PROTACS of MALT1

Abstract

The present invention relates to compounds of formula (I), which are characterized as PROTACs of MALT1. The PROTACs described herein may be useful in the treatment of diseases or disorders associated with MALT1, such as lymphoma. In particular, the present invention relates to compounds and pharmaceutical compositions capable of degrading MALT1, methods of treating diseases or disorders associated with MALT1, and methods of synthesizing these compounds. JPEG2025507758000627.jpg63170

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 314,205, entitled "PROTAC OF MALT1," filed February 25, 2022, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] The present invention relates to the use of targeted proteolytic chimera (PROTAC) technology to treat diseases or disorders associated with mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), in particular to compounds and methods that degrade MALT1. [Background technology]

[0003] Targeted proteolytic chimera (PROTAC) technology is a recently developed, effective endogenous protein degradation tool that can ubiquitinate target proteins via the ubiquitin-proteasome system (UPS) to achieve antitumor effects. Numerous literature studies on PROTAC technology have provided insights into the feasibility of PROTAC technology for target protein degradation. Furthermore, the first oral PROTACs (ARV-110 and ARV-471) have shown promising results in clinical trials for prostate and breast cancer treatment, stimulating greater interest in PROTAC research (Min Si Qi et al., Front. Pharmacol., 07 May 2021, https: / / doi.org / 10.3389 / fphar.2021.692574).

[0004] As a traditional treatment method, chemotherapy plays an irreplaceable role in the cancer treatment process. The main drawback of traditional anticancer drugs is that most of them have low selectivity and are prone to developing drug resistance (Mangal et al., Acta Pharmacol. Sin. 2017, 38, 782-797. doi:10.1038 / aps.2017.34; Dong et al., Drug Resist. Updates. 2020, 49, 100681. doi:10.1016 / j.drup.2020.100681; Yuan et al., Mol. Cancer. 2020, 19, 96. doi:10.1186 / s12943-020-01219-0). As a result, targeted cancer therapy has attracted increasing attention. Based on this, the discovery of new targets and small molecule inhibitors (SMIs) represents a powerful therapeutic strategy. In particular, the development of small molecule kinase inhibitors has become one of the most widely pursued areas in drug discovery and has achieved significant success in cancer treatment (Wu et al., Trends Pharmacol. Sci. 2015, 36, 422-439. doi:10.1016 / j.tips.2015.04.005). However, even after success, therapeutic strategies also face the same drug resistance problem as chemotherapy (Xu et al., Front. Cel Dev Biol 2020, 8, 621428. doi:10.3389 / fcell.2020.621428). Therefore, drug resistance is a major limitation of cancer treatment and urgently needs to be resolved.

[0005] In recent years, novel strategies for targeting disease-related proteins for degradation have attracted considerable attention. Targeted proteolytic chimeras (PROTACs), also known as bivalent chemical proteolytic agents, are heterobifunctional molecules that degrade specific endogenous proteins via the E3 ubiquitin ligase pathway (Potjewyd et al., Cel Chem. Biol. 2020, 27, 47-56. doi:10.1016 / j.chembiol.2019.11.006). They structurally link a protein of interest (POI)-binding ligand to an E3 ubiquitin ligase (E3) ligand via an appropriate linker (Vollmer et al., J. Med. Chem. 2020, 63, 157-162. doi:10.1021 / acs.jmedchem.9b00810). The potential advantages of PROTAC technology can compensate for the shortcomings of traditional drug therapies, facilitating their rapid development (Sun and Rao, Biochemistry 2020, 59, 240-249. doi:10.1021 / acs.biochem.9b00848).

[0006] Bifunctional PROTAC molecules consist of a ligand (mostly a small molecule inhibitor) of a protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit the E3 for POI ubiquitination, which then undergoes proteasome-mediated degradation. PROTACs complement nucleic acid-based gene knockdown / out technologies for targeted protein reduction and can mimic pharmacological protein inhibition. To date, PROTACs targeting approximately 50 proteins, many of which are clinically validated drug targets, have been successfully developed in several clinical trials for cancer treatment.

[0007] PROTAC molecules consist of a ligand for the POI (primarily a small molecule inhibitor) and a ligand for an E3 ubiquitin ligase (E3), which are covalently interconnected with a linker, typically 5–15 carbon or other atoms. Mechanistically, upon binding to the POI, the PROTAC can recruit the E3 for proximity-induced ubiquitination of the POI, which is then subjected to degradation by the endogenous 26S proteasome. A recent X-ray structure of a POI-PROTAC-E3 ternary complex provides strong evidence supporting this mechanism (Gadd, M. et al., Nat Chem Biol. 2017, 13(5):514).

[0008] PROTAC technology offers numerous potential advantages (Xin Li et al., J Hematol Oncol 2020, 13, 50. https: / / doi.org / 10.1186 / s13045-020-00885-3). First, despite their relatively large molecular weight, PROTACs are more drug-like, in contrast to RNA / DNA-based protein reductants. By selecting drug-like ligands for the POI and E3 and subsequently optimizing their medicinal chemistry, PROTACs can possess the favorable ADME (absorption, distribution, metabolism, and excretion) properties required to become clinically useful drugs. Second, PROTACs can be reused after a single proteolysis, allowing for substoichiometric elimination of the POI. Therefore, the DC50 of a PROTAC can potentially be significantly lower than its binding affinity (or inhibitory IC50) for the POI. For example, as little as 10 pM of PROTAC can efficiently induce BRD4 degradation (Qin C. et al., J Med Chem. 2018, 61(15), 6685-704). This feature offers a potentially significant advantage over pharmacological protein inhibition. Third, because PROTACs only require transient binding to the POI, they offer an opportunity to overcome mutation-induced drug resistance. For example, the ibrutinib-containing PROTAC MT-802 induced the degradation of C481S mutant BTK (which is resistant to ibrutinib) as effectively as the wild-type protein and potently inhibited the growth of ibrutinib-resistant leukemia cells (Buhimschi AD et al., Biochemistry 2018, 57(26), 3564-75). Fourth, PROTACs only require a ligand that binds to the POI and may not necessarily affect the function of the POI. Thus, PROTACs can potentially target any protein, including those that are considered undruggable. Furthermore, PROTAC-induced degradation also depends on lysine residues on the POI surface, which represents an additional selectivity requirement.This may result in higher selectivity and has been successfully used to develop selective PROTACs targeting isoforms of protein families such as CDK9 (Robb CM et al., Chem Commun. 2017, 53(54), 7577-80), BRD4 (Zengerle M. et al., ACS Chem Biol. 2015, 10(8), 1770-7), MALT1 (Fontan L. et al., Blood 2019, 134(Supplement 1), 2073-4) and HDAC6 (An Z. et al., Protein&cell 2019, 10(8), 606-9), starting from pan-inhibitors of protein families.

[0009] Mucosal-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a protein encoded by the MALT1 gene in humans. It is a human paracaspase. Genetic deletion of the paracaspase gene in mice and biochemical studies have shown that paracaspase is a key protein for T and B lymphocyte activation. It plays a key role in the activation of the transcription factor NF-κB, interleukin-2 (IL-2) production, and T and B lymphocyte proliferation. Furthermore, the role of paracaspase has been shown in the innate immune response mediated by the zymosan receptor Dectin-1 in macrophages and dendritic cells and in response to stimulation of specific G protein-coupled receptors. Activation of MALT1 downstream NF-κB signaling and protease activity occurs when BCL10 / MALT1 is recruited to activated CARD-CC family proteins (CAR9, -10, -11, or -14) in the so-called CBM (CARD-CC / BCL10 / MALT1) signaling complex. Paracaspases have been shown to have proteolytic activity through their caspase-like domains in T lymphocytes. Targeting paracaspase proteolytic activity may enable the development of novel drugs that may be useful in the treatment of certain lymphomas or autoimmune disorders.

[0010] In summary, approximately 50 protein-targeting PROTACs have been successfully developed to date, two of which are currently in clinical trials for treating therapy-resistant prostate cancer and breast cancer. Clinical outcomes have not been disclosed. Given the relatively small number of POIs and clinical candidates, it remains to be seen whether these PROTACs can become clinically useful anticancer drugs. However, PROTAC technology has not been fully explored and developed. It has great potential in terms of cancer treatment. There are over 600 E3 ubiquitin ligases in humans, many of which can be used to design PROTACs (Ottis P. et al., ACS Chem Biol. 2017, 12(10), 2570-8). Success in this area, along with a greater understanding of the function and tissue-specific expression of these E3s, could greatly expand the feasibility, utility, and selectivity of PROTAC technology. Summary of the Invention

[0011] A first aspect of the present invention is a compound of formula (A): [ka] and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof, During the ceremony, each X is independently selected from N and CH; Y is [ka] selected from -NR5C(O)NR5- and -NR5C(O)-; Ring A is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; Ring B is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; Ring C is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; M is -CH2-, -C(O)-, -C(O)NRL -, -C(O)O-, -NR L -, -NR L C(O)-, -NR L C(O)NR L -, -NR L C(O)O-, -NR L SO2-, -O-, -OC(O)-, -OC(O)NR L -, -OC(O)O-, -S(O)2NR L -, -S-, and -S(O)2-; L1 and L2 are bonds, C1 to C 12 Alkanediyl, C2-C 12 Alkenediyl, C2-C 12 Alkynediyl, C3-C8 cycloalkanediyl, C3-C8 cycloalkanediyl-(CH2) p -, C1~C 12 Alkoxylenyl, -((CH2) 1~6 O) o -(CH2) p -, -((CH2) 1~6 O) o -(CH2) p -NH-, -((CH2) 1~6 O) o -(CH2) p -NH-C(O)-, and -((CH2) 1~6 O) o -(CH2) p -C(O)-NH-; or M and L2 are both a bond, or L1-M-L2 is a bond, L3 and L4 are bonds, C1 to C 12 Alkanediyl, C2-C 12 Alkenediyl, C2-C 12 Alkynediyl, C1-C 12 Alkoxylenyl, -((CH2) 1~6 O) o -(CH2) p -, -C(O)-, -C(O)NR L -, -C(O)O-, -NR L -, -NR L C(O)-, -NRL C(O)NR L -, -NR L C(O)O-, -NR L SO2-, -O-, -OC(O)-, -OC(O)NR L -, -OC(O)O-, -S(O)2NR L -, -S-, and -S(O)-; R1 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CH2-OC(O)C1-C6 alkyl, -CH2-OP(O)(OC1-C6 alkyl)2, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 11 and optionally substituted with Each of R2, R3, and R9 is hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 or optionally replaced by or two R3 are =O, Each of R4, R6, R7, and R 10 are hydrogen, halogens, -OH, -CN, -NO2, -NR 12 R 13, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 and optionally substituted with each R5 is independently selected from hydrogen and C1-C6 alkyl; R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is selected from one or more R 11 and optionally substituted with Each R 11 are halogens, -OH, -CN, -NO2, -NR 12 R 13、 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl; Each R L are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R 12 and R 13 are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl; g is 0, 1, and 2, m and n are integers independently selected from 0, 1, 2, and 3; o is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t is an integer selected from 0 and 1; u is an integer selected from 0, 1 and 2; w is an integer selected from 0, 1 and 2; provided that when t is 0, L4 is a bond; However, at least one of L3 and L4 is not a bond, Cycloalkyl is a saturated or partially unsaturated C3-C 10 Monocyclic, C5~C 18 Bicyclic (fused, bridged or spiro) or C6-C 18 a tricyclic (fused, bridged or spiro) ring system; Aryl is a cyclic, aromatic hydrocarbon ring system containing 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic ring system (fused, bridged, or spirocyclic) containing 1-7 heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic ring system containing 5 to 24 ring atoms, in which 1 to 7 ring atoms are heteroatoms selected from N, O, S, P, or B, and the remaining ring atoms are C.

