Acetic acid; preparation of 3-(5-piperazin-1-yl-2-pyridyl)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-pyridyl]piperazine-1-carboxylate (5') (280 mg, 0.65 mmol, 1 equiv.), acetic acid (3.3 mL), and concentrated sulfur (255 mg, 2.60 mmol, 4 equiv.). The reaction mixture was allowed to stir at 118 °C. After 70 min, LCMS indicated complete conversion. Volatiles were removed under reduced pressure, and the residue was purified by reverse-phase flash chromatography (20 g C18Aq column, liquid precipitate (HO), elution: 0% MeCN / 0.1% HCOOH over 8 CV). The fractions were combined and concentrated to give (C-37) (300 mg, 98% yield) as a yellow solid, which was used directly in the next step.

[0470] LCMS Method 1: 85.5% purity at 215 nm, [M-2CH3COOH+H] + =275.1

[0471] CBM intermediates prepared using general procedure CBM-4 are summarized in Table 5. Table 5. CBM intermediates prepared via general procedure CBM-4 [Table 91] [Table 92] [Table 93] [Table 94] [Table 95] [Table 96] [Table 97]

[0472] General Operation CBM-5 Example S10. 3-[4-[2-(4-piperidyl)ethynyl]phenyl]piperidine-2,6-dione hydrochloride (C-21) [ka]

[0473] Step 1. Preparation of tert-butyl 4-[2-[4-(2,6-dioxo-3-piperidyl)phenyl]ethynyl]piperidine-1-carboxylate (3): 3-(4-bromophenyl)piperidine-2,6-dione (1) (250 mg, 0.932 mmol, 1.0 equiv.), tert-butyl A solution of 4-ethynylpiperidine-1-carboxylate (2) (234.1 mg, 1.118 mmol, 1.2 equiv.), CuI (17.76 mg, 0.093 mmol, 0.1 equiv.), DIPEA (1.62 mL, 9.320 mmol, 10.0 equiv.), and PdCl(PPh) (65.45 mg, 0.093 mmol, 0.1 equiv.) in THF (6.2 mL, 0.15 M) was degassed by sparging with nitrogen for 20 min. The reaction was stirred at room temperature for 48 h. 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 column; elution: 0–20% CHCl / EtOAc over 15 CV, eluting with 7% EtOAc to remove the product). The fractions were combined and concentrated to give tert-butyl 4-[2-[4-(2,6-dioxo-3-piperidyl)phenyl]ethynyl]piperidine-1-carboxylate (3) (183 mg, 49% yield) as a yellow solid.

[0474] LCMS Method 1: Retention time: 1.820 min, purity 92.8% at 215 nm, [M-Boc+H] + =297.2;[M-tBu+H] + = 341.2; [M+Na] + =419.2

[0475] 1H NMR (400MHz, DMSO-d6) δ ppm 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)

[0476] Step 2. Preparation of 3-[4-[2-(4-piperidyl)ethynyl]phenyl]piperidine-2,6-dione hydrochloride (C-21): Under nitrogen, a mixture of tert-butyl 4-[2-[4-(2,6-dioxo-3-piperidyl)phenyl]ethynyl]piperidine-1-carboxylate (3) (180 mg, 0.454 mmol, 1.0 equiv.) and 4 M HCl in 1,4-dioxane (1.5 mL, 6.0 mmol, 13.0 equiv.) in DCM (4.5 mL, 0.1 M) was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and coevaporated three times with acetonitrile to give 3-[4-[2-(4-piperidyl)ethynyl]phenyl]piperidine-2,6-dione hydrochloride (C-21) (150 mg, 98% yield) as a yellow solid.

[0477] LCMS Method 1: Retention time: 1.121 min, purity 99.9% at 215 nm, [M-HCl+H] + =297.2

[0478] 1H NMR (400MHz, DMSO-d6) δ ppm 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), 3.17-3.2 4(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)

[0479] CBM intermediates prepared using general procedure CBM-5 are summarized in Table 6. Table 6. CBM intermediates produced via general procedure CBM-5 [Table 98]

[0480] General Operation CBM-6 Example S11. 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione (C-25) [ka]

[0481] Step 1. Preparation of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-1-carboxylate (3): A solution of tert-butyl 4-(p-tolylsulfonyloxy)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′-dipyridyl (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 minutes. NiBr₂·DME (104.6 mg, 0.34 mmol) was then added, and nitrogen was bubbled through the solution for 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 × 50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by reverse-phase chromatography (C₁₈-100 g, 5–100% MeCN / 0.1% formic acid in water, 20 CV) afforded tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-1-carboxylate (3) (504.6 mg, 1.35 mmol, 48% yield) as a slightly pink solid.

[0482] 1 H NMR (400MHz, DMSO-d6) δ ppm 1.41(s,9H), 1.44-1.54(m,2H), 1.74(brd,J=12.6Hz,2H), 1.98-2.06(m,1 H), 2.10-2.23(m,1H), 2.45(brt,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(brd,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

[0483] 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-piperidyl)phenyl]piperidine-1-carboxylate (3) (137 mg, 0.3700 mmol) in 1,4-dioxane (1.8 mL) was added HCl in dioxane (1.8 mL, 7.2 mmol) (3:03 PM) at room temperature. The resulting solution was stirred at room temperature. After 1 hour, the reaction mixture was concentrated on a rotovap. 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 hours. After HPLC analysis showed complete conversion, the mixture was concentrated on a rotovap to give 119.6 mg of the product (C-25) as a light yellow solid (quantitative yield), which was 99.9% pure by HPLC (2.5 min run, 215 nm).

[0484] Luna C18 50x3mm 45℃ (C-25) Retention time (product) = 1.170 min

[0485] CBM intermediates prepared using general procedure CBM-6 are summarized in Table 7. Table 7. CBM intermediates produced via general procedure CBM-6 [Table 99]

[0486] General Operation CBM-7 Example S12. 3-[4-(4-piperidylmethoxy)phenyl]piperidine-2,6-dione·2,2,2-trifluoroacetic acid (C-33) [ka]

[0487] Step 1. Preparation of tert-butyl 4-[[4-(2,6-dioxo-3-piperidyl)phenoxy]methyl]piperidine-1-carboxylate (3): A Schlenk flask was charged with quinuclidine (8.29 mg, 0.07 mmol, 0.1 equiv.), NiCl DME (8.2 mg, 0.04 mmol, 0.05 equiv.), 3-(4-bromophenyl)piperidine-2,6-dione ( 1) (200 mg, 0.75 mmol, 1 equiv.), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (8.37 mg, 0.01 mmol, 0.01 equiv.), K2CO3 (103.1 mg, 0.75 mmol, 1 equiv.), and dtbbpy (10.01 mg, 0.04 mmol, 0.05 equiv.) were added in MeCN (5 mL, 0.15 M). The flask was placed under nitrogen, and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2) (401.5 mg, 1.86 mmol, 2 equiv.) was then added. The Schlenk tube was then frozen at -78 °C, placed under nitrogen, and slowly heated to room temperature using a water bath under high vacuum. This procedure was repeated three times, and the Schlenk tube was checked for oxygen. The tube was then irradiated under a blue LED over the weekend. After 3 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 precipitate (DMSO), 5% MeOH / 0.1% HCOOH over 4 CV, then 5 to 80% MeOH / 0.1% HCOOH over 10 CV, then 80% MeOH / 0.1% HCOOH over 4 CV, with product coming off at 80% MeOH). Fractions were combined and concentrated to give 3 (126 mg, 42% yield) as a yellow solid.

[0488] LCMS Method 1: 99.9% purity at 215 nm, [M-tBu+H] + =347.2

[0489] 1H NMR (400MHz, chloroform-d) δ ppm 1.13-1.35(m,4H), 1.46-1.48(m,9H), 1.82(brd,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)

[0490] Step 2. Preparation of 3-[4-(4-piperidylmethoxy)phenyl]piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (C-33): To a solution of tert-butyl 4-[[4-(2,6-dioxo-3-piperidyl)phenoxy]methyl]piperidine-1-carboxylate (3) (126 mg, 0.31 mmol, 1 equiv.) in DCM (1 mL, 0.31 M) was added TFA (0.36 mL, 4.7 mmol, 15 equiv.). 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 (2x) and MeCN (2x) to give (C-33) (157 mg, quantitative yield) as a yellow solid trifluoroacetate salt.

[0491] LCMS Method 1: 91.8% purity at 215 nm, [M-CF3COOH+H] + =303.2

[0492] 1 H NMR (400MHz, DMSO-d6) δ ppm 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); one proton1 1 H NMR spectrum showed a loss.

[0493] CBM intermediates prepared using general procedure CBM-7 are summarized in Table 8. Table 8. CBM intermediates produced via general procedure CBM-7 [Table 100]

[0494] General Operation CBM-8 Example S13. 3-[4-[4-(hydroxymethyl)-1-piperidyl]phenyl]piperidine-2,6-dione (C-38) [ka]

[0495] 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 under a nitrogen atmosphere for 30 minutes, TLC showed complete conversion to compound (2). Water was added to the reaction mixture, which was extracted twice with EtOAc. The organic phase was washed twice with water, 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 precipitate, elution: 0% to 40% heptane / EtOAc over 20 CV, product came out at 10% EtOAc). The fractions were combined and concentrated to give 2 (2.28 g, quantitative yield) as a colorless oil.