[0012] Another aspect of the present invention is a compound of formula (I): [ka] and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs or tautomers thereof, During the ceremony, each X is independently selected from N and CH; Y is [ka] -NR5C(O)NR5-, and -NR5C(O)-; Ring A is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; Ring B is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; M is -CH2-, -C(O)-, -C(O)NR L -, -C(O)O-, -NR L -, -NR L C(O)-, -NR L C(O)NR L -, -NR L C(O)O-, -NR L SO2-, -O-, -OC(O)-, -OC(O)NR L -, -OC(O)O-, -S(O)2NR L -, -S-, and -S(O)2-; L1 and L2 are bonds, C1 to C 12 Alkanediyl, C2-C 12 Alkenediyl, C2-C 12 Alkynediyl, C3-C8 cycloalkanediyl, C3-C8 cycloalkanediyl-(CH2) p -, C1~C 12 Alkoxylenyl, and -((CH2) 1~6 O) o -(CH2) p -, -((CH2) 1~6 O) o -(CH2) p -NH-, -((CH2) 1~6 O) o -(CH2) p -NH-C(O)-, and -((CH2) 1~6 O) o -(CH2) p -C(O)-NH-; or M and L2 are both a bond, or L1-M-L2 is a bond, L3 and L4 are bonds, C1 to C 12 Alkylenyl, C2-C 12 Alkenylenyl, C2-C 12 Alkynylenyl, C1-C 12 Alkoxylenyl, -((CH2) 1~6 O) o -(CH2) p-, -C(O)-, -C(O)NR L -, -C(O)O-, -NR L -, -NR L C(O)-, -NR L C(O)NR L -, -NR L C(O)O-, -NR L SO2-, -O-, -OC(O)-, -OC(O)NR L -, -OC(O)O-, -S(O)2NR L -, -S-, and -S(O)-; R1 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CH2-OC(O)C1-C6 alkyl, -CH2-OP(O)(OC1-C6 alkyl)2, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 11 and optionally substituted with Each of R2, R3, and R9 is hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 optionally substituted with, or Two R3 form =O, Each of R4, R6, R7, and R 10 are hydrogen, halogens, -OH, -CN, -NO2, -NR 12 R 13, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 and optionally substituted with each R5 is independently selected from hydrogen and C1-C6 alkyl; R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is selected from one or more R 11 and optionally substituted with Each R 11 are halogens, -OH, -CN, -NO2, -NR 12 R 13、 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl; Each R L are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R 12 and R 13 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl; m and n are integers independently selected from 0, 1, 2, and 3; o is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t is an integer selected from 0 and 1; u is an integer selected from 0, 1 and 2; w is an integer selected from 0, 1 and 2; provided that when t is 0, L4 is a bond; However, at least one of L3 and L4 is not a bond, Cycloalkyl is a saturated or partially unsaturated C3-C 10 Monocyclic, C5~C 18 Bicyclic (fused, bridged or spiro) or C6-C 18 a tricyclic (fused, bridged or spiro) ring system; Aryl is a cyclic, aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic ring system (fused, bridged, or spirocyclic) having 1 to 7 heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical ring atom of 5 to 24 ring atoms containing 1 to 7 heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.

[0013] Another aspect of the present invention is a compound of formula (II): [ka] and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs or tautomers thereof, During the ceremony, each X is independently selected from N and CH; Y is [ka] selected from -NR5C(O)NR5- and -NR5C(O)-; Ring A is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; Ring B is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; M is -CH2-, -C(O)-, -C(O)NR L -, -C(O)O-, -NR L -, -NR L C(O)-, -NR L C(O)NR L -, -NR L C(O)O-, -NR L SO2-, -O-, -OC(O)-, -OC(O)NR L -, -OC(O)O-, -S(O)2NR L -, -S-, and -S(O)2-; L1 and L2 are bonds, C1 to C 12 Alkanediyl, C2-C 12 Alkenediyl, C2-C 12 Alkynediyl, C3-C8 cycloalkanediyl, C3-C8 cycloalkanediyl-(CH2) p -, C1~C 12 Alkoxylenyl, -((CH2) 1~6 O) o -(CH2) p -, -((CH2) 1~6 O) o -(CH2) p -NH-, -((CH2) 1~6 O) o -(CH2) p -NH-C(O)-, and -((CH2) 1~6 O) o -(CH2) p -C(O)-NH-; or M and L2 are both a bond, or L1-M-L2 is a bond, L3 and L4 are bonds, C1 to C 12 Alkylenyl, C2-C 12 Alkenediyl, C2-C 12 Alkynediyl, C1-C 12 Alkoxylenyl, -((CH2) 1~6 O) o -(CH2) p-, -C(O)-, -C(O)NR L -, -C(O)O-, -NR L -, -NR L C(O)-, -NR L C(O)NR L -, -NR L C(O)O-, -NR L SO2-, -O-, -OC(O)-, -OC(O)NR L -, -OC(O)O-, -S(O)2NR L -, -S-, and -S(O)-; R1 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CH2-OC(O)C1-C6 alkyl, -CH2-OP(O)(OC1-C6 alkyl)2, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 11 and optionally substituted with Each of R2 and R9 is hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 and optionally substituted with R4, R6, R7, and R 10 Each of these represents hydrogen, halogen, -OH, -CN, -NO2, and -NR 12 R 13, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 and optionally substituted with each R5 is independently selected from hydrogen and C1-C6 alkyl; R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is selected from one or more R 11 and optionally substituted with Each R 11 are halogens, -OH, -CN, -NO2, -NR 12 R 13、 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl; Each R L are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R 12 and R 13 are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl; m and n are integers independently selected from 0, 1, 2, and 3; o is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t is an integer selected from 0 and 1; u is an integer selected from 0, 1 and 2; w is an integer selected from 0, 1 and 2; provided that when t is 0, L4 is a bond; However, at least one of L3 and L4 is not a bond, Cycloalkyl is a saturated or partially unsaturated C3-C 10 Monocyclic, C5~C 18 Bicyclic (fused, bridged, or spiro) or C6-C 18 a tricyclic (fused, bridged or spiro) ring system; Aryl is a cyclic aromatic hydrocarbon ring system containing 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic ring system (fused, bridged, or spirocyclic) containing 1-7 heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic ring system containing 5 to 24 ring atoms, in which 1 to 7 ring atoms are heteroatoms selected from N, O, S, P, or B, and the remaining ring atoms are C.

[0014] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of Formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant.

[0015] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant.

[0016] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant.

[0017] Another aspect of the present invention relates to a method for treating a MALT1-associated disease or disorder, comprising administering to a patient in need of treatment for a MALT1-associated disease or disorder an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0018] Another aspect of the present invention relates to a method for treating a MALT1-associated disease or disorder, comprising administering to a patient in need of treatment for a MALT1-associated disease or disorder an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0019] Another aspect of the present invention relates to a method for treating a MALT1-associated disease or disorder, comprising administering to a patient in need of treatment for a MALT1-associated disease or disorder an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0020] Another aspect of the present invention relates to a method for degrading MALT1, comprising administering to a patient in need thereof an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0021] Another aspect of the present invention relates to a method for degrading MALT1, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0022] Another aspect of the present invention relates to a method for degrading MALT1, comprising administering to a patient in need thereof an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0023] Another aspect of the present invention relates to a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for the degradation of MALT1.

[0024] Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament for the degradation of MALT1.

[0025] Another aspect of the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament for the degradation of MALT1.

[0026] Another aspect of the present invention relates to the use of a compound of formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a MALT1-associated disease.

[0027] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof in the treatment of a MALT1-associated disease.

[0028] Another aspect of the present invention relates to the use of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof in the treatment of a MALT1-associated disease.

[0029] Another aspect of the present invention pertains to a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0030] Another aspect of the present invention pertains to a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0031] Another aspect of the present invention pertains to a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0032] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0033] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0034] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0035] Another aspect of the present invention relates to the use of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0036] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0037] Another aspect of the present invention relates to the use of a compound of formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0038] The present invention further provides a method for treating a disease or disorder associated with MALT1, comprising administering to a patient suffering from at least one of the diseases or disorders a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0039] The present invention further provides a method for treating a disease or disorder associated with MALT1, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0040] The present invention further provides a method for treating a disease or disorder associated with MALT1, comprising administering to a patient suffering from at least one of the diseases or disorders a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0041] The present invention provides PROTACs of MALT1 that are therapeutic agents in the treatment of diseases and disorders.

[0042] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known PROTACs of MALT1.

[0043] The present invention further provides a method for treating a disease or disorder associated with MALT1, comprising administering to a patient suffering from at least one of the diseases or disorders a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0044] The present invention further provides a method for treating a disease or disorder associated with MALT1, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0045] The present invention further provides a method for treating a disease or disorder associated with MALT1, comprising administering to a patient suffering from at least one of the diseases or disorders a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0046] The present invention provides PROTACs of MALT1 that are therapeutic agents in the treatment of diseases and disorders.

[0047] The present invention further provides a method of treating a disease, disorder, or condition selected from Immunodeficiency 12; Lymphoma, Mucosa-Associated Lymphoid Type (MALTOMA); Combined Immunodeficiency; Combined T and B Cell Immunodeficiency; or Lymphoma, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0048] The present invention further provides a method of treating a disease, disorder, or condition selected from immunodeficiency 12; lymphoma, mucosa-associated lymphocyte type (MALTOMA); combined immunodeficiency; combined immunodeficiency of T-cell and B-cell; or lymphoma, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0049] The present invention further provides a method of treating a disease, disorder, or condition selected from immunodeficiency 12; lymphoma, mucosal-associated lymphocyte type (MALTOMA); combined immunodeficiency; combined immunodeficiency of T-cell and B-cell; or lymphoma, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0050] In some embodiments, the disclosure provides compounds obtainable by or obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in the section entitled "General Procedures").

[0051] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in methods of preparing compounds described herein (e.g., the intermediates are selected from the intermediates described in the Synthetic Methods section of the present disclosure).

[0052] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0053] In some embodiments, the present disclosure provides methods of preparing compounds of the present disclosure, comprising one or more steps described herein.

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular forms include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety for all purposes. In case of conflict, the present specification, including definitions, will prevail. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure will prevail.

[0055] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. [Brief explanation of the drawings]

[0056] [Figure 1] FIG. 1 shows a bar graph of the PROTAC activity of compounds 10, 12, and 13 of the present disclosure against MALT1 compared to reference compounds Ref-1 and Ref-2 according to the experimental conditions presented in Example C.

[0057] [Figure 2] FIG. 1 shows a bar graph of the PROTAC activity of compounds 14, 16, and 17 of the present disclosure against MALT1 compared to the reference compound, Ref. 3, according to the experimental conditions shown in Example C. DETAILED DESCRIPTION OF THE INVENTION

[0058] Detailed Description of the Invention The present disclosure provides methods for treating, preventing, or ameliorating a MALT1-associated disease or disorder by administering a therapeutically effective amount of a compound disclosed herein to a subject in need thereof.

[0059] Details of the present disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, exemplary methods and materials are described here. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety. definition

[0060] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0061] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise stated.

[0062] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For example, it can be bonded at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily have additional functional groups. Suitable substituents used for optional substitution of a described group include, but are not limited to, halogen, oxo, -OH, -CN, -COOH, -CHCN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)halo ... 6) Haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C 6) Examples of alkyl include alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. The substituents themselves are optionally substituted. As used herein, "optionally substituted" also refers to substituted or unsubstituted, the meaning of which is described below.

[0063] As used herein, the term "substituted" means that the specified group or moiety has one or more suitable substituents that may be attached to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl is bonded to one atom of the aryl or is fused to the aryl and is attached by sharing two or more common atoms.

[0064] As used herein, the term "unsubstituted" means that the particular group bears no substituents.

[0065] Unless otherwise specifically defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group can be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). An aryl group can be optionally substituted at any point of attachment with one or more substituents, for example, 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -O-P(O)(OH), -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH, -NH((C-C)alkyl), -N((C-C)alkyl), -S(O)-(C-C)alkyl, -S(O)NH(C-C)alkyl, and -S(O)N((C-C)alkyl). The substituents themselves are optionally substituted. Additionally, when containing two fused rings, aryl groups as defined herein can have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannurenyl, and the like.

[0066] Unless otherwise specifically defined, "heteroaryl" refers to a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. Polycyclic aromatic radicals contain two or more fused rings and may further contain two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specified, "fused" refers to two rings that share two ring atoms. Unless otherwise specified, "spiro-fused" refers to two rings that share one ring atom. Heteroaryl, as defined herein, also refers to bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to tricyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl ... pyrazolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro Pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, furo[2,3-b]pyridinyl diphenyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,Examples of heteroaryl groups include, but are not limited to, 3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings. In heteroaryl ring systems containing three or more fused rings, the saturated or partially unsaturated rings may be further fused with a saturated or partially unsaturated ring as described herein. Furthermore, when containing three or more fused rings, the heteroaryl groups defined herein may have one or more spiro-fused saturated or partially unsaturated rings. Any saturated or partially unsaturated ring as described herein is optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyridin ...-7-onyl, 1,5,6,7-tetrahydrocyclopenta[b]pyridin-7-onyl, 1,5,6,7-tetrahydrocyclopenta[b]pyridin-7-onyl pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxaborole-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl, or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9'-onyl.

[0067] Halogen or "halo" refers to fluorine, chlorine, bromine or iodine.

[0068] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0069] "Alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms containing a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0070] "Alkenyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group may be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. Alkenyl groups may be unsubstituted or substituted. Alkenyl may be straight-chain or branched, as defined herein.

[0071] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0072] The term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can be a C1-C6 alkylene. Alkylene can be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0073] The term "alkoxylenyl" refers to a divalent alkoxy radical. Any of the above monovalent alkoxy groups can be alkoxylenyl by abstraction of a second hydrogen atom from the alkyl. Typical alkylene groups include, but are not limited to, -O-CH-, -O-CH(CH)-, -OC(CH)-, -O-CHCH-, -O-CHCH(CH)-, -O-CHC(CH)-, -O-CHCHCH-, -O-CHCHCHCH-, and the like.

[0074] "Cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring containing 3 to 18 carbon atoms. Polycyclic cycloalkyls can be fused bicyclic cycloalkyls, bridged bicyclic cycloalkyls, or spiro-fused bicyclic cycloalkyls. Polycyclic cycloalkyls contain at least one non-aromatic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0075] A "heterocyclyl," "heterocycle," or "heterocycloalkyl" is a monocyclic or polycyclic ring containing 3 to 24 atoms, including carbon and one or more heteroatoms selected from N, O, S, P, or B, wherein the ring is not aromatic. The heterocycloalkyl ring structure may be substituted with one or more substituents, which themselves are optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[0076] The term "aromatic" refers to a planar ring with 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a system of connected p orbitals with delocalized electrons, which may include lone pairs.

[0077] The term "halogenalkyl" as used herein refers to an alkyl group, as defined herein, that is substituted with one or more halogens. Examples of halogenalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0078] The term "halogenalkoxy" as used herein refers to an alkoxy group, as defined herein, substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0079] As used herein, the term "cyano" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, i.e., C≡N.

[0080] "Spirocycloalkyl" or "spirocyclyl" refers to a bicarbonate ring system in which both rings are bonded through a single atom. The rings may be different in size and nature or may be identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both rings in a spiro ring can be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spiro ring can be replaced with a heteroatom (e.g., O, N, S, or P). (C3-C 12 A spirocycloalkyl is a spiro ring containing 3 to 12 carbon atoms, one or more of which may be replaced by a heteroatom.

[0081] The terms "spiroheterocycloalkyl," "spiroheterocycle," or "spiroheterocyclyl" are understood to mean a spirocycle in which at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0082] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For the purposes of this disclosure, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically called hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0083] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences can be in constitution (geometric isomers) or ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, compounds of formula (I) can have one or more asymmetric carbon atoms and can exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0084] The present disclosure also provides isotopically labeled compounds of Formula I, such as 2 H and 14 C) are intended to be deuterated (i.e., 2 H or D) and carbon-14 (i.e., 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced required dosage) and therefore may be preferred in some circumstances. Isotopically labeled compounds of Formula I can generally be prepared by procedures similar to those disclosed in the following schemes and / or examples, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.

[0085] The present disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetate, anthonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiocyanate, hydroxybenzo ... nitrate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, nafilate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, hypoacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theocrate, tosylate, triethyl iodide, and valerate.

[0086] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey.

[0087] An "effective amount" when used in reference to a compound is an amount effective to treat or prevent a disease in a subject as described herein.

[0088] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0089] The term "treatment" with respect to a subject refers to improving at least one symptom of the subject's disorder. Treatment includes curing, ameliorating, or at least partially alleviating the disorder.

[0090] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0091] The terms "administer," "administering," or "administration," as used in this disclosure, refer to either administering a disclosed compound or a pharmaceutically acceptable salt or composition of a disclosed compound directly to a subject, or administering to a subject a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt of the compound or composition that is capable of forming an equivalent amount of the active compound in the subject's body.

[0092] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (eg, by hydrolysis) to a disclosed compound.

[0093] The term "salts" refers to pharmaceutically acceptable salts.

[0094] The term "pharmaceutically acceptable salt" also refers to a salt of a composition of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.

[0095] As used herein, "MALT1 PROTAC" refers to a compound of formula I and / or a composition comprising a compound of formula I that degrades MALT1.

[0096] The amount of a compound of a composition described herein required to achieve a therapeutic effect can be empirically determined according to conventional procedures for a particular purpose. Generally, for administering a therapeutic agent (e.g., a compound of Formula I or a composition described herein (and / or additional agents)) for therapeutic purposes, the therapeutic agent is administered at a pharmacologically effective dose. A "pharmacologically effective amount," "pharmacologically effective dose," "therapeutically effective amount," or "effective amount" refers to an amount sufficient to produce a desired physiological effect or achieve a desired result, particularly for treating a disorder or disease. As used herein, an effective amount includes, for example, an amount sufficient to delay the onset of symptoms of a disorder or disease, alter the course of symptoms of a disorder or disease (e.g., slow the progression of symptoms of a disease), reduce or eliminate one or more symptoms or manifestations of a disorder or disease, or reverse symptoms of a disorder or disease. For example, administration of a therapeutic agent to a subject suffering from cancer provides therapeutic benefit not only if the underlying disease is eradicated or ameliorated, but also if the subject reports a decrease in the severity or duration of symptoms associated with the disease, such as a decrease in tumor burden, a decrease in circulating tumor cells, or an increase in progression-free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized. Compounds of the Disclosure

[0097] In one aspect, the present disclosure provides compounds of formula (A) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: [ka] provide In the formula, R1, R2, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 , X, g, m, n, t, u, and w are as described herein.

[0098] For compounds of formula (A), R1, R2, C, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10, X, g, m, n, t, u, and w may each be selected from groups described herein, where applicable, and R1, R2, C, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 , X, g, m, n, t, u, and w, any groups described herein may be selected from R1, R2, C, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 , X, g, m, n, t, u, and w may be combined with any group described herein for one or more of the remaining.

[0099] In some embodiments, the disclosure provides compounds of formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: [ka] In the formula, R1, R2, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 , X, m, n, t, u, and w are as described herein.

[0100] For compounds of formula (I), R1, R2, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 , X, m, n, t, u, and w may each be selected from groups described herein, where applicable, and R1, R2, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 , X, m, n, t, u, and w, any group described herein may be selected from R1, R2, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 , X, m, n, t, u, and w may be combined with any group described herein for one or more of the remainder.

[0101] In some embodiments, the present disclosure provides compounds of formula (II) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: [ka] In the formula, R1, R2, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 , X, m, n, t, u, and w are as described herein.

[0102] For compounds of formula (I), R1, R2, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 , X, m, n, t, u, and w may each be selected from groups described herein, where applicable, and R1, R2, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 , X, m, n, t, u, and w, any group described herein may be selected from R1, R2, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 , X, m, n, t, u, and w may be combined with any group described herein for one or more of the remainder.