[0496] 1H NMR (400MHz, 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=6.8Hz,2H), 5.65(s,2H)

[0497] 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 equiv.) in t-BuOH (35 mL, 0.2 M) and THF (17.5 mL, 0.2 M) was stirred at room temperature for 5 min. Then, OsO (0.66 mL, 4.0% w / w in HO, 0.104 mmol, 0.01 equiv.) and NMO (1.46 g, 12.43 mmol, 1.2 equiv.) were added sequentially. After stirring at room temperature for 18 h under nitrogen, TLC showed complete conversion to compound (3). The mixture was concentrated to remove t-BuOH and THF, and the residue was then 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 column; elution: 0-10% methanol / dichloromethane over 14 CV, eluting with 10% methanol to remove the product). The fractions were combined and concentrated to give 3 (2.44 g, 88% yield) as a brown oil.

[0498] 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)

[0499] Step 3. Preparation of 3-[[tert-butyl(dimethyl)silyl]oxymethyl]pentanedial (4): Under nitrogen, a solution of (1S,2R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopentane-1,2-diol (3) (2.4 g, 9.74 mmol, 1 equiv.) in THF (35 mL, 0.19 M) and HO (17.5 mL, 0.19 M) was stirred at room temperature for 5 min, and then NaIO (2.5 g, 11.69 mmol, 1.2 equiv.) was added. After stirring at room temperature for 1 h under nitrogen, TLC (CHCl / MeOH 95:5, KMnO stain) showed complete conversion to compound (4). The mixture was concentrated to remove THF, and then brine (40 mL) was added. The aqueous phase was then extracted three times with ethyl acetate (3 × 75 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (150 mL) and stirred in the presence of a large excess of magnesium sulfate at room temperature for 16 hours. The solid was filtered, and the organic phase was then concentrated and dried under high vacuum to give 4 (2.04 g, 86% yield) as a colorless oil.

[0500] 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)

[0501] Step 4. Preparation of 3-[4-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-piperidyl]phenyl]piperidine-2,6-dione (6): To a solution of 3-(4-aminophenyl)piperidine-2,6-dione (5) (250 mg, 1.22 mmol, 1 equiv.) and 3-[[tert-butyl(dimethyl)silyl]oxymethyl]pentanedial (4) (360 mg, 1.47 mmol, 1.2 equiv.) in DCE (12.2 mL, 0.1 M) was added NaBH(OAc) (649 mg, 3.06 mmol, 2.5 equiv.). The mixture was stirred at room temperature. After 2 h, LCMS indicated complete conversion to compound (6). The reaction mixture was partitioned between DCM (20 mL) and saturated 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 give 6 (413 mg, 81% yield) as a white solid, which was used directly without further purification.

[0502] LCMS method 1: 99.9% purity at 215 nm, [M+H] + =417.4

[0503] 1 H NMR (400MHz, chloroform-d) δ ppm 0.06(s,6H), 0.91(s,9H), 1.28-1.41(m,2H), 1.61-1.68(m,1H), 1.82(brd,J=12.5Hz,2H), 2.19-2.33(m,2H), 2.57 -2.77(m,4H), 3.49(d,J=6.4Hz,2H), 3.66-3.76(m,3H), 6.93(d,J=8.8Hz,2H), 7.08(d,J=8.6Hz,2H), 7.90(brs,1H)

[0504] Step 5. Preparation of 3-[4-[4-(hydroxymethyl)-1-piperidyl]phenyl]piperidine-2,6-dione (C-38): To a mixture of 3-[4-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-piperidyl]phenyl]piperidine-2,6-dione (6) (410 mg, 0.98 mmol, 1 equiv.) in DCM (12.2 mL, 0.08 M) was added 4 M HCl in dioxane (12.3 mL, 49.20 mmol, 50 equiv.). The reaction mixture was stirred at room temperature. After 1.5 h, LCMS indicated complete conversion to compound (7). The solvent was removed under reduced pressure, and the residue was co-evaporated with toluene followed by MeCN. The residue was dried under high vacuum to give (C-38) (453 mg, quantitative yield) as an off-white solid, which was used directly as such in the next step.

[0505] CMS Method 1: 99.9% purity at 215 nm, [M+H] + =303.4

[0506] CBM intermediates prepared using general procedure CBM-8 are summarized in Table 9. Table 9. CBM intermediates produced via general procedure CBM-8 [Table 101]

[0507] General Operation CBM-9 Example S14. tert-Butyl 4-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (C-40) [ka]

[0508] Step 1. General procedure for preparing compound (2): To a solution of 2-(4-bromophenyl)acetonitrile (1) (100 g, 510 mmol) in DMF (1000 mL) was added MeNH-BH (30 g, 510 mmol) and t-BuONa (73.5 g, 765 mmol). After the addition, the reaction was stirred at 80 °C for 1 h. TLC (petroleum ether / ethyl acetate, 10:1) showed that the starting material was consumed. The reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (300 mL x 2). The organic layers were combined, washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash chromatography to give 2-(4-bromophenyl)propanenitrile (2) (49 g, 45.7% yield) as an orange oil.

[0509] 1 H NMR (400MHz, CDCl3) δ 7.47-7.43(m,2H), 7.19-7.15(m,2H), 3.82-3.77(m,1H), 1.56(d,J=3.2Hz,1H)

[0510] Step 2. General procedure for preparing compound 4: To a solution of 2-(4-bromophenyl)propanenitrile 2 (49 g, 233 mmol) in toluene (500 mL) was added tert-butyl prop-2-enoate 3 (59.8 g, 467 mmol), KCO (64.4 g, 467 mmol), and benzyltriethylammonium chloride (10.6 g, 46.7 mmol). The reaction mixture was stirred at 90 °C for 16 h. HPLC showed that the starting material had been consumed. The reaction mixture was cooled to room temperature and filtered, and the cake was washed with ethyl acetate (200 mL). The organic layers were combined and concentrated to give crude tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate 4 (80 g, crude) as an orange oil, which was used in the next step without any further purification.

[0511] 1H 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)

[0512] Step 3. General procedure for preparing compound 6: To a solution of tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate 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 minutes and then stirred at 90 °C for 16 hours. TLC (petroleum ether / ethyl acetate, 2:1) indicated 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 organic layers were combined and 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.

[0513] 1 H 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=4.8 Hz,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)

[0514] Step 4. General procedure for preparing 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 the reaction was complete. The reaction mixture was cooled to room temperature and concentrated. Crude 7 was used in the next step without any further purification as an orange oil based on the theoretical amount (64.8 g).

[0515] 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 BocO (100 g, 458 mmol) and KCO (187 g, 1.35 mol). The reaction mixture was stirred at 20 °C for 5 h. TLC (petroleum ether / ethyl acetate, 1:1) showed the reaction was complete. The reaction mixture was diluted with DCM (1000 mL) and EtOH (1000 mL), stirred for 1 h, filtered, the filter cake was washed with DCM (1000 mL), and the organic layer was concentrated to give the crude product, which was combined with Page 11 to give a total of 230 g of crude product. The mixture was diluted with ethyl acetate (2000 mL) and water (1000 mL), stirred at 20° C. for 1 hour, and then filtered. The filter cake was dried to give 85 g of product (for batch 1). The mother liquor was separated, the organic layer was concentrated, and 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) (71% yield) as a gray solid.

[0516] 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)

[0517] CBM intermediates prepared using general procedure CBM-9 are summarized in Table 10. Table 10. CBM intermediates produced via general procedure CBM-9 [Table 102]

[0518] General Operation CBM-10 Example S15. (3R)-3-Fluoro-3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione dihydrochloride (C-46 and C-46i) [ka]

[0519] 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 hours and monitored by HPLC / TLC. The reaction mixture was partitioned between DCM and saturated NH4Cl. The layers were separated, and the aqueous phase was extracted with DCM (1 x 20 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness, which was then purified by flash chromatography on 120 g of SiO2 eluting with EtOAc in heptane (0% over 1 CV, then 0-30% EtOAc over 8 CV, followed by 30% EtOAc over 4 CV). The desired product emerged around 25-30% (@225 nm). Pure fractions were collected and concentrated to dryness to give 2 (285 mg, 0.7740 mmol, 52% yield) as an orange semi-solid.

[0520] LCMS Method 1: The product was not stable in water.

[0521] 1 H NMR (400MHz, DMSO-d6) δ ppm 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)

[0522] Step 2. Preparation of tert-butyl 3-(4-bromophenyl)-3-fluoro-2,6-dioxo-piperidine-1-carboxylate (3): To a flame-dried flask was added 1 M NaHMDS in THF (1.94 mL, 1.94 mmol) and freshly distilled THF (5.5 mL) under nitrogen. 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 minutes. The reaction was then cooled 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 once more, and the reaction was stirred at 0°C for 60 minutes. Upon completion, the reaction mixture was quenched with saturated NH4Cl, then extracted with EtOAc (3x) and washed with brine (1x). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness to give a crude off-white solid. The crude material was purified by normal phase chromatography eluting with EtOAc / heptane (0% EtOAc over 1 CV, then 0-30% EtOAc over 12 CV, followed by 30% EtOAc over 3 CV). The product came out at approximately 27% EtOAc. Fractions containing the NFSI-contaminated product were collected and concentrated to dryness. This mixture was used in the next step without further purification. (3) (348 mg, 0.712 mmol, 40% yield)

[0523] LCMS Method 1: 96.6% purity at 215 nm, [M-Boc+H] + =286.0

[0524] 1 H NMR (400MHz, DMSO-d6) δ ppm 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)

[0525] 19 F NMR (377MHz, DMSO-d6) δ ppm -149.19--148.99(m,1F)

[0526] Step 3. Preparation of 3-(4-bromophenyl)-3-fluoro-piperidine-2,6-dione (4): A flask was charged with 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 hour. The reaction mixture was concentrated under reduced pressure to give a white solid. To remove the remaining amount of NFSI from the previous step, the crude material was purified by reverse-phase chromatography (eluting with MeCN / 0.1% FA (aqueous (5-100%))). The product emerged around 50-55% MeCN. Pure fractions were concentrated under reduced pressure to give (4) (160 mg, 0.559 mmol, 93% yield) as a white solid.