[0103] In some compounds having the structure of formula (A): each X is independently selected from N and CH; Y is [ka] -NR5C(O)NR5-, and -NR5C(O)-; Ring A is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; Ring B is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; Ring C is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl; M is -CH2-, -C(O)-, -C(O)NR L -, -C(O)O-, -NR L -, -NR L C(O)-, -NR L C(O)NR L -, -NR L C(O)O-, -NR L SO2-, -O-, -OC(O)-, -OC(O)NR L -, -OC(O)O-, -S(O)2NR L -, -S-, and -S(O)2-; L1 and L2 are bonds, C1 to C 12 Alkanediyl, C2-C 12 Alkenediyl, C2-C 12 Alkynediyl, C3-C8 cycloalkanediyl, C3-C8 cycloalkanediyl-(CH2) p -, C1~C 12 Alkoxylenyl, -((CH2) 1~6 O) o -(CH2) p -, -((CH2) 1~6 O) o -(CH2) p -NH-, -((CH2) 1~6 O) o -(CH2) p -NH-C(O)-, and -((CH2) 1~6 O) o -(CH2) p -C(O)-NH-; or M and L2 are both a bond, or L1-M-L2 is a bond, L3 and L4 are bonds, C1 to C 12 Alkanediyl, C2-C 12 Alkenediyl, C2-C 12 Alkynediyl, C1-C 12 Alkoxylenyl, -((CH2) 1~6 O) o -(CH2) p -, -C(O)-, -C(O)NR L -, -C(O)O-, -NR L -, -NRL C(O)-, -NR L C(O)NR L -, -NR L C(O)O-, -NR L SO2-, -O-, -OC(O)-, -OC(O)NR L -, -OC(O)O-, -S(O)2NR L -, -S-, and -S(O)-; R1 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CH2-OC(O)C1-C6 alkyl, -CH2-OP(O)(OC1-C6 alkyl)2, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 11 and optionally substituted with Each of R2, R3, and R9 is hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 optionally substituted with, or Two R3 are =O, Each of R4, R6, R7, and R 10 are halogens, -OH, -CN, -NO2, -NR 12 R 13, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 and optionally substituted with each R5 is independently selected from hydrogen, C1-C6 alkyl; R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is selected from one or more R 11 and optionally substituted with Each R 11 are halogens, -OH, -CN, -NO2, -NR 12 R 13、 independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl; Each R L are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R 12 and R 13 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl; g is an integer selected from 0, 1, and 2; m and n are integers independently selected from 0, 1, 2, and 3; o is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t is an integer selected from 0 and 1; u is an integer selected from 0, 1 and 2; w is an integer selected from 0, 1 and 2; provided that when t is 0, L4 is a bond; However, at least one of L3 and L4 is not a bond.

[0104] In some embodiments, ring A is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl.

[0105] In some embodiments, ring A is cycloalkyl. In some embodiments, ring A is aryl. In some embodiments, ring A is heterocyclyl. In some embodiments, ring A is heteroaryl.

[0106] In some embodiments, each X is independently selected from N or CH.

[0107] In some embodiments, at least one of the two X's is nitrogen.

[0108] In some embodiments, one X is N and the other X is CH.

[0109] In some embodiments, both X are N. In some embodiments, both X are CH.

[0110] In some embodiments, ring A is cycloalkyl.

[0111] In some embodiments, ring A is C3-C 12 It is cycloalkyl.

[0112] In some embodiments, ring A is a C3-C8 monocyclic cycloalkyl.

[0113] In some embodiments, ring A is [ka] is.

[0114] In some embodiments, ring A is [ka] is.

[0115] In some embodiments, ring A is [ka] is.

[0116] In some embodiments, ring A is [ka] is.

[0117] In some embodiments, ring A is a fused C3-C 12 In some embodiments, ring A is a bridged C-C 12 In some embodiments, Ring A is a spiro-fused C-C 12 It is a bicyclic cycloalkyl.

[0118] In some embodiments, ring A is aryl.

[0119] In some embodiments, ring A is C6-C 10 It is aryl.

[0120] In some embodiments, ring A is [ka] is.

[0121] In some embodiments, ring A is [ka] is.

[0122] In some embodiments, ring A is [ka] is.

[0123] In some embodiments, ring A is [ka] is.

[0124] In some embodiments, ring A is heterocyclyl.

[0125] In some embodiments, ring A is a 3-10 membered heterocyclyl.

[0126] In some embodiments, ring A is a 3-membered heterocyclyl.

[0127] In some embodiments, ring A is a 3-membered heterocyclyl containing 1 heteroatom selected from O and N.

[0128] In some embodiments, ring A is a 4-membered heterocyclyl.

[0129] In some embodiments, ring A is a 4-membered heterocyclyl containing 1 or 2 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0130] In some embodiments, ring A is a 5-membered heterocyclyl.

[0131] In some embodiments, ring A is a 5-membered heterocyclyl containing 1 or 2 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0132] In some embodiments, ring A is a 6-membered heterocyclyl.

[0133] In some embodiments, ring A is a 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0134] In some embodiments, ring A is a 7-membered heterocyclyl.

[0135] In some embodiments, ring A is a 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0136] In some embodiments, ring A is [ka] is.

[0137] In some embodiments, ring A is [ka] is.

[0138] In some embodiments, ring A is [ka] is.

[0139] In some embodiments, ring A is [ka] is.

[0140] In some embodiments, ring A is [ka] is.

[0141] In some embodiments, ring A is [ka] is.

[0142] In some embodiments, ring A is [ka] is.

[0143] In some embodiments, ring A is [ka] is.

[0144] In some embodiments, ring A is [ka] is.

[0145] In some embodiments, ring A is [ka] is.

[0146] In some embodiments, ring A is heteroaryl.

[0147] In some embodiments, ring A is a 5-membered heteroaryl.

[0148] In some embodiments, ring A is a 5-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0149] In some embodiments, ring A is a 6-membered heteroaryl.

[0150] In some embodiments, ring A is a 6-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0151] In some embodiments, ring A is [ka] is selected from.

[0152] In some embodiments, ring A is [ka] is.

[0153] In some embodiments, ring A is [ka] is.

[0154] In some embodiments, ring A is [ka] is.

[0155] In some embodiments, ring A is [ka] is.

[0156] In some embodiments, ring A is [ka] is.

[0157] In some embodiments, ring A is [ka] is.

[0158] In some embodiments, ring A is [ka] is.

[0159] In some embodiments, ring A is [ka] is.

[0160] In some embodiments, ring A is [ka] is.

[0161] In some embodiments, ring A is [ka] is.

[0162] In some embodiments, Ring B is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl.

[0163] In some embodiments, Ring B is cycloalkyl. In some embodiments, Ring B is aryl. In some embodiments, Ring B is heterocyclyl. In some embodiments, Ring B is heteroaryl.

[0164] In some embodiments, t is 0. In some embodiments, t is 1.

[0165] In some embodiments, t is 0.

[0166] In some embodiments, t is 1.

[0167] In some embodiments, ring B is one or more R 11 is cycloalkyl optionally substituted with

[0168] In some embodiments, Ring B is cycloalkyl.

[0169] In some embodiments, ring B is C3-C 12 It is cycloalkyl.

[0170] In some embodiments, Ring B is a C3-C8 monocyclic cycloalkyl.

[0171] In some embodiments, ring B is [ka] is.

[0172] In some embodiments, ring B is [ka] is.

[0173] In some embodiments, ring B is [ka] is.

[0174] In some embodiments, ring B is [ka] is.

[0175] In some embodiments, ring B is a fused C3-C 12 In some embodiments, ring B is a bridged C-C 12 In some embodiments, Ring B is a spiro-fused C-C 12It is a bicyclic cycloalkyl.

[0176] In some embodiments, Ring B is aryl.

[0177] In some embodiments, ring B is C6-C 10 It is aryl.

[0178] In some embodiments, ring B is [ka] is.

[0179] In some embodiments, ring B is [ka] is.

[0180] In some embodiments, Ring B is heterocyclyl.

[0181] In some embodiments, Ring B is a 3-membered heterocyclyl.

[0182] In some embodiments, Ring B is a 3-membered heterocyclyl containing 1 heteroatom selected from O and N.

[0183] In some embodiments, Ring B is a 4-membered heterocyclyl.

[0184] In some embodiments, Ring B is a 4-membered heterocyclyl containing 1 or 2 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0185] In some embodiments, Ring B is a 5-membered heterocyclyl.

[0186] In some embodiments, Ring B is a 5-membered heterocyclyl containing 1 or 2 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0187] In some embodiments, Ring B is a 6-membered heterocyclyl.

[0188] In some embodiments, Ring B is a 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0189] In some embodiments, Ring B is a 7-membered heterocyclyl.

[0190] In some embodiments, Ring B is a 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0191] In some embodiments, ring B is [ka] is.

[0192] In some embodiments, ring B is [ka] is.

[0193] In some embodiments, ring B is one or more R 11 is heteroaryl optionally substituted with

[0194] In some embodiments, Ring B is heteroaryl.

[0195] In some embodiments, Ring B is a 5-membered heteroaryl.

[0196] In some embodiments, Ring B is a 5-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0197] In some embodiments, Ring B is a 6-membered heteroaryl.

[0198] In some embodiments, Ring B is a 6-membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0199] In some embodiments, ring B is [ka] is.

[0200] In some embodiments, ring B is [ka] is.

[0201] In some embodiments, ring B is [ka] is.

[0202] In some embodiments, ring B is [ka] is.

[0203] In some embodiments, ring B is [ka] is.

[0204] In some embodiments, ring B is [ka] is.

[0205] In some embodiments, ring B is [ka] is.

[0206] In some embodiments, ring B is [ka] is.

[0207] In some embodiments, ring B is [ka] is.

[0208] In some embodiments, ring B is [ka] is.

[0209] In some embodiments, ring B is [ka] is.

[0210] In some embodiments, Ring C is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl.

[0211] In some embodiments, Ring C is aryl.

[0212] In some embodiments, ring C is [ka] is.

[0213] In some embodiments, ring C is [ka] is.

[0214] In some embodiments, Ring C is heterocyclyl.

[0215] In some embodiments, Ring C is a bicyclic heterocyclyl.

[0216] In some embodiments, Ring C is a bicyclic heterocyclyl wherein one ring is a C6 arene.

[0217] In some embodiments, Ring C is heteroaryl.

[0218] In some embodiments, Ring C is a bicyclic heteroaryl.

[0219] In some embodiments, ring C is [ka] is.

[0220] In some embodiments, ring C is [ka] is.

[0221] In some embodiments, ring C is [ka] is.

[0222] In some embodiments, ring C is [ka] is.

[0223] In some embodiments, ring C is [ka] is.

[0224] In some embodiments, ring C is [ka] is.

[0225] In some embodiments, ring C is [ka] is.

[0226] In some embodiments, Y is [ka] It is selected from -NR5C(O)NR5-, and -NR5C(O)-.

[0227] In some embodiments, Y is [ka] is.

[0228] In some embodiments, Y is —NR 5 C(O)NR 5 —.

[0229] In some embodiments, Y is [ka] In some embodiments, Y is —NHC(O)NH—.

[0230] In some embodiments, Y is [ka] is.

[0231] In some embodiments, Y is —NHC(O)NH—.

[0232] In some embodiments, Y is —NR 5 C(O)—.

[0233] In some embodiments, -NR5C(O)- links cycle C and L1, as shown here: (Ring C)-NR5C(O)-(L1).

[0234] In some embodiments, -NR5C(O)- links cycle C and L1, as shown here: (L1)-NR5C(O)-(ring C).

[0235] In some embodiments, Y is —NHC(O)—.

[0236] In some embodiments, -NHC(O)- links cycle C and L1 as shown here: (Ring C)-NHC(O)-(L1).

[0237] In some embodiments, -NHC(O)- links cycle C and L1 as shown here: (L1)-NHC(O)-(ring C).

[0238] In some embodiments, M is -CH2-. In some embodiments, M is -C(O)-. In some embodiments, M is -C(O)NR L In some embodiments, M is -C(O)O-. In some embodiments, M is -NR L In some embodiments, M is -NR L In some embodiments, M is -NR L C(O)NR L In some embodiments, M is -NR L In some embodiments, M is -NR L In some embodiments, M is -SO2-. In some embodiments, M is -O-. In some embodiments, M is -OC(O)-. In some embodiments, M is -OC(O)NR L In some embodiments, M is -OC(O)O-. In some embodiments, M is -S(O)NR LIn some embodiments, M is -S-. In some embodiments, M is -S(O)2-.

[0239] In some embodiments, M is —CH 2 —.

[0240] In some embodiments, M is —C(O)—.

[0241] In some embodiments, M is —O—.

[0242] In some embodiments, M is —NR L It is C(O)-.

[0243] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. In some embodiments, o is 5. In some embodiments, o is 6. In some embodiments, o is 7. In some embodiments, o is 8. In some embodiments, o is 9. In some embodiments, o is 10.

[0244] In some embodiments, o is 0.

[0245] In some embodiments, o is 1.

[0246] In some embodiments, o is 2.

[0247] In some embodiments, o is 3.

[0248] In some embodiments, each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0249] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10.

[0250] In some embodiments, p is 0.

[0251] In some embodiments, p is 1.

[0252] In some embodiments, p is 2.

[0253] In some embodiments, p is 3.

[0254] In some embodiments, L1 is a bond. In some embodiments, L1 is C1 to C 12 In some embodiments, L is C2-C alkanediyl. 12 In some embodiments, L is C-C alkenediyl. 12 In some embodiments, L1 is C3-C8 cycloalkanediyl. In some embodiments, L1 is C3-C8 cycloalkanediyl-(CH2). p In some embodiments, L1 is C1 to C 12 In some embodiments, L is -((CH) 1~6 O) o -(CH2) p In some embodiments, L is -((CH) 1~6 O) o -(CH2) p In some embodiments, L is -NH-. In some embodiments, L is -((CH) 1~6 O) o -(CH2)p In some embodiments, L is -NH-C(O)-. In some embodiments, L is -((CH) 1~6 O) o -(CH2) p -C(O)-NH-.

[0255] In some embodiments, L1 is a bond.

[0256] In some embodiments, L1 is C1 to C 12 It is alkylenyl.

[0257] In some embodiments, L1 is -CH2-.

[0258] In some embodiments, L1 is -CH2CH2-.

[0259] In some embodiments, L1 is -CH2CH2CH2-.

[0260] In some embodiments, L1 is -CH2CH2CH2CH2-.

[0261] In some embodiments, L1 is -CH2CH2CH2CH2CH2-.

[0262] In some embodiments, L is -((CH) 1~6 O) o -(CH2) p -It is.

[0263] In some embodiments, L1 is -CH2CH2-O-CH2CH2-.

[0264] In some embodiments, L is -((CH) 1~6 O) o -(CH2) p -It is.

[0265] In some embodiments, L is -((CH) 1~6 O) o -(CH2)p -NH-.

[0266] In some embodiments, L is -((CH) 1~6 O) o -(CH2) p -NH-C(O)-.

[0267] In some embodiments, L is -((CH) 1~6 O) o -(CH2) p -C(O)-NH-.

[0268] In some embodiments, L1 is C3-C8 cycloalkanediyl.

[0269] In some embodiments, L1 is [ka] is.

[0270] In some embodiments, L1 is [ka] is.

[0271] In some embodiments, L1 is [ka] is.

[0272] In some embodiments, L1 is [ka] is.

[0273] In some embodiments, L1 is [ka] is.

[0274] In some embodiments, L1 is [ka] is.

[0275] In some embodiments, L1 is [ka] is.

[0276] In some embodiments, L1 is [ka] is.

[0277] In some embodiments, L2 is a bond. In some embodiments, L2 is a C1-C 12 In some embodiments, L2 is a C2-C alkanediyl. 12 In some embodiments, L2 is C2-C 12 In some embodiments, L2 is C3-C8 cycloalkanediyl. In some embodiments, L2 is C3-C8 cycloalkanediyl-(CH2). p In some embodiments, L2 is C1 to C 12 In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p In some embodiments, L2 is -NH-. In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p In some embodiments, L2 is -NH-C(O)-. In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p -C(O)-NH-.

[0278] In some embodiments, L2 is a bond.

[0279] In some embodiments, L2 is C1-C 12 It is alkylenyl.

[0280] In some embodiments, L2 is -CH2-.

[0281] In some embodiments, L2 is -CH2CH2-.

[0282] In some embodiments, L2 is -CH2CH2CH2-.

[0283] In some embodiments, L2 is -CH2CH2CH2CH2-.

[0284] In some embodiments, L2 is -CH2CH2CH2CH2CH2-.

[0285] In some embodiments, L2 is -CH2-C(CH3)2-CH2-.

[0286] In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p -It is.

[0287] In some embodiments, L2 is -CH2-O-CH2CH2CH2-.

[0288] In some embodiments, L2 is -CH2CH2CH2CH2-O-CH2-.

[0289] In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p -It is.

[0290] In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p -NH-.

[0291] In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p -NH-C(O)-.

[0292] In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p -C(O)-NH-.

[0293] In some embodiments, L2 is C3-C8 cycloalkanediyl-(CH2) p -It is.

[0294] In some embodiments, L2 is C3-C8 cycloalkanediyl-CH2-.

[0295] In some embodiments, L2 is [ka] is.

[0296] In some embodiments, L2 is a C3-C8 cycloalkanediyl.

[0297] In some embodiments, L2 is [ka] is.

[0298] In some embodiments, L2 is [ka] is.

[0299] In some embodiments, L2 is [ka] is.

[0300] In some embodiments, L2 is [ka] is.

[0301] In some embodiments, L2 is [ka] is.

[0302] In some embodiments, L2 is [ka] is.

[0303] In some embodiments, L2 is [ka] is.

[0304] In some embodiments, L2 is [ka] is.

[0305] In some embodiments, M-L2 is a bond.

[0306] In some embodiments, L1-M-L2 is a bond.

[0307] In some embodiments, L3 is a bond. In some embodiments, L3 is C1-C 12 In some embodiments, L3 is C2-C alkanediyl. 12In some embodiments, L3 is C2-C 12 In some embodiments, L3 is C1-C 12 In some embodiments, L is -((CH) 1~6 O) o -(CH2) p In some embodiments, L3 is -C(O)-. In some embodiments, L3 is -C(O)NR L In some embodiments, L3 is -C(O)O-. In some embodiments, L3 is -NR L In some embodiments, L3 is -NR L In some embodiments, L3 is -NR L C(O)NR L In some embodiments, L3 is -NR L In some embodiments, L3 is -NR L In some embodiments, L3 is -SO2-. In some embodiments, L3 is -O-. In some embodiments, L3 is -OC(O)-. In some embodiments, L3 is -OC(O)NR L In some embodiments, L3 is -OC(O)O-. In some embodiments, L3 is -S(O)NR L In some embodiments, L3 is -S-. In some embodiments, L3 is -S(O)2-.

[0308] In some embodiments, L3 is a bond.

[0309] In some embodiments, L4 is a bond. In some embodiments, L4 is C1-C 12 In some embodiments, L4 is C2-C alkanediyl. 12 In some embodiments, L4 is C2-C alkenediyl. 12 In some embodiments, L4 is C1-C 12In some embodiments, L is -((CH) 1~6 O) o -(CH2) p In some embodiments, L4 is -C(O)-. In some embodiments, L4 is -C(O)NR L In some embodiments, L4 is -C(O)O-. In some embodiments, L4 is -NR L In some embodiments, L4 is -NR L In some embodiments, L4 is -NR L C(O)NR L In some embodiments, L4 is -NR L In some embodiments, L4 is -NR L In some embodiments, L4 is -SO2-. In some embodiments, L4 is -O-. In some embodiments, L4 is -OC(O)-. In some embodiments, L4 is -OC(O)NR L In some embodiments, L4 is -OC(O)O-. In some embodiments, L4 is -S(O)NR L In some embodiments, L4 is -S-. In some embodiments, L4 is -S(O)2-.

[0310] In some embodiments, L4 is -NR L C(O)NR L -It is.

[0311] In some embodiments, L4 is -NHC(O)NH-.

[0312] In some embodiments, L4 is -NR L It is C(O)-.

[0313] In some embodiments, L4 is -NHC(O)-.

[0314] In some embodiments, L4 is -C(O)NH-.

[0315] In some embodiments, R1 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, —CH2—OC(O)C1-C6 alkyl, —CH2—OP(O)(OC1-C6 alkyl)2, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is selected from one or more R 11 is optionally replaced by

[0316] In some embodiments, R1 is hydrogen. In some embodiments, R1 is deuterium. In some embodiments, R1 is C1-C6 alkyl. In some embodiments, R1 is C2-C6 alkenyl. In some embodiments, R1 is C2-C6 alkynyl. In some embodiments, R1 is C1-C6 haloalkyl. In some embodiments, R1 is C1-C6 alkoxy. In some embodiments, R1 is C1-C6 haloalkoxy. In some embodiments, R1 is cycloalkyl. In some embodiments, R1 is aryl. In some embodiments, R1 is heterocyclyl.

[0317] In some embodiments, R1 is hydrogen.

[0318] In some embodiments, R1 is C1-C6 alkyl.

[0319] In some embodiments, R1 is methyl.

[0320] In some embodiments, R1 is -CH2-OC(O)C1-C6 alkyl.

[0321] In some embodiments, R1 is [ka] is.

[0322] In some embodiments, R1 is -CH2-OP(O)(OC1-C6 alkyl)2.

[0323] In some embodiments, R1 is [ka] is.

[0324] In some embodiments, each R2 is hydrogen, halogen, —OH, —CN, —NO2, —NR2 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 is optionally replaced by

[0325] In some embodiments, each R2 is H.

[0326] In some embodiments, at least one R2 is halogen.

[0327] In some embodiments, at least one R2 is methyl.

[0328] In some embodiments, at least one R2 is methoxy.

[0329] In some embodiments, at least one R2 is -CN.

[0330] In some embodiments, each R3 is hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 is optionally replaced by

[0331] In some embodiments, each R3 is H.