[0527] LCMS Method 1: 99.9% purity at 215 nm, [M+ 2H] + =288.0

[0528] 1 H NMR (400MHz, DMSO-d6) δ ppm 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(brs,1H)

[0529] 19 F NMR (377MHz, DMSO-d6) δ ppm -150.17--149.95(m,1F)

[0530] Step 4. Preparation of tert-butyl 4-[4-[rac-(3R)-3-fluoro-2,6-dioxo-3-piperidyl]phenyl]piperidine-1-carboxylate (6,6′): In a flame-dried sealed tube, add tert-butyl 4-(p-Tolylsulfonyloxy)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), NiBr DME (9.71 mg, 0.03 mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (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) were added. The reaction mixture was sparged with N for 15 min, and then the tube was sealed. The reaction mixture was stirred at 80 °C overnight. Upon completion, the mixture was poured into 0.5 M HCl and extracted with EtOAc (3x). The organic phases were combined, washed with brine (1x), passed through a pad of Celite and MgSO4, and concentrated under reduced pressure. The crude material was purified by reverse-phase chromatography (eluting with MeCN (5-60%) in water / 0.1% FA (aqueous)). The product emerged at 60% MeCN. Pure fractions were combined and concentrated under reduced pressure to give the product as a white solid. The material was submitted to chiral SFC, which separated the stereoisomers (6, 6') (160 mg, 0.559 mmol, 93% yield for both isomers). After SFC, there were two isomers: chiral resolution 1, designated (6), and chiral resolution 2, designated (6'). The stereochemistry was arbitrarily assigned.

[0531] LCMS Method 1: 99.9% purity at 215 nm [M-Boc] + =291.2m / z

[0532] 1H NMR (400MHz, DMSO-d6) δ ppm 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)

[0533] 19 F NMR (377MHz, DMSO-d6) δ ppm -146.87--146.48(m,1F)

[0534] Step 5. Preparation of (3R)-3-fluoro-3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione dihydrochloride (7): To a flask was added tert-butyl 4-[4-[(3R)-3-fluoro-2,6-dioxo-3-piperidyl]phenyl]piperidine-1-carboxylate (6) (85 mg, 0.22 mmol), 1,4-dioxane (1.5 mL), and 4 M 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 (2x) and MeCN (2x) to give (C-46) (81 mg, 0.2025 mmol, 93% yield), which was used directly in the next step.

[0535] LCMS Method 1: 90.7% purity at 215 nm, [M+H] + =291.2

[0536] Step 5'. Preparation of (3R)-3-fluoro-3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione; dihydrochloride (C-46i): To a solution of tert-butyl 4-[4-[(3S)-3-fluoro-2,6-dioxo-3-piperidyl]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 hour, then concentrated in vacuo and chased with MeCN to give crude product (C-46i) (73.5 mg, 0.2249 mmol, 99.9% yield) as a tan solid, which was used directly in the next step.

[0537] LCMS Method 1: 99.9% purity at 215 nm, [M+H] + =291.2

[0538] CBM intermediates prepared using general procedure CBM-10 are summarized in Table 11. Table 11. CBM intermediates produced via general procedure CBM-10 [Table 103]

[0539] Typical Operation CBM-11 (CBM-11A and CBM-11B) General Operation CBM-11A [ka] where R 7 is as defined in formula (I') or (I).

[0540] 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 equiv.), and sodium tert-butoxide (3.0 equiv.) in toluene (0.089 M) was purged with nitrogen for 5 minutes. Pd2(dba)3 (0.08 equiv.) and Xantphos (0.16 equiv.) were added to the reaction mixture under nitrogen, followed by heating to 110 °C. After the reaction was complete, the RM was slowly poured into a 10.0% aqueous solution of acetic acid. The RM was then extracted with ethyl acetate. The organic layer was separated and washed with water, followed by brine solution. The combined organic layer was then dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel to give compound (3).

[0541] Step 2': To a stirred solution of compound (3) (1.0 equivalent) in 1,4-dioxane (0.16 M) was added 4.0 M HCl in dioxane (5.0 equivalents) at room temperature. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure to give the crude product (CBM-11), which was used in the next step without further purification.

[0542] General Operation CBM-11B [ka] where R 7 is as defined in formula (I') or (I).

[0543] Step 1. Preparation of 2-(4-bromophenyl)propanenitrile (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 × 150 mL). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (6% ethyl acetate / petroleum ether) on silica gel (230-400 mesh) to give 2-(4-bromophenyl)propanenitrile (2) (2.6 g, 12.38 mmol, 48.5% yield) as a pale yellow oil.

[0544] Step 2. Preparation of tert-butyl (R)-4-(4-bromophenyl)-4-cyanopentanoate (4a) and tert-butyl (S)-4-(4-bromophenyl)-4-cyanopentanoate (4b): To a solution of 2-(4-bromophenyl)propanenitrile (2) (3.8 g, 18.09 mmol) in toluene (40 mL) was added tert-butyl acrylate (3') (4.64 g, 36.2 mmol), KCO (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 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography (5% ethyl acetate / petroleum ether) on silica gel (230-400 mesh) to give a racemic mixture of tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate (5.5 g, 16.26 mmol, 90% yield) as a pale yellow liquid. 4.5 g of the material was purified by chiral SFC to give tert-butyl (R)-4-(4-bromophenyl)-4-cyanopentanoate (4a) (1.8 g) and tert-butyl (S)-4-(4-bromophenyl)-4-cyanopentanoate (4b) (1.76 g).

[0545] SFC method: CHIRALPAK AD-H, 250x4.6mm, 5.0μm; flow rate: 3.0mL / min; co-solvent: 10.0%IPA

[0546] Step 3. Preparation of Compound (6): To a stirred solution of tert-butyl (R)-4-(4-bromophenyl)-4-cyanopentanoate (4a) (1.0 equiv.) in 1,4-dioxane (0.3 M) was added heterocycle (5) (1.1 equiv.), followed by CsCO (3.0 equiv.). The resulting reaction mixture was degassed with nitrogen gas for 10 minutes, and then RuPhos-Pd-G (0.02 equiv.) 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 give the crude product. The crude product was purified by column chromatography on silica gel to give product (6).

[0547] Step 4. Preparation of CBM-11: To a stirred solution of (6) (1.0 equiv.) in AcOH (0.2 M) was added HSO (2.0 equiv.). The resulting reaction mixture was heated to 120 °C and stirred. The reaction mixture was concentrated under reduced pressure to give the product (CBM-11).

[0548] Example S16. (R)-3-methyl-3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (C-73) [ka]

[0549] LCMS Method 1. Kinetex XB-C18, 75x3.0 mm, 2.6 μm, Temperature: RT, Flow Rate: 1.0 mL / min, Run Time: 5 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 80% Mobile Phase A and 20% Mobile Phase B, Linear Gradient to 100% Mobile Phase B in 4.0 min. MSD Positive

[0550] LCMS Method 2. Aquity UPLC BEH C18, 50x3.0 mm, 1.7 μm, Temperature: RT, Flow Rate: 1.0 mL / min, Run Time: 5 min, Mobile Phase Conditions: Mobile Phase A: 0.1% TFA in HO, Mobile Phase B: 0.1% TFA in ACN, Gradient: Initially 80% Mobile Phase A and 20% Mobile Phase B, Linear Gradient to 100% Mobile Phase B over 3.0 min. MSD Positive

[0551] Step 1'. Preparation of tert-butyl (R)-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 minutes. Pd2(dba)3 (0.26 g, 0.284 mmol) and Xantphos (0.328 g, 0.567 mmol) were added to RM under nitrogen. The RM was then heated to 110° C. in a sealed vial for 16 hours. After the reaction was complete, the RM was slowly poured into a 10.0% aqueous solution of acetic acid. The RM was then extracted with ethyl acetate (2×25 mL). The organic layer was separated and washed with water followed by a brine solution (10.0 mL). The combined organic layers were then dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (100-200 mesh) (30-50% ethyl acetate in petroleum ether) to give pure tert-butyl (R)-4-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (3′) (225 mg, 13.75% yield) as a pale yellow solid.

[0552] LCMS Method 1: Retention time: 2.181 min, Purity at 220 nm: 83.19%, [M+H] + =388.2

[0553] Step 2'. Preparation of (R)-3-methyl-3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione C-73: To a stirred solution of tert-butyl (R)-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 RT. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure to give the crude product, (R)-3-methyl-3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (C-73) (231 mg) as a pale yellow solid, which was used in the next step without further purification.

[0554] LCMS Method 2: Retention time: 0.456-0.643 min, Purity at 220 nm: 66.24%, [M+H] + =288.2

[0555] Example S17. (R)-3-methyl-3-(4-((S)-2-methylpiperazin-1-yl)phenyl)piperidine-2,6-dione (C-80) [ka]

[0556] LCMS Method 1. Kinetex XB-C18, 50x4.6mm, 5.0μm; Temperature: RT, Flow rate: 1.0mL / min; Run time: 5.5 min; Mobile phase conditions: Mobile phase A: 0.1% TFA in HO, Mobile phase B: 0.1% TFA in ACN, Gradient: Initially 95% Mobile phase A and 5% Mobile phase B, Linear gradient to 95% Mobile phase B over 2.5 min.

[0557] UPLC Method 2. Acquity BEH-C18, 50x2.1 mm, 1.7 μm; Temperature: RT, Flow Rate: 0.7 mL / min; Run Time: 2.5 min; Mobile Phase Conditions: Mobile Phase A: 0.1% TFA in HO, Mobile Phase B: 0.1% TFA in ACN; Gradient: Initially 95% Mobile Phase A and 5% Mobile Phase B, linear gradient to 98% Mobile Phase B over 1.5 min.

[0558] LCMS Method 3. Kinetex XB-C18, 75x3.0 mm, 2.6 μm; Temperature: RT, 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:CHCN (98:02), Mobile Phase B: CHCN: 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.

[0559] Step 1'. Preparation of 2-(4-bromophenyl)propanenitrile (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 organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (6% ethyl acetate / petroleum ether) on silica gel (230-400 mesh) to give 2-(4-bromophenyl)propanenitrile (2') (2.6 g, 12.38 mmol, 48.5% yield) as a pale yellow oil.

[0560] 1 H NMR (400MHz, CDCl3): δ ppm 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)

[0561] Step 2'. Preparation of tert-butyl (R)-4-(4-bromophenyl)-4-cyanopentanoate (4a') and tert-butyl (S)-4-(4-bromophenyl)-4-cyanopentanoate (4b'): To a solution of 2-(4-bromophenyl)propanenitrile (2') (3.8 g, 18.09 mmol) in toluene (40 mL) was added tert-butyl acrylate (3') (4.64 g, 36.2 mmol), KCO (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 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography (5% ethyl acetate / petroleum ether) on silica gel (230-400 mesh) to give a racemic mixture of tert-butyl 4-(4-bromophenyl)-4-cyanopentanoate (5.5 g, 16.26 mmol, 90% yield) as a pale yellow liquid. 4.5 g of the material was purified by chiral SFC to give tert-butyl (R)-4-(4-bromophenyl)-4-cyanopentanoate (4a') (1.8 g) and tert-butyl (S)-4-(4-bromophenyl)-4-cyanopentanoate (4b') (1.76 g).

[0562] SFC method: CHIRALPAK AD-H, 250x4.6mm, 5.0μm; flow rate: 3.0mL / min; co-solvent: 10.0%IPA

[0563] Characterization of tert-butyl (R)-4-(4-bromophenyl)-4-cyanopentanoate (4a'): rt 2.25; ee 97%; 1 H NMR (400MHz, CDCl3): δ ppm 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)

[0564] Characterization of tert-butyl (S)-4-(4-bromophenyl)-4-cyanopentanoate (4b'): rt 1.941; ee 99.9%; 1 H NMR (400MHz, CDCl3): δ ppm 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)

[0565] Step 3'. Preparation of tert-butyl (S)-4-(4-((R)-5-(tert-butoxy)-2-cyano-5-oxopentan-2-yl)phenyl)-3-methylpiperazine-1-carboxylate (6'): To a stirred solution of tert-butyl (R)-4-(4-bromophenyl)-4-cyanopentanoate (4a') (2.0 g, 5.91 mmol, 1.0 equiv.) in 1,4-dioxane (20.0 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (5') (1.303 g, 6.50 mmol, 1.1 equiv.), followed by CsCO (5.78 g, 17.74 mmol, 3.0 equiv.). The reaction mixture was degassed with nitrogen gas for 10 minutes, and then RuPhos-Pd-G4 (0.101 g, 0.118 mmol, 0.02 equiv.) was added. The reaction mixture was heated and stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh) (25% ethyl acetate / petroleum ether) to give tert-butyl (S)-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 gummy liquid.

[0566] LCMS Method 1: Retention time: 2.859 min, Purity at 220 nm: 96.2%, [M+H] + =458.3

[0567] 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 tert-butyl (S)-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 equiv.) in AcOH (20.0 mL) was added HSO (0.466 mL, 8.74 mmol, 2.0 equiv.). The resulting reaction mixture was heated to 120 °C and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to give (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.

[0568] UPLC method 2: Retention time: 0.809 min, [M+H] + =302.2

[0569] 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 equiv.) in acetonitrile (20 mL) at 0°C, DIPEA (5.84 mL, 33.4 mmol, 8.0 equiv.) was added and stirred for 5 minutes. Di-tert-butyl dicarbonate (1.941 mL, 8.36 mmol, 2.0 equiv.) was then added to the reaction mixture, and the resulting reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was then concentrated under reduced pressure to provide the crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh) (40% ethyl acetate / petroleum ether) to give tert-butyl (S)-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.

[0570] LCMS Method 1: Retention time: 2.150 min, Purity at 220 nm: 97.3%, [M+H] + =402.3

[0571] 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 tert-butyl (S)-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 equiv) in DCM (4 mL, 0.903 M) at 0° C. was added 4.0 N HCl in 1,4-dioxane (4.51 mL, 18.06 mmol, 5.0 equiv). The resulting reaction mixture was stirred at room temperature for 2 hours. 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.

[0572] LCMS Method 3: Retention time: 1.565 min, Purity at 220 nm: 95.17%, [M+H] + =302.1

[0573] CBM intermediates prepared using general procedure CBM-11 are summarized in Table 12. Table 12. CBM intermediates produced via general procedure CBM-11 [Table 104] [Table 105]

[0574] General Operation CBM-12 Example S18. (R)-3-Methyl-3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione hydrochloride (C-76) [ka]

[0575] LCMS Method 1. Kinetex XB-C18, 75x3.0mm, 2.6µm, Temperature: RT, Flow Rate: 1.0mL / min, Run Time: 5min, Mobile Phase Conditions: Mobile Phase A: 5.0mM ammonium formate pH 3.3:CH3CN (98:02), Mobile Phase B: CH3CN: 5.0mM ammonium formate pH 3.3 (98:02), Gradient: Initially 80% Mobile Phase A and 20% Mobile Phase B, Linear Gradient to 100% Mobile Phase B over 4.0 min: MSD Positive

[0576] Step 1'. Synthesis of tert-butyl (R)-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·BF4 (3') (314 mg, 0.794 mmol) in a 20 mL vial, anhydrous tert-butyl methyl ether (4.0 mL) was added, and the reaction mixture was stirred at room temperature for 5 minutes. Next, pyridine (0.064 mL, 0.794 mmol) in 1.0 mL of anhydrous tert-butyl methyl ether was added dropwise at room temperature. The resulting solution was stirred at room temperature for 10 minutes. During this time, a white solid precipitated. Another 40.0 mL vial was charged with [Ir(dtbbpy)(ppy)]PF (6.80 mg, 7.44 μmol), NiBr(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.

[0577] 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 reaction was degassed with nitrogen for 15 minutes and sealed with a screw cap. The reaction mixture vial was irradiated with a blue LED for 2 hours with 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 (30% ethyl acetate / petroleum ether) to obtain the compound tert-butyl (R)-4-(4-(3-methyl-2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate (4') (90 mg, 47.0% yield) as an off-white solid.

[0578] LCMS Method 1: Retention time: 2.82 min, Purity at 220 nm: 99.09%, [M+H-Boc] + =287.2

[0579] 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 tert-butyl (R)-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 in dioxane (1.5 mL) at RT. 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.

[0580] LCMS Method 1: Retention time 1.647 min, Purity at 220 nm: 98.14%, [M+H] + =287.2

[0581] CBM intermediates prepared using general procedure CBM-12 are summarized in Table 13. Table 13. CBM intermediates produced via general procedure CBM-12 [Table 106]

[0582] Synthesis of TBM molecules The numbering of intermediate compounds referred to in this section is 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 listed in different sections.

[0583] General Operation TBM-1 [ka] wherein ring B is heteroaryl; R 4 is C3-C6 cycloalkyl; R 0 is as defined in formula (I') or (I).

[0584] Step 1: To a solution of ethyl 4,6-dichloropyridine-3-carboxylate (1) (1 equivalent) in MeCN (0.45 M) was added amine (2) (3 equivalents). The reaction was stirred at room temperature. Once complete by LCMS, the reaction mixture was cooled to room temperature and purified to give (3).

[0585] Step 2 (Option 1): To a reaction vessel was added ethyl 6-chloro-4-(amino)pyridine-3-carboxylate (3) (1 equivalent), heterocyclic aniline (4) (1.2 equivalents), Xantphos (0.05 equivalents), CsCO (1.4 equivalents), and Pd(dba) (0.05 equivalents) in 1,4-dioxane (0.2 M). The solution was sparged with nitrogen for 5 minutes, the tube was sealed, and stirred at 150 °C. Once LCMS showed conversion, the reaction mixture was cooled to room temperature, and the reaction was then purified by reverse-phase column chromatography to give the product (5).