[0332] In some embodiments, at least one R3 is halogen.

[0333] In some embodiments, one R3 is halogen and the other is H.

[0334] In some embodiments, at least one R3 is methyl.

[0335] In some embodiments, each R3 is methyl.

[0336] In some embodiments, one R3 is methyl and the other is H.

[0337] In some embodiments, two R3 form =O.

[0338] In some embodiments, each R4 is halogen, -OH, -CN, -NO2, -NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 is optionally replaced by

[0339] In some embodiments, w is an integer selected from 0, 1, and 2.

[0340] In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2.

[0341] In some embodiments, w is 0.

[0342] In some embodiments, R4 is halogen.

[0343] In some embodiments, R4 is F.

[0344] In some embodiments, w is 1 and R4 is halogen.

[0345] In some embodiments, w is 1 and R4 is F. In some embodiments, w is 1 and R4 is Cl. In some embodiments, w is 1 and R4 is Br. In some embodiments, w is 1 and R4 is I.

[0346] In some embodiments, w is 1 and R4 is F.

[0347] In some embodiments, w is 1 and R4 is -CN.

[0348] In some embodiments, w is 1 and R4 is -OH.

[0349] In some embodiments, w is 1 and R4 is methyl.

[0350] In some embodiments, w is 1 and R4 is methoxy.

[0351] In some embodiments, each R5 is independently selected from hydrogen, C1-C6 alkyl.

[0352] In some embodiments, each R5 is H.

[0353] In some embodiments, each R6 is hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 is optionally replaced by

[0354] In some embodiments, m is an integer selected from 0, 1, 2, and 3.

[0355] In some embodiments, m is 0.

[0356] In some embodiments, m is 1 and R6 is halogen.

[0357] In some embodiments, m is 1 and R6 is F. In some embodiments, m is 1 and R6 is Cl. In some embodiments, m is 1 and R6 is Br. In some embodiments, m is 1 and R6 is I.

[0358] In some embodiments, m is 1 and R6 is -OH.

[0359] In some embodiments, m is 1 and R6 is -CN.

[0360] In some embodiments, m is 1 and R6 is C1-C6 alkyl.

[0361] In some embodiments, m is 1 and R6 is -NR 12 R 13 is.

[0362] In some embodiments, m is 2.

[0363] In some embodiments, m is 3.

[0364] In some embodiments, each R7 is hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R 11 is optionally replaced by

[0365] In some embodiments, n is an integer selected from 0, 1, 2, and 3.

[0366] In some embodiments, n is 0.

[0367] In some embodiments, n is 1 and R7 is halogen.

[0368] In some embodiments, n is 1 and R7 is Cl.

[0369] In some embodiments, n is 1 and R7 is C1-C6 alkyl.

[0370] In some embodiments, n is 1 and R7 is CH3.

[0371] In some embodiments, n is 2.

[0372] In some embodiments, n is 3.

[0373] In some embodiments, R is selected from H, C-C alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is selected from one or more R 11 will be substituted as necessary.

[0374] In some embodiments, R8 is H.

[0375] In some embodiments, R8 is C1-C6 alkyl.

[0376] In some embodiments, R8 is one or more R 11 is C1-C6 alkyl optionally substituted with

[0377] In some embodiments, R8 is methyl.

[0378] In some embodiments, R8 is ethyl.

[0379] In some embodiments, R8 is propyl.

[0380] In some embodiments, R8 is n-propyl.

[0381] In some embodiments, R8 is iso-propyl.

[0382] In some embodiments, R8 is butyl.

[0383] In some embodiments, R8 is tert-butyl.

[0384] In some embodiments, R8 is [ka] is.

[0385] In some embodiments, R8 is [ka] is.

[0386] In some embodiments, R8 is cycloalkyl.

[0387] In some embodiments, R8 is C3-C 12 It is cycloalkyl.

[0388] In some embodiments, R8 is a C3-C8 monocyclic cycloalkyl.

[0389] In some embodiments, R is a 3-membered cycloalkyl. In some embodiments, R is a 4-membered cycloalkyl. In some embodiments, R is a 5-membered cycloalkyl. In some embodiments, R is a 6-membered cycloalkyl. In some embodiments, R is a 7-membered cycloalkyl.

[0390] In some embodiments, R8 is [ka] is.

[0391] In some embodiments, R8 is [ka] is.

[0392] In some embodiments, R8 is [ka] is.

[0393] In some embodiments, R8 is [ka] is.

[0394] In some embodiments, ring R8 is a fused C5-C 12 In some embodiments, R is a bridged C-C 12 In some embodiments, ring R is a spiro-fused C5-C 12 It is a bicyclic cycloalkyl.

[0395] In some embodiments, R8 is aryl.

[0396] In some embodiments, R is C 10 It is aryl.

[0397] In some embodiments, R8 is phenyl.

[0398] In some embodiments, R8 is [ka] is.

[0399] In some embodiments, R8 is heterocyclyl.

[0400] In some embodiments, R8 is 3-10 membered heterocyclyl.

[0401] In some embodiments, R is a 3-membered heterocyclyl. In some embodiments, R is a 4-membered heterocyclyl. In some embodiments, R is a 5-membered heterocyclyl. In some embodiments, R is a 6-membered heterocyclyl. In some embodiments, R is a 7-membered heterocyclyl.

[0402] In some embodiments, R8 is a 3-membered heterocyclyl.

[0403] In some embodiments, R8 is a 3-membered heterocyclyl containing 1 heteroatom selected from O and N.

[0404] In some embodiments, R8 is a 4-membered heterocyclyl.

[0405] In some embodiments, R 8 is a 4-membered heterocyclyl containing 1 or 2 heteroatoms, wherein each heteroatom is independently selected from N, O, and S.

[0406] In some embodiments, R8 is a 5-membered heterocyclyl.

[0407] In some embodiments, R 8 is a 5-membered heterocyclyl containing 1 or 2 heteroatoms, wherein each heteroatom is independently selected from N, O, and S.

[0408] In some embodiments, R8 is a 6-membered heterocyclyl.

[0409] In some embodiments, R 8 is a 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms, wherein each heteroatom is independently selected from N, O, and S.

[0410] In some embodiments, R8 is 7-membered heterocyclyl.

[0411] In some embodiments, R 8 is a 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms, wherein each heteroatom is independently selected from N, O, and S.

[0412] In some embodiments, R8 is [ka] is.

[0413] In some embodiments, R8 is [ka] is.

[0414] In some embodiments, R8 is [ka] is.

[0415] In some embodiments, R8 is heteroaryl.

[0416] In some embodiments, R8 is a 5-membered heteroaryl. In some embodiments, R8 is a 6-membered heteroaryl.

[0417] In some embodiments, R8 is [ka] is.

[0418] In some embodiments, R9 is hydrogen, halogen, —OH, —CN, —NO2, —NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are selected from one or more R 11 is optionally replaced by

[0419] In some embodiments, R9 is hydrogen.

[0420] In some embodiments, R9 is cycloalkyl.

[0421] In some embodiments, R9 is C3-C8 cycloalkyl.

[0422] In some embodiments, R9 is [ka] is.

[0423] In some embodiments, R 10 are halogens, -OH, -CN, -NO2, -NR 12 R 13 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are selected from one or more R 11 is optionally replaced by

[0424] In some embodiments, u is 0. In some embodiments, u is 1.

[0425] In some embodiments, u is 1.

[0426] In some embodiments, R 10 is a halogen.

[0427] In some embodiments, R 10 is F.

[0428] In some embodiments, R 10 is Cl.

[0429] In some embodiments, R 10 is Br.

[0430] In some embodiments, R 10 is a C1-C6 alkyl.

[0431] In some embodiments, R 10 is -CH3.

[0432] In some embodiments, each R 11 are halogens, -OH, -CN, -NO2, -NR 12 R 13、 and independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl.

[0433] In some embodiments, R 11 is a halogen.

[0434] In some embodiments, R 11 is F. In some embodiments, R 11 is Cl. In some embodiments, R 11 is Br.

[0435] In some embodiments, R 11 is -OH.

[0436] In some embodiments, R 11 is -CN.

[0437] In some embodiments, R 11 is a C1-C6 alkyl.

[0438] In some embodiments, R 11 is -CF3.

[0439] In some embodiments, each R L are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.

[0440] In some embodiments, R L is hydrogen.

[0441] In some embodiments, R Lis a C1-C6 alkyl.

[0442] In some embodiments, R 12 and R 13 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl.

[0443] In some embodiments, R 12 and R 13 are hydrogen atoms.

[0444] In some embodiments, R 12 is methyl and R 13 is H.

[0445] In some embodiments, R 12 is H and R 13 is methyl.

[0446] In some embodiments, R 12 and R 13 are methyl, respectively.

[0447] In some embodiments, R 12 and R 13 are ethyl, respectively.

[0448] In some embodiments, R 12 is H and R 13 is -OH.

[0449] In some embodiments, the compound has formula (II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0450] In some embodiments, the compound has Formula (I-II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0451] In some embodiments, the compound has Formula (I-III): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0452] In some embodiments, the compound has the formula (IIH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0453] In some embodiments, the compound has formula (I-II-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0454] In some embodiments, the compound has the formula (IIO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0455] In some embodiments, the compound has formula (I-II-O): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0456] In some embodiments, the compound has the formula (II'): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0457] In some embodiments, the compound has formula (I-II'): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0458] In some embodiments, the compound has formula (IIA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0459] In some embodiments, the compound has formula (IIA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0460] In some embodiments, the compound has formula (IIA-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0461] In some embodiments, the compound has formula (IIA-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0462] In some embodiments, the compound has formula (IIA-1-a-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0463] In some embodiments, the compound has formula (IIA-1-a-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0464] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, wherein each R3 is H or two R3 form =O, and all other variables are as defined herein.

[0465] In some embodiments, the compound has formula (IIA-1-a-1-IA-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, wherein each R3 is H or two R3 form =O, and all other variables are as defined herein.

[0466] In some embodiments, the compound has the formula (I-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0467] In some embodiments, the compound has formula (I-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0468] In some embodiments, the compound has formula (I-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0469] In some embodiments, the compound has formula (I-4): [ka]

[0470] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0471] In some embodiments, the compound has formula (I-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0472] In some embodiments, the compound has formula (I-6): [ka]

[0473] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0474] In some embodiments, the compound has formula (I-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0475] In some embodiments, the compound has formula (I-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0476] In some embodiments, the compound has formula (I-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0477] In some embodiments, the compound has formula (I-10): [ka]

[0478] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0479] In some embodiments, the compound has formula (I-11): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0480] In some embodiments, the compound has formula (I-12): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0481] In some embodiments, the compound has formula (I-13): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0482] In some embodiments, the compound has formula (I-14): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0483] In some embodiments, the compound has formula (I-15): [ka] (I-15), or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3 forms =0, and the remainder of the variables are as defined herein.