[0586] Step 2 (Option 2): To a reaction vessel was added ethyl 6-chloro-4-(amino)pyridine-3-carboxylate (3) (1 equivalent), heterocyclic aniline (4) (1.5 equivalents), p-toluenesulfonic acid monohydrate (0.3 equivalents), and ethanol (3 mL). The tube was purged with nitrogen, sealed, and stirred at 105 °C. When LCMS showed conversion, EtOH was removed under reduced pressure, and the residue was purified by reverse-phase flash chromatography to give product (5).

[0587] Step 3: In a round-bottom flask, ethyl 4-(amino)-6-[heterocyclic]pyridine-3-carboxylate (5) (1 equivalent), lithium hydroxide monohydrate (5 equivalents), THF (1 mL), MeOH (1 mL), and water (1 mL) were added. The reaction was stirred at 60 °C. When LCMS showed conversion, the volatiles were removed in vacuo, and the residue was dissolved in water (5 mL). A 6 M aqueous solution of HCl was added to reach a pH of 3. The precipitate was filtered and dried under vacuum to give the product (TBM-1).

[0588] Example S19. 6-(1,3-Benzothiazol-6-ylamino)-4-(cyclopentylamino)pyridine-3-carboxylic acid (A-1) [ka]

[0589] 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 cyclopentanamine (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 h. 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.

[0590] LCMS Method 1: 96.5% purity at 215 nm, [M+H] + =269.2

[0591] 1 H NMR (400MHz, DMSO-d6) δ ppm 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), 3.9 7(sxt,J=6.3Hz,1H), 4.29(q,J=7.1Hz,2H), 6.82(s,1H), 8.08(brd,J=7.0Hz,1H), 8.52(s,1H)

[0592] 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 mixed with ethanol (37.2 mL) in a sealed tube. The reaction mixture was stirred at 105 °C for 40 h. The organic solvent was evaporated under reduced pressure, and the crude mixture was then dissolved in a minimum amount of EtOAc and basified with saturated NaHCO (aq.) to crash out the product. The precipitate was filtered and triturated with 1:1 MeCN / H2O, then it was filtered again and rinsed with water to give (5') (4.72 g, 12.34 mmol, 66% yield) as a green solid.

[0593] LCMS Method 1: 98.5% purity at 215 nm, [M+H] + =383.2

[0594] 1 H NMR (400MHz, DMSO-d6) δ ppm 1.29(t,J=7.1Hz,3H), 1.49(brdd,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=7.1H) z,2H), 6.06(s,1H), 7.56(dd,J=8.8, 1.7Hz,1H), 7.78(brd,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)

[0595] Step 3. Preparation of 6-(1,3-benzothiazol-6-ylamino)-4-(cyclopentylamino)pyridine-3-carboxylic acid (A-1): A solution of LiOH·HO (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 h. The organic solvent was evaporated under reduced pressure, and the crude mixture was then 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 give (A-1) (4.03 g, 11.2 mmol, 91% yield) as a tan solid.

[0596] LCMS Method 2: 98.7% purity at 215 nm, [M+H] + =355.1

[0597] 1 H NMR (400MHz, DMSO-d6) δ ppm 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(brd,J=8.2Hz,1H ), 8.05(brd,J=8.8Hz,1H), 8.38(brd,J=3.3Hz,1H), 8.43(brs,2H), 9.27(s,1H), 10.02(brs,1H), 12.95(brs,1H)

[0598] Example S20. 6-(2-chloro-4-cyano-anilino)-4-(isopropylamino)pyridine-3-carboxylic acid (A-53) [ka]

[0599] LCMS Method 1. Column: Luna C18(2) 50x3mm, 3µm; Temperature: 45°C, Flow Rate: 1.5mL / min; Run Time: 2.5 min; Mobile Phase Conditions: Initially 95% HO 0.1% FA / 5% MeCN 0.1% FA, linear gradient over 1.3 min to 95% MeCN 0.1% FA, then hold at 95% MeCN 0.1% FA for 1.2 min; MSD: ESI positive

[0600] LCMS Method 3. Kinetex Polar C18 2.6 μm, 50x3.0 mm; Temperature: 45°C, Flow Rate: 1.2 mL / min, Run Time: 3 min; Mobile Phase Conditions: Initially 95% HO + 0.1% FA / 5% MeCN + 0.1% FA, then a linear gradient over 1.5 min to 95% MeCN, then hold at 95% MeCN for 1.5 min; MSD: Positive

[0601] 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 equiv.) in MeCN (50 mL, 0.45 M) was added propan-2-amine (2″) (5.86 mL, 68.17 mmol, 3 equiv.). The reaction was stirred at 65°C. After an overnight period, LCMS showed complete conversion to compound (3″). The reaction mixture was cooled to room temperature, water was added, and the solution was sonicated for 1 minute and stirred at 0°C for 1 hour. The precipitate was filtered and dried under vacuum to give (3″) (5.35 g, 97% yield) as a light pink solid.

[0602] LCMS Method 1: 99.9% purity at 215 nm [M+H] + =243.2

[0603] 1H 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 (brs, 1H), 8.67 (s, 1H)

[0604] Step 2'. Preparation of ethyl 6-(2-chloro-4-cyano-anilino)-4-(isopropylamino)pyridine-3-carboxylate (5"): To a flame-dried, sealed tube was added ethyl 6-chloro-4-(isopropylamino)pyridine-3-carboxylate (3') (100 mg, 0.41 mmol, 1 equiv.), 4-amino-3-chloro-benzonitrile (4") (75.44 mg, 0.49 mmol, 1.2 equiv.), Xantphos (11.92 mg, 0.02 mmol, 0.05 equiv.), CsCO (187.9 mg, 0.58 mmol, 1.4 equiv.), and Pd(dba) (18.86 mg, 0.02 mmol, 0.05 equiv.) in 1,4-dioxane (2 mL, 0.2 M). The solution was sparged with nitrogen for 5 minutes, the tube was sealed, and stirred at 150 °C. After an overnight period, LCMS showed 77% conversion to compound 5'. The reaction was cooled to room temperature, and the mixture was passed through Celite, washing the pad with EtOAc. The solvent was evaporated under reduced pressure, and the residue was purified by reverse-phase FC purification (50 g C18 column, liquid precipitate (DMSO), 5% MeOH / 0.1% HCOOH over 4 CV, then 5 to 95% MeOH / 0.1% HCOOH over 15 CV, with the product coming off near 70% MeOH). The pure tubes were combined and concentrated to dryness to give 5'' (105 mg, 55% yield) as a red oil.

[0605] LCMS Method 3: 77.5% purity at 215 nm [M+H] + =359.1

[0606] 1H NMR (400MHz, DMSO-d6) δ ppm 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)

[0607] 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 ethyl 6-(2-chloro-4-cyano-anilino)-4-(isopropylamino)pyridine-3-carboxylate (5') (105 mg, 0.29 mmol, 1 equiv.) and LiOH·HO (61.39 mg, 1.46 mmol, 5 equiv.) in HO: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 h, LCMS indicated complete conversion to compound 6'. The organic solvent was evaporated under reduced pressure, and the crude mixture was then purified by reverse-phase FC purification (50 g C18 column, liquid precipitate (DMSO), 5% MeCN / 0.1% HCOOH over 4 CV, then 5 to 95% MeCN / 0.1% HCOOH over 15 CV, with the product coming off near 35% MeCN). The pure tubes were combined and concentrated to dryness to give (A-53) (40 mg, 38% yield) as a white solid.

[0608] LCMS Method 3: 91.5% purity at 215 nm, [M+H] + =331.1

[0609] 1H NMR (400MHz, DMSO-d6) δ ppm 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,1H), 7.94-8.02(m,2H), 8.45(d,J=8.8Hz,1H), 8.50(s,1H), 8.77(s,1H), 12.70(brs,1H)

[0610] Example S21. 4-(Cyclopropylamino)-6-[(2-oxo-3H-1,3-benzothiazol-6-yl)amino]pyridine-3-carboxylic acid (A-59) [ka]

[0611] LCMS Method 1. Column: Luna C18(2) 50x3mm, 3µm; Temperature: 45°C; Flow Rate: 1.5mL / min; Run Time: 2.5min; Mobile Phase Conditions: Initially 95% HO 0.1% FA / 5% MeCN 0.1% FA, linear gradient over 1.3min to 95% MeCN 0.1% FA, then hold at 95% MeCN 0.1% FA for 1.2min; MSD: ESI positive

[0612] 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 equiv.), MeCN (50 mL), and cyclopropanamine (2''') (1.26 mL, 20.45 mmol, 3 equiv.), and the mixture was stirred at 70 °C. After 18 h, LCMS indicated complete conversion. Volatiles were removed in vacuo, and the residue was purified by normal-phase flash chromatography (40 g silica column; elution: 0% EtOAc / heptane over 3 CV, changing from 0% to 20% EtOAc / heptane over 13 CV). The fractions were collected and concentrated to give 3''' (1.5 g, 6.232 mmol, 92% yield) as a white solid.

[0613] LCMS Method 1: 99.9% purity at 215 nm, [M+H] + =241.2

[0614] 1 H NMR (400MHz, CDCl3) δ ppm 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(brs,1H), 8.68(s,1H)

[0615] 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 equiv.), 6-aminobenzo[d]thiazol-2(3H)-one (4") (104 mg, 0.62 mmol, 1.5 equiv.), p-toluenesulfonic acid monohydrate (24 mg, 0.12 mmol, 0.3 equiv.), 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 precipitate (DMSO), elution: 5% MeCN / water over 10 CV, 5% to 40% MeCN / water over 10 CV, 40% to 100% MeCN / water over 10 CV). The product came off 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.

[0616] LCMS Method 1: 99.9% purity at 215 nm, [M+H] + =371.1

[0617] 1H NMR (400MHz, DMSO-d6) δ ppm 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(brs,1H), 8.44(s,1H), 9.47(brs,1H), 11.81(brs,1H)

[0618] 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, ethyl 4-(cyclopropylamino)-6-[(2-oxo-3H-1,3-benzothiazol-6-yl)amino]pyridine-3-carboxylate (5'") (100 mg, 0.27 mmol, 1 equiv), lithium hydroxide monohydrate (32 mg, 1.35 mmol, 5 equiv), THF (1 mL), MeOH (1 mL), and water (1 mL) were added. The reaction was stirred at 60 °C. After 6 h, LCMS indicated complete conversion. The volatiles were removed in vacuo, and the residue was dissolved in water (5 mL). The pH was adjusted to 3 by adding 6 M aqueous HCl. The precipitate was filtered and dried under vacuum to give (A-59) (73 mg, 0.213 mmol, 79% yield) as a brown solid.

[0619] LCMS Method 1: 85.2% purity at 215 nm, [M+H] + =343.1

[0620] 1H NMR (400MHz, DMSO-d6) δ ppm 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(brs,1H), 11.99(s,1H), 13.22(brs,1H)

[0621] TBM intermediates prepared using general procedure TBM-1 are summarized in Table 14. Table 14. TBM intermediates produced via general procedure TBM-1 [Table 107]

[0622] General Operation TBM-2 Example S22. 1-(4-(cyclopentylamino)-5-ethynylpyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (A-9) [ka]

[0623] Step 1'. Preparation of 2-chloro-N-cyclopentyl-5-iodopyridin-4-amine (3'): To a stirred solution of 2-chloro-5-iodo-pyridin-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 reaction was stirred at room temperature for 1 h. The reaction mixture was heated to 80 °C and stirred at this temperature for 30 min. Bromocyclopentane (1.05 mL, 9.82 mmol) (2') was added dropwise at that temperature, and the reaction was stirred at 80 °C overnight. The reaction was quenched with NH4Cl (sat.) solution and extracted with EtOAc. The organic phase was washed with brine (x3). The aqueous phase was extracted with EtOAc (x3). The organic phases were combined, washed with brine, dried (MgSO), and then concentrated to dryness. Purification was achieved by normal-phase flash chromatography on an 80 g SNAP column pre-adsorbed onto SiO and eluted with 1–50% EtOAc / heptane over 10 CV. The desired product appeared as 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 recovered starting material.

[0624] LCMS (3.0 min run, low pH): rt = 1.9670 min; [M+H] + =323.0 m / z

[0625] 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), and NEt (22.47 mL, 161.21 mmol) were dissolved in DMF (37.201 mL) and degassed with N. Next, PdCl(PPh) (565.75 mg, 0.8100 mmol) was added to the mixture, and N was bubbled through it for 10 min. The reaction was stirred at room temperature until complete conversion was observed by LCMS. The crude mixture was diluted with HO and extracted with MTBE (2x), MeTHF (2x), and the organic layers were combined. After washing the organic layer with HCl (1M), NaHCO (sat), and brine, it was dried over MgSO, filtered, and concentrated under reduced pressure for purification. Purification was via normal phase chromatography on an 80 g SNAP column pre-adsorbed onto SiO, eluting with 2–20% EtOAc / heptane over 15 CV, with the product eluting with 8% EA. Fractions from the major peak were combined and concentrated under reduced pressure to give 2.75 g (66% yield) of the desired product (4') as a white solid.

[0626] LCMS (3.5 min run, low pH): pdt rt=2.499 min; [M+H] + =335.4m / z

[0627] 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), Zn(OAc) (1506.36 mg, 8.21 mmol) in 1,4-dioxane (50 mL) was degassed with N. Next, Pd2(dba)3·CHCl3 (1127.7 mg, 1.23 mmol) was added to the mixture, and N2 was bubbled through it for 10 minutes. The rxn mixture was stirred at 105 °C for 10 hours, showing incomplete conversion (approximately 50%). At RT, additional Zn(OAc)2 (753.18 mg, 4.1 mmol), Xantphos (1425.13 mg, 2.46 mmol), and Pd2(dba)3 (751.8 mg, 0.8200 mmol) were added to the mixture, and N2 was bubbled through for 10 minutes. The rxn mixture was stirred at 105 °C for an additional 10 hours, at which point LCMS showed complete conversion. The reaction mixture was passed through Celite, washed with MeTHF, and the solvent was concentrated under reduced pressure before being purified via normal-phase flash chromatography (pre-adsorbed onto SiO2 and eluted on an 80 g SNAP column with 1 to 65% EtOAc / heptane over 15 CV). Fractions from the final peak (approximately 58% EtOAc / heptane) were combined and concentrated under reduced pressure to give 1.5 g (41% yield) of the final product (6').

[0628] LCMS (2.5 min run, low pH): rt = 2.278 min; [M+H] + =443.2m / z

[0629] 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-pyridyl]pyrazolo[3,4-b]pyridine-5-carbonitrile (265 mg, 0.6000 mmol) in THF (5.9869 mL) was added 1 M TBAF in THF (2.39 mL, 2.39 mmol) 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 with EtOAc. The organic layer was washed with NaHCO3 and brine, dried over MgSO4, filtered, concentrated under reduced pressure, and then purified via reverse FC (MeOH / 0.1% FA aqueous, 5% to 100% MeOH over 17 CV, product coming off at 41% MeOH) to give (A-9), M = 80 mg, 95% purity (215 nm).

[0630] LCMS (2.5 min run, low pH): 1.677 min; [M+H] + =329.1m / z

[0631] TBM intermediates prepared using general procedure TBM-2 are summarized in Table 15. Table 15. TBM intermediates produced via general procedure TBM-2 [Table 108]

[0632] General Operation TBM-3 [ka] R 4 is as defined in formula (I') or (I), and X', Y', and Z' are selected from C, N, O, and S.

[0633] Step 1. Preparation of tert-butyl 4,6-dichloropyridine-3-carboxylate (2): To a solution of 4,6-dichloropyridine-3-carboxylic acid (1) (1 equivalent) and DMAP (0.2 equivalents) in THF (0.52 M) at 70° C., tert-butoxycarbonyl tert-butyl carbonate (2 equivalents) in THF (0.52 M) was added dropwise over 2 hours using a dropping funnel. The reaction mixture was then stirred at 70° C. for an additional hour. The THF was evaporated under reduced pressure, and the residue was purified by normal phase flash chromatography to give the product (2).

[0634] 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 equivalent) in MeCN (0.45 M) was added amine (3) (3 equivalents). The reaction was stirred at 70°C. When LCMS showed conversion, the reaction mixture was cooled to room temperature and water (350 mL) was added, forming a white semi-solid. The resulting slurry was stirred at 0°C for 1 hour. The aqueous solution was extracted with 2x DCM and 2x MeTHF. The solvent was evaporated under reduced pressure, and the residue was purified by normal phase flash chromatography to give the product (4).

[0635] In some cases, DIPEA was added to help facilitate the SNAr reaction, especially when amine salt formation was employed.

[0636] Step 3. Preparation of tert-butyl 6-(heterobicyclic)-4-(amino)pyridine-3-carboxylate (6): A round-bottom flask was charged with (4) (1.0 equiv.), (5) (1.1 equiv.), Xantphos (0.3 equiv.), Zn(OAc) (0.6 equiv.), and Pd(dba) CHCl (0.15 equiv.). 1,4-Dioxane (0.2 M) was added, and the mixture was sonicated. Then, nitrogen was sparged through the mixture for 5 minutes. The mixture was stirred at 110 °C for 16 hours. The mixture was passed through Celite and washed with DCM. The solution was dry-packed with silica. Purification by normal-phase flash chromatography (heptane / EtOAc) gave (6).

[0637] 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 hours. The solvent was removed under vacuum. The remaining TFA was co-evaporated with toluene (2×) and then with MeCN. The residue was dried under high vacuum to give a yellow solid. MTBE was added to the solid, and the mixture was sonicated and stirred at room temperature for 16 hours. The suspension was filtered through a Buchner funnel and rinsed with MTBE to give (TBM-3).

[0638] Similar acidic conditions can be used in ester hydrolysis.

[0639] Example S23. 6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopentylamino)pyridine-3-carboxylic acid (A-7) [ka]

[0640] LCMS Method 1. Column: Luna C18(2) 50x3mm, 3µm; Temperature: 45°C; Flow rate: 1.5mL / min; Run time: 2.5 min; Mobile phase conditions: Initially 95% HO 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.3 min, then hold at 95% MeCN 0.1% FA for 1.2 min; MSD: ESI positive

[0641] 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 equiv.) and DMAP (2.5 g, 20.8 mmol, 0.2 equiv.) in THF (150 mL, 0.52 M) at 70 °C, tert-butoxycarbonyl tert-butyl carbonate (45.4 g, 208.3 mmol, 2 equiv.) in THF (50 mL, 0.52 M) was added dropwise over 2 h 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 (380 g column, solid precipitate, eluting with 0–15% heptane / EtOAc over 15 CV). The fractions were combined and concentrated to give (2') (22 g, 85% yield) as a light yellow oil.