[0484] In some embodiments, the compound has formula (I-16): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein both R are H or two R 3forms =0, and the remainder of the variables are as defined herein.

[0485] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is an integer selected from 0 and 1, and wherein each R is H or two R 3 forms =0, and all other variables are as defined herein.

[0486] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each R is H or two R 3 forms =0, n is selected from 0 and 1, and all other variables are as defined herein.

[0487] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IA-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each R is H or two R 3 forms =0, where each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0488] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IA-1-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0489] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IA-1-aO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0490] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each R3 is H or two R3 form =O, n is selected from 0 and 1, and all other variables are as defined herein.

[0491] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IA-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0492] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IA-2-O): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0493] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IA-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each R3 is H or two R3 form =O, n is selected from 0 and 1, and all other variables are as defined herein.

[0494] In some embodiments, the compound has formula (IIA-1-a-1-IA-1-IA-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0495] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IA-3-O): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0496] In some embodiments, the compound has formula (IIA-1-a-1-IA-1-IB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0497] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IB-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each R3 is H or two R3 form =O, n is selected from 0 and 1, and all other variables are as defined herein.

[0498] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IB-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, each R3 is H or two R3 are =O, and all other variables are as defined herein.

[0499] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IB-1-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0500] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IB-1-aO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0501] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IB-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each R3 is H or two R3 form =O, n is selected from 0 and 1, and all other variables are as defined herein.

[0502] In some embodiments, the compound has formula (IIA-1-a-1-IA-1-IB-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0503] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IB-2-O): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0504] In some embodiments, the compound has formula (IIA-1-a-1-IA-1-IB-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each R3 is H or two R3 form =O, n is selected from 0 and 1, and all other variables are as defined herein.

[0505] In some embodiments, the compound has formula (IIA-1-a-1-IA-1-IB-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0506] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IB-3-O): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0507] In some embodiments, the compound has formula (IIA-1-a-1-IA-1-IC): [ka] (IIA-1-a-1-IA-1-IC), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0508] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each R3 is H or two R3 are =O, each n is independently selected from 0 and 1, and all other variables are as defined herein.

[0509] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, each R3 is H or two R3 are =O, and all other variables are as defined herein.

[0510] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-1-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0511] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-1-aO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0512] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, each R3 is H or two R3 are =O, and all other variables are as defined herein.

[0513] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-1-bH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0514] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-1-bO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0515] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, each R3 is H or two R3 are =O, and all other variables are as defined herein.

[0516] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-1-cH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0517] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-1-cO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0518] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, each R3 is H or two R3 are =O, and all other variables are as defined herein.

[0519] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each x is independently selected from 0 and 1, each R is H or two R are =0, and all other variables are as defined herein.

[0520] In some embodiments, the compound has formula (IIA-1-a-1-IA-1-IC-2-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each x is independently selected from 0 and 1, and all other variables are as defined herein.

[0521] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-2-aO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each x is independently selected from 0 and 1, and all other variables are as defined herein.

[0522] In some embodiments, the compound has formula (IIA-1-a-1-IA-1-IC-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, each R3 is H or two R3 are =O, and all other variables are as defined herein.

[0523] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-3-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each x is independently selected from 0 and 1, each R is H or two R are =0, and all other variables are as defined herein.

[0524] In some embodiments, the compound has formula (IIA-1-a-1-IA-1-IC-3-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each x is independently selected from 0 and 1, and all other variables are as defined herein.

[0525] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-IC-3-aO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each x is independently selected from 0 and 1, and all other variables are as defined herein.

[0526] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-ID): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each n is independently selected from 0 and 1, and all other variables are as defined herein.

[0527] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-ID-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each R3 is H or two R3 are =O, each n is independently selected from 0 and 1, and all other variables are as defined herein.

[0528] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-ID-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, each R3 is H or two R3 are =O, and all other variables are as defined herein.

[0529] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-ID-1-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0530] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-ID-1-aO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0531] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-ID-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, each R3 is H or two R3 are =O, and all other variables are as defined herein.

[0532] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-ID-1-bH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each of w, u, and n is independently selected from 0 and 1, and all other variables are as defined herein.

[0533] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-ID-1-bO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each x is independently selected from 0 and 1, and all other variables are as defined herein.

[0534] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-ID-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each x is independently selected from 0 and 1, each R is H or two R are =0, and all other variables are as defined herein.

[0535] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-ID-1-cH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each x is independently selected from 0 and 1, and all other variables are as defined herein.

[0536] In some embodiments, the compound has the formula (IIA-1-a-1-IA-1-ID-1-cO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each x is independently selected from 0 and 1, and all other variables are as defined herein.

[0537] In some embodiments, the compound has formula (IIA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0538] In some embodiments, the compound has formula (IIA-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0539] In some embodiments, the compound has formula (IIA-2-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0540] In some embodiments, the compound has formula (IIA-2-a-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0541] In some embodiments, the compound has formula (IIA-2-a-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0542] In some embodiments, the compound has formula (IIB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0543] In some embodiments, the compound has formula (IIB-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0544] In some embodiments, the compound has formula (IIB-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0545] In some embodiments, the compound has formula (IIB-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0546] In some embodiments, the compound has formula (IIB-1-a-1-I): [ka] (IIB-1-a-1-I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0547] In some embodiments, the compound has formula (IIB-1-a-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0548] In some embodiments, the compound has formula (IIB-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0549] In some embodiments, the compound has formula (IIB-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0550] In some embodiments, the compound has formula (IIB-2-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0551] In some embodiments, the compound has formula (IIB-2-a-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0552] In some embodiments, the compound has formula (IIB-2-a-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0553] In some embodiments, the compound has formula (IIB-2-a-1-IA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0554] In some embodiments, the compound has formula (IIB-2-a-1-IA-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0555] In some embodiments, the compound has formula (IIB-2-a-1-IA-1-IC): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is selected from 0 and 1, and all other variables are as defined herein.

[0556] In some embodiments, the compound has formula (IIB-2-a-1-IA-1-IC-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is selected from 0 and 1, each R3 is H or two R3 are =O, and all other variables are as defined herein.

[0557] In some embodiments, the compound has formula (IIB-2-a-1-IA-1-IC-3-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each R3 is H or two R3 are =O, and all other variables are as defined herein.

[0558] In some embodiments, the compound has formula (IIB-2-a-1-IA-1-IC-3-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0559] In some embodiments, the compound has formula (IIB-2-a-1-IA-1-IC-3-aO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0560] In some embodiments, the compound has formula (I-II-A): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0561] In some embodiments, the compound has formula (I-II-A-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0562] In some embodiments, the compound has the formula (I-II-A-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0563] In some embodiments, the compound has the formula (I-II-A-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0564] In some embodiments, the compound has formula (I-II-A-1-a-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0565] In some embodiments, the compound has formula (I-II-A-1-a-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0566] In some embodiments, the compound has the formula (I-II-A-1-a-1-IA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is 0 or 1, and all other variables are as defined herein.

[0567] In some embodiments, the compound has formula (I-II-A-1-a-1-IA-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is 0 or 1, and all other variables are as defined herein.

[0568] In some embodiments, the compound has formula (I-II-A-1-a-1-IA-1-IC): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where n is 0 or 1, and all other variables are as defined herein.

[0569] In some embodiments, the compound has the formula (I-II-A-1-a-1-IA-1-IC-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein n is 0 or 1, each R is H or two R are =0, and all other variables are as defined herein.

[0570] In some embodiments, the compound has the formula (I-II-A-1-a-1-IA-1-IC-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein each R3 is H or two R3 are =O, and all other variables are as defined herein.

[0571] In some embodiments, the compound has the formula (I-II-A-1-a-1-IA-1-IC-1-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0572] In some embodiments, the compound has the formula (I-II-A-1-a-1-IA-1-IC-1-aO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0573] In some embodiments, the compound has formula (I-II-A-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0574] In some embodiments, the compound has formula (I-II-A-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0575] In some embodiments, the compound has formula (I-II-A-2-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0576] In some embodiments, the compound has formula (I-II-A-2-a-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0577] In some embodiments, the compound has formula (I-II-A-2-a-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0578] In some embodiments, the compound has formula (I-II-B): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0579] In some embodiments, the compound has formula (I-II-B-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0580] In some embodiments, the compound has the formula (I-II-B-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0581] In some embodiments, the compound has the formula (I-II-B-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0582] In some embodiments, the compound has formula (I-II-B-1-a-1-I): [ka] (I-II-B-1-a-1-I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0583] In some embodiments, the compound has formula (I-II-B-1-a-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0584] In some embodiments, the compound has formula (I-II-B-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0585] In some embodiments, the compound has formula (I-II-B-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0586] In some embodiments, the compound has formula (I-II-B-2-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0587] In some embodiments, the compound has formula (I-II-B-2-a-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0588] In some embodiments, the compound has formula (I-II-B-2-a-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0589] In some embodiments, the compound has formula (II-A): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0590] In some embodiments, the compound has formula (II-AI): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0591] In some embodiments, the compound has formula (II-AIa): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0592] In some embodiments, the compound has formula (II-AIa-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0593] In some embodiments, the compound has formula (II-AIa-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0594] In some embodiments, the compound has formula (II-AIa-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0595] In some embodiments, the compound has formula (II-AIa-1-IA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0596] In some embodiments, the compound has formula (II-B): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0597] In some embodiments, the compound has formula (II-BI): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0598] In some embodiments, the compound has the formula (II-BIa): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0599] In some embodiments, the compound has the formula (II-BIa-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0600] In some embodiments, the compound has formula (II-BIa-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0601] In some embodiments, the compound has the formula (II-BIa-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0602] In some embodiments, the compound has the formula (II-BIa-1-IA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0603] In some embodiments, the compound has the formula (AI): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0604] In some embodiments, the compound has the formula (AI-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0605] In some embodiments, the compound has the formula (AI-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0606] In some embodiments, the compound has the formula (AI-1-aI): [ka] (AI-1-aI) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0607] In some embodiments, the compound has the formula (AI-1-aIA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0608] In some embodiments, the compound has the formula (AI-1-aIA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0609] In some embodiments, the compound has the formula (AI-1-aIA-1-a): [ka] (AI-1-aIA-1-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0610] In some embodiments, the compound has the formula (AI-1-aIA-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0611] In some embodiments, the compound has the formula (AI-1-aIA-1-a-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0612] In some embodiments, the compound has the formula (AI-1-aIA-1-a-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6; R7 is selected from F, Cl, Br, I, CN, SO2CH3, and all other variables are as defined herein.