[0642] LCMS Method 1: 99.9% purity at 215 nm [M+H] + =248.2

[0643] 1 H NMR (400 MHz, chloroform-d) δ ppm 1.63 (s, 9H), 7.45 (s, 1H), 8.77 (s, 1H)

[0644] 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 cyclopentanamine (3') (2.41 mL, 24.38 mmol, 3 eq.). The reaction was stirred at 70 °C. After 2.5 h, LCMS indicated complete conversion to compound (4'). The reaction mixture was cooled to room temperature, and water (350 mL) was added, resulting in the formation of a white semi-solid. The resulting slurry was stirred at 0 °C for 1 h. No precipitate 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 precipitate, eluting with 0% to 30% EtOAc / heptane over 15 CV). The fractions were combined and concentrated to give 4' (2.4 g, 99% yield) as a colorless oil.

[0645] LCMS Method 1: 99.9% purity at 215 nm [M+H] + =297.2

[0646] 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 (brd, J = 5.1 Hz, 1H), 8.50 (s, 1H)

[0647] Step 3'. Preparation of tert-butyl 6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopentylamino)pyridine-3-carboxylate (6'): In a flame-dried sealed tube, add tert-butyl 6-Chloro-4-(cyclopentylamino)pyridine-3-carboxylate 4' (1.0 g, 3.37 mmol, 1 equiv.), 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 5' (631.3 mg, 4.38 mmol, 1.3 equiv.), Xantphos (623.8 mg, 1.08 mmol, 0.3 equiv.), Zn(OAc) (197.8 mg, 1.08 mmol, 0.3 equiv.), and Pd(dba) CHCl (523.1 mg, 0.51 mmol, 0.15 equiv.) in 1,4-dioxane (13.5 mL, 0.25 M) were added. The solution was sparged with nitrogen for 35 minutes, sealed, and stirred at 110 °C. After overnight, LCMS showed complete conversion to compound 6'. The mixture was passed through Celite and the pad was washed with DCM. The solvent was evaporated under reduced pressure, and the residue was purified by normal-phase flash chromat...

Claims

1. Equation (I'): 【Chemistry 1】 [In the formula: Ring A is a phenyl, a monocyclic 5- to 6-membered heteroaryl, or a condensed bicyclic 9- to 10-membered heteroaryl or heterocyclil, where the heteroaryl and heterocyclil contain 1 to 4 heteroatoms independently selected from N, O, and S, each containing 1 to 3 R ０ It may be substituted by the element; Each R ０ is, independently, halo, -CN, -NH ２ , -NH(C １ -C ６ alkyl), C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, -(6 to 10-member bridged heterocyclylene)-and C １ -C ６ alkoxy, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, or two R ０ groups together form an oxo group; L １ is -NH- or a bond; L ２ is -NHC(O)-, -C(O)NH-, -SO ２ NH-, -NHSO ２ - or - (C １ -C ６ Alkilen) ｚ (A five-membered heteroarylene) - wherein the heteroarylene contains one to three heteroatoms selected from N, O, and S; L ３ is, -NR ９ (C １ -C ６ Alkylene) NR ９ -, -NR ９ C(O)(C １ -C ６ Alkilen) 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) (C １ -C ６ Alkilen) ｚ -, -NR ９ (C １ -C ６ Alkilen) ｚ (4- to 7-membered heterocyclylene) -, -NR ９ C(O)(phenylene)NR ９ -, -(C １ -C ６ Alkilen) ｚ (4- to 7-membered heterocyclylene) (C １ -C ６ Alkilen) ｚ -, -O(C) １ -C ６ Alkilen) ｚ (4- to 7-membered heterocyclylene) (C １ -C ６ Alkilen) ｚ -, - (6 to 10-membered cross-linked heterocyclylene) (C １ -C ６ Alkilen) ｚ -, - (7 to 10-membered condensed bicyclic heterocyclylene) (C １ -C ６ Alkilen) ｚ - or - (O) ｚ (6 to 10 member spiroheterocyclylene) (C １ -C ６ Alkilen) ｚ - wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R ７ Substitution with the base is also acceptable; L ４ teeth 【Chemistry 2】 Phenylene, -N(H)(phenylene), 5- to 6-membered heteroarylene, -N(H)(5- to 6-membered heteroarylene)-, 8- to 10-membered condensed bicyclic heteroarylene, or 5- to 6-membered heterocyclene, wherein the phenylene, heteroarylene, or heterocyclene contains 1 to 4 R １０ They may be substituted with groups, where the heteroarylene and heterocyclylene contain one to three heteroatoms selected from N, S, and O; R １ａ and R １ｂ Each H is either a separate H or together they form an oxo group; R ２ and R ３ H and C are independent of each other. １ -C ６ Alkyl, halo, or R ２ and R ３ They come together to form an oxo group; Or R ３ and R １１ They are together C ３ -C ６ Forming a cycloalkylene group; Y is NH, O, or a bond; R ４ is C ３ -C ６ -cycloalkyl, C １ -C ６ -alkylene-(C ３ -C ６ -cycloalkyl), a 4- to 6-membered heterocyclyl, C １ -C ６ -alkylene-(a 4- to 6-membered heterocyclyl), a 5- to 6-membered heteroaryl, C １ -C ６ -alkylene-(a 5- to 6-membered heteroaryl), C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -alkyl-OH, or C １ -C ６ -alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from N and O, and wherein the cycloalkyl, heterocyclyl, or heteroaryl may be substituted with 1 to 5 R ８ groups; W is O, -NR ５ -, or a joint; R ５ is H or C １ -C ６ It is alkyl; Each R ６ Independently, C １ -C ６ It is either an alkyl, halo, or -OH group, or two R groups. ６ The bases are joined together, forming a bridge C １ -C ３ Forms an alkylene group; Each R ７ Independently, C １ -C ６ Alkyl, Halo, C １ -C ６ It is either a haloalkyl group, an -OH group, or two R groups. ７ The groups come together to form an oxo group; Each R ８ It is independently, -SO ２ (C １ -C ６ Alkyl), -C(O)(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C １ -C ６ It is a haloalkyl, halo, -CN, or -OH; Each R ９ H or C １ -C ６ It is alkyl; Each R １０ Independently, C １ -C ６ Alkoxy, C １ -C ６ It is either an alkyl, halo, or -OH group, or two R groups. １０ The groups come together to form an oxo group; R １１ and R １２ These are H, Halo, and C, each independent of the others. ３ -C ６ Cycloalkyl, -OH, -NH(C １ -C ６ Alkyl), C １ -C ６ Haloalkyl, or C １ -C ６ Is it alkyl? Or R １１ and R ３ Together, C ３ -C ６ Forming a cycloalkylene group; x is either 0 or 1; y is 0, 1, 2, 3, 4, or 5; Each z is independently either 0 or 1; X is N or CR １３ And; R １３ is H, halo, -OH, or C １ -C ６ It is alkyl; Z １ is CH or N; Z ２ is CH or N: However, Z １ and Z ２ [It is not possible for both to be N] The compound indicated by, or a pharmaceutically acceptable salt thereof.

2. The compound is given by formula (I): 【Transformation 3】 [In the formula: Ring A is a phenyl, a monocyclic 5- to 6-membered heteroaryl, or a condensed bicyclic 9- to 10-membered heteroaryl or heterocyclil, wherein the heteroaryl and heterocyclil contain 1 to 4 heteroatoms independently selected from N, O, and S, each of which contains 1 to 3 R ０ It may be substituted by the element; Each R ０ These are independently: Halo, -CN, -NH ２ ,-NH(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl and C １ -C ６ Selected from alkoxys, or two R ０ The groups combine to form an oxo group; L １ is -NH- or a bond; L ２ is -NHC(O)-, -C(O)NH-, -SO ２ NH-, -NHSO ２ - or a five-membered heteroarylene containing one to three heteroatoms selected from N, O, and S; L ３ is, -NR ９ (C １ -C ６ Alkylene) NR ９ -, -NR ９ C(O)(C １ -C ６ Alkilen) 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) (C １ -C ６ Alkilen) ｚ -, -NR ９ (C １ -C ６ Alkilen) ｚ (4- to 7-membered heterocyclylene) -, -NR ９ C(O)(phenylene)NR ９ -, -(C １ -C ６ Alkilen) ｚ (4- to 7-membered heterocyclylene) -, -O(C １ -C ６ Alkilen) ｚ (4- to 7-membered heterocyclylene) -, - (6- to 10-membered cross-linked heterocyclylene) (C １ -C ６ Alkilen) ｚ -, - (9 or 10-membered condensed bicyclic heterocyclylene) (C １ -C ６ Alkilen) ｚ - or - (O) ｚ (6 to 10 member spiroheterocyclylene) (C １ -C ６ Alkilen) ｚ - wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 to 5 R ７ Substitution with the base is also acceptable; L ４ teeth 【Chemistry 4】 Phenylene, a 5- to 6-membered heteroarylene, or a 5- to 6-membered heterocycline, wherein the phenylene, heteroarylene, or heterocycline has 1 to 4 R １０ They may be substituted with groups, where the heteroarylene and heterocyclylene contain 1 to 3 heteroatoms selected from N and O; R １ａ and R １ｂ Each H is either a separate H or together they form an oxo group; R ２ and R ３ H and C are independent of each other. １ -C ６ Alkyl, halo, or R ２ and R ３ They come together to form an oxo group; Or R ３ and R １１ They are together C ３ -C ６ Forming a cycloalkylene group; Y is either NH or O; R ４ C ３ -C ６ Cycloalkyl, C １ -C ６ Alkylene-(C) ３ -C ６ Cycloalkyl, 4- to 6-membered heterocyclyl, C １ -C ６ Alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C １ -C ６ Alkylene (5 or 6-membered heteroaryl), C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-OH, or C １ -C ６ Alkyl-CN, wherein the heterocyclyl and heteroaryl contain 1 to 3 heteroatoms selected from N and O, and the cycloalkyl, heterocyclyl, or heteroaryl contains 1 to 5 R ８ Substitution with the base is also acceptable; W is O, -NR ５ -, or a joint; R ５ is H or C １ -C ６ It is alkyl; Each R ６ Independently, C １ -C ６ It is either an alkyl, halo, or -OH group, or two R groups. ６ The bases are joined together, forming a bridge C １ -C ３ Forms an alkylene group; Each R ７ Independently, C １ -C ６ Alkyl, Halo, C １ -C ６ It is either a haloalkyl group, an -OH group, or two R groups. ７ The groups come together to form an oxo group; Each R ８ It is independently, -SO ２ (C １ -C ６ Alkyl), -C(O)(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C １ -C ６ It is a haloalkyl, halo, -CN, or -OH; Each R ９ H or C １ -C ６ It is alkyl; Each R １０ Independently, C １ -C ６ Alkoxy, C １ -C ６ It is either an alkyl, halo, or -OH group, or two R groups. １０ The groups come together to form an oxo group; R １１ and R １２ These are H, Halo, and C, each independent of the others. ３ -C ６ Cycloalkyl, -OH, -NH(C １ -C ６ Alkyl), C １ -C ６ Haloalkyl, or C １ -C ６ Is it alkyl? Or R １１ and R ３ Together, C ３ -C ６ Forming a cycloalkylene group; x is either 0 or 1; y is 0, 1, 2, 3, 4, or 5; Each z is independently either 0 or 1; X is N or CR １３ And; R １３ is H, halo, or C １ -C ６ It is alkyl; Z １ is CH or N; Z ２ is CH or N: However, Z １ and Z ２ [It is not possible for both to be N] The compound according to claim 1, as shown in [the provided text], or a pharmaceutically acceptable salt thereof.

3. Ring A is: (i) 1 to 3 R ０ Phenyls that may be substituted with a group; Each R ０ However, they became independent: Hallo, -CN, -NH ２ ,-NH(C １ -C ３ Alkyl), C １ -C ３ Alkyl, C ３ -C ６ Cycloalkyl and C １ -C ３ Selected from alkoxy; (ii) Containing one to two heteroatoms independently selected from N and O, and one to three R ０ A monocyclic six-membered heteroaryl which may be substituted with a group; Each R ０ However, they became independent: Hallo, -CN, -NH ２ ,-NH(C １ -C ３ Alkyl), C １ -C ３ Alkyl, C ３ -C ６ Cycloalkyl and C １ -C ３ Selected from alkoxy; or (iii) Containing 2 to 4 heteroatoms independently selected from N, O, and S, and 1 to 3 R ０ A condensed bicyclic nine-membered heteroaryl or heterocyclyl, which may be optionally substituted with a group; Each R ０ However, they became independent: Hallo, -CN, -NH ２ ,-NH(C １ -C ３ Alkyl), C １ -C ３ Alkyl, C ３ -C ６ Cycloalkyl, -(6- to 8-membered crosslinked heterocyclylene)- and C １ -C ３ Selected from alkoxys, where the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, or 2 R atoms. ０ The groups combine to form an oxo group. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. Ring A 【Transformation 5】 The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

5. L ２ However, -NHC(O)- or -(C １ -C ３ Alkilen) ｚ (A five-membered heteroarylene) - wherein the heteroarylene contains one to three heteroatoms selected from N and O. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. L ２ が-NHC(O)-、 【Transformation 6】 The compound according to claim 5, or a pharmaceutically acceptable salt thereof.

7. L ４ but 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. 【Request Item 8】 【Transformation 8】 but 【Chemistry 9】 And; W is O, -NR ５ -, or a joint; R ５ is H or C １ -C ３ It is alkyl The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. X is N The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. X is CR １３ And; R １３ However, H, halo, -OH, or C １ -C ３ It is alkyl The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. Y is NH; R ４ However, C ３ -C ６ Cycloalkyl, C １ -C ３ Alkylene-(C) ３ -C ６ Cycloalkyl, 4- to 6-membered heterocyclyl, C １ -C ３ Alkylene-(4- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, C １ -C ３ Alkylene (5 or 6-membered heteroaryl), C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-OH, or C １ -C ６ Alkyl-CN, where the heterocyclyl and heteroaryl contain one or two heteroatoms selected from N and O, where the cycloalkyl, heterocyclyl, or heteroaryl contains one to two R ８ Substitution with the base is also acceptable; Each R ８ However, independently, -SO ２ (C １ -C ３ Alkyl), -C(O)(C １ -C ３ Alkyl), C １ -C ３ Alkyl, C １ -C ３ It is a haloalkyl, halo, -CN, or -OH. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. R ４ However, methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CH ２ CH (CH ３ ) ２ ien-CH ２ CF ３ ien-CH ２ CH ２ F, -CH ２ CF ２ CH ３ , -CH(CH ３ ) CF ３ ien-CH ２ CH ２ CF ３ , -CH(CH ３ )CH ２ H, -CH ２ C (CH ３ ) ２ OH, -CH ２ CN, -CH(CH ３ )CN, -C(CH ３ ) ２ CN, -CH(CH ２ CH ３ ) CN, -CH ２ CH (CH ３ ) CN, 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. L ３ However, -NR ９ (C １ -C ３ Alkylene) NR ９ -, -NR ９ C(O)(C １ -C ３ Alkilen) 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) (C １ -C ３ Alkilen) ｚ -, -NR ９ (C １ -C ３ Alkilen) ｚ (4- to 7-membered heterocyclylene) -, -NR ９ C(O)(phenylene)NR ９ -, -(C １ -C ３ Alkilen) ｚ (4- to 7-membered heterocyclylene) (C １ -C ３ Alkilen) ｚ -, -O(C) １ -C ３ Alkilen) ｚ (4- to 7-membered heterocyclylene) (C １ -C ３ Alkilen) ｚ -, - (6 to 10-membered cross-linked heterocyclylene) (C １ -C ３ Alkilen) ｚ -, - (7 to 10-membered condensed bicyclic heterocyclylene) (C １ -C ６ Alkilen) ｚ - or - (O) ｚ (6 to 10 member spiroheterocyclylene) (C １ -C ３ Alkilen) ｚ - wherein the heterocyclylene contains 1 to 3 heteroatoms selected from N and O, and 1 or 2 R ７ It may be substituted by the element; Each z is independently either 0 or 1; Each R ９ However, independently, H or C １ -C ３ It is alkyl; Each R ７ However, independently, C １ -C ３ Alkyl, Halo, C １ -C ３ It is either a haloalkyl group, an -OH group, or two R groups. ７ The groups come together to form an oxo group; R １１ and R １２ However, each independently, H or -CH ３ That is The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. L ３ but 【Chemistry 11】 The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

15. The compound is of formula (Ia) or (Ia'): 【Chemistry 12】 【Chemistry 13】 [In the formula: Ring A is a condensed bicyclic 9- to 10-membered heteroaryl (containing 2 to 4 heteroatoms independently selected from N, O, and S, and 1 to 3 R ０ (It may be substituted with the base; R ４ C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-OH, or C １ -C ６ Alkyl-CN; Z ３ and Z ４ Independently, is N or CH: however, Z ３ and Z ４ At least one of them is N. The compound according to claim 1, as shown in [the formula], or a pharmaceutically acceptable salt thereof.

16. The compound is of formula (If) or (If'): 【Chemistry 14】 【Chemistry 15】 The compound according to claim 15, as shown in [the provided symbol], or a pharmaceutically acceptable salt thereof.

17. The following: 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Transformation 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 【Transformation 73】 【Chemistry 74】 【Chemistry 75】 【Transformation 76】 【Chemical Formula 77】 【Transformation 78】 【Transformation 79】 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 【Chemistry 83】 【Chemical 84】 【Chemical 85】 【Chemical 86】 【Chemistry 87】 【Chemical 88】 【Chemical 89】 【Chemistry 90】 【Chemistry 91】 【Chemistry 92】 【Chemistry 93】 【Chemical 94】 【Chemical 95】 【Chemistry 96】 【Chemistry 97】 【Chem.98】 【Chem.99】 A more selected compound, or a pharmaceutically acceptable salt thereof.

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

19. The pharmaceutical composition according to claim 18 for regulating interleukin-1 (IL1) receptor-related kinase 4 (IRAK4) activity.

20. A pharmaceutical composition according to claim 18 for treating an inflammatory or autoimmune disease, wherein the inflammatory or autoimmune disease may be atopic dermatitis, asthma, lupus, rheumatoid arthritis, familial Mediterranean fever, psoriasis, generalized pustular psoriasis, cryoprin-associated periodic syndrome, hidradenitis pustularis, Beckett syndrome, or familial cold autoinflammatory syndrome.

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