[0613] In some embodiments, the compound has the formula (AI-1-aIA-1-a-1-a-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0614] In some embodiments, the compound has the formula (AI-1-aIA-1-a-1-a-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0615] In some embodiments, the compound has the formula (AI-1-aIA-1-a-1-a-1-a-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0616] In some embodiments, the compound has the formula (AI-1-aIA-1-a-1-a-1-a-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0617] In some embodiments, the compound has the formula (AI-1-aIA-1-a-1-a-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0618] In some embodiments, the compound has the formula (AI-1-aIA-1-a-1-a-1-b-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0619] In some embodiments, the compound has the formula (AI-1-aIA-1-a-1-a-1-b-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0620] In some embodiments, the compound has the formula (AI-1-aIA-1-a-1-a-1-b-3): [ka] (AI-1-aIA-1-a-1-a-1-b-3) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0621] In some embodiments, the compound has the formula (AI-1-aIA-1-a-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0622] In some embodiments, the compound has the formula (AI-1-aIA-1-a-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0623] In some embodiments, the compound has the formula (AI-1-aIA-1-a-2-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6; R7 is selected from F, Cl, Br, I, CN, SO2CH3, and all other variables are as defined herein.

[0624] In some embodiments, the compound has the formula (AI-1-aIA-1-a-2-a-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0625] In some embodiments, the compound has the formula (AI-1-aIA-1-a-2-a-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0626] In some embodiments, the compound has the formula (AI-1-aIA-1-a-2-a-1-a-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0627] In some embodiments, the compound has the formula (AI-1-aIA-1-a-2-a-1-a-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0628] In some embodiments, the compound has the formula (AI-1-aIA-1-a-2-a-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0629] In some embodiments, the compound has the formula (AI-1-aIA-1-a-2-a-1-b-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0630] In some embodiments, the compound has the formula (AI-1-aIA-1-a-2-a-1-b-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0631] In some embodiments, the compound has the formula (AI-1-aIA-1-a-2-a-1-b-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0632] In some embodiments, the compound has the formula (AI-1-aIA-1-a-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0633] In some embodiments, the compound has the formula (AI-1-aIA-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0634] In some embodiments, the compound has the formula (AI-1-aIA-1-b-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0635] In some embodiments, the compound has the formula (AI-1-aIA-1-b-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0636] In some embodiments, the compound has the formula (AI-1-aIA-1-b-1-a*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0637] In some embodiments, the compound has the formula (AI-1-aIA-1-b-1-a**): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0638] In some embodiments, the compound has the formula (AI-1-aIA-1-b-1-a***): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0639] In some embodiments, the compound has the formula (AI-1-aIA-1-b-1-a****): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0640] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0641] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0642] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0643] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2-a-1*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0644] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2-a-1**): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0645] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2-a-1***): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0646] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2-a-1****): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0647] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2-a-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0648] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2-a-2*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0649] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2-a-2**): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0650] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2-a-2***): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0651] In some embodiments, the compound has the formula (AI-1-aIA-1-b-2-a-2****): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0652] In some embodiments, the compound has the formula (AI-1-aIA-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0653] In some embodiments, the compound has the formula (AI-1-aIA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0654] In some embodiments, the compound has the formula (AI-1-aIA-2-a): [ka] (AI-1-aIA-2-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0655] In some embodiments, the compound has the formula (AI-1-aIA-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0656] In some embodiments, the compound has the formula (AI-1-aIA-3-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0657] In some embodiments, the compound has the formula (AI-1-aIA-3-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0658] In some embodiments, the compound has the formula (AI-1-aIA-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where m' is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0659] In some embodiments, the compound has the formula (AI-1-aIA-4-a): [ka] (AI-1-aIA-4-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where m' is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0660] In some embodiments, the compound has the formula (AI-1-aIA-4-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where m' is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0661] In some embodiments, the compound has the formula (AI-1-aIA-4-a-1-A): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where m' is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0662] In some embodiments, the compound has the formula (AI-1-aIA-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where m' is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0663] In some embodiments, the compound has the formula (AI-1-aIA-5-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where m' is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0664] In some embodiments, the compound has the formula (AI-1-aIA-5-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where m' is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0665] In some embodiments, the compound has the formula (AI-1-aIA-5-a-1-A): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where m' is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0666] In some embodiments, the compound has the formula (AI-1-aIA-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where m' is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0667] In some embodiments, the compound has the formula (AI-1-aIA-6-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0668] In some embodiments, the compound has the formula (AI-1-aIA-6-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0669] In some embodiments, the compound has the formula (AI-1-aIA-6-a-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0670] In some embodiments, the compound has the formula (AI-1-aIA-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0671] In some embodiments, the compound has the formula (AI-1-aIA-7-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0672] In some embodiments, the compound has the formula (AI-1-aIA-7-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0673] In some embodiments, the compound has the formula (AI-1-aIA-7-a-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0674] In some embodiments, the compound has formula (AI-1-a-II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0675] In some embodiments, the compound has the formula (AI-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0676] In some embodiments, the compound has the formula (AI-1-bI): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0677] In some embodiments, the compound has the formula (AI-1-bIA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0678] In some embodiments, the compound has the formula (AI-1-bIA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0679] In some embodiments, the compound has the formula (AI-1-bIA-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0680] In some embodiments, the compound has the formula (AI-1-bIA-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0681] In some embodiments, the compound has the formula (AI-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0682] In some embodiments, the compound has the formula (AI-1-cI): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0683] In some embodiments, the compound has the formula (AI-1-cIA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0684] In some embodiments, the compound has the formula (AI-1-cIA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0685] In some embodiments, the compound has the formula (AI-1-cIA-1-a): [ka] (AI-1-cIA-1-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0686] In some embodiments, the compound has the formula (AI-1-cIA-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0687] In some embodiments, the compound has the formula (AI-1-cIA-1-a-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0688] In some embodiments, the compound has the formula (AI-1-cIA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0689] In some embodiments, the compound has the formula (AI-1-cIA-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0690] In some embodiments, the compound has the formula (AI-1-cIA-2-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein r is an integer selected from 1, 2, 3, 4, 5, and 6, and all other variables are as defined herein.

[0691] In some embodiments, the compound has the formula (AI-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0692] In some embodiments, the compound has formula (A-II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0693] In some embodiments, the compound has formula (A-II-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0694] In some embodiments, the compound has the formula (A-II-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0695] In some embodiments, the compound has the formula (A-II-1-aI): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0696] In some embodiments, the compound has the formula (A-II-1-aIA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0697] In some embodiments, the compound has the formula (A-II-1-aIA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0698] In some embodiments, the compound has the formula (A-II-1-aIA-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0699] In some embodiments, the compound has the formula (A-II-1-aIA-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0700] In some embodiments, the compound has formula (A-II-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0701] In some embodiments, the compound has formula (A-II-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0702] In some embodiments, the compound has the formula (A-II-2-aI): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0703] In some embodiments, the compound has the formula (A-II-2-aIA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0704] In some embodiments, the compound has the formula (A-II-2-aIA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0705] In some embodiments, the compound has the formula (A-II-2-aIA-1): [ka] (A-II-2-aIA-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where all variables are as defined herein.

[0706] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of the compounds of the present disclosure, which are sufficiently basic, for example, with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid methanesulfonate, or maleic acid. Additionally, suitable pharmaceutically acceptable salts of the compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide a pharmaceutically acceptable cation, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0707] It will be understood that the compounds of any one of the formulae disclosed herein, and any pharmaceutically acceptable salts thereof, include all isomeric forms, stereoisomers, mixtures of stereoisomers, and polymorphs of the compounds.

[0708] In some embodiments, the compound is selected from the compounds set forth in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[0709] In some embodiments, the compound is selected from the compounds set forth in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0710] In some embodiments, the compound is selected from the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0711] In some embodiments, the compound is selected from prodrugs of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0712] In some embodiments, the compound is selected from the compounds set forth in Table 1.

[0713] JPEG2025507758000358.jpg236170JPEG2025507758000359.jpg225170JPEG2025507758000360.jpg225170JPEG2025507758000361.jpg210170JPEG2025507758000362.jpg203170JPEG2025507758000363.jpg196170JPEG2025507758000364.jpg204170JPEG2025507758000365.jpg242170JPEG2025507758000366.jpg203170JPEG2025507758000367.jpg243170JPEG2025507758000368.jpg246170JPEG2025507758000369.jpg245170JPEG2025507758000370.jpg241170JPEG2025507758000371.jpg200170JPEG2025507758000372.jpg242170JPEG2025507758000373.jpg219170JPEG2025507758000374.jpg240170JPEG2025507758000375.jpg244170JPEG2025507758000376.jpg225170JPEG2025507758000377.jpg248170JPEG2025507758000378.jpg236170JPEG2025507758000379.jpg220170JPEG2025507758000380.jpg239170JPEG2025507758000381.jpg240170JPEG2025507758000382.jpg243170JPEG2025507758000383.jpg233170JPEG2025507758000384.jpg242170JPEG2025507758000385.jpg247170JPEG2025507758000386.jpg237170JPEG2025507758000387.jpg246170JPEG2025507758000388.jpg237170JPEG2025507758000389.jpg233170JPEG2025507758000390.jpg203170JPEG2025507758000391.jpg179170JPEG2025507758000392.jpg214170JPEG2025507758000393.jpg182170JPEG2025507758000394.jpg212170JPEG2025507758000395.jpg222170JPEG2025507758000396.jpg247170JPEG2025507758000397.jpg226170JPEG2025507758000398.jpg188170JPEG2025507758000399.jpg186170JPEG2025507758000400.jpg213170JPEG2025507758000401.jpg223170JPEG2025507758000402.jpg222170JPEG2025507758000403.jpg217170JPEG2025507758000404.jpg237170JPEG2025507758000405.jpg202170JPEG2025507758000406.jpg240170JPEG2025507758000407.jpg182170JPEG2025507758000408.jpg224170JPEG2025507758000409.jpg245170JPEG2025507758000410.jpg218170JPEG2025507758000411.jpg244170JPEG2025507758000412.jpg241170JPEG2025507758000413.jpg216170JPEG2025507758000414.jpg208170JPEG2025507758000415.jpg246170JPEG2025507758000416.jpg232170JPEG2025507758000417.jpg240170JPEG2025507758000418.jpg211170JPEG2025507758000419.jpg238170JPEG2025507758000420.jpg232170JPEG2025507758000421.jpg247170JPEG2025507758000422.jpg237170JPEG2025507758000423.jpg248170JPEG2025507758000424.jpg242170JPEG2025507758000425.jpg159170.

[0714] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 1.

[0715] In some embodiments, the compound is a lithium, sodium, potassium, calcium, or magnesium salt of any one of the compounds listed in Table 1.

[0716] In some embodiments, the compound is the sodium or potassium salt of any one of the compounds listed in Table 1.

[0717] In some embodiments, the compound is a salt of any acid listed in Table 2 with any one of the compounds listed in Table 1.

[0718] JPEG2025507758000426.jpg251170JPEG2025507758000427.jpg70170

[0719] In some embodiments, the compound is a salt of acetic acid and any one of the compounds listed in Table 1.

[0720] In some embodiments, the compound is a salt of adipic acid and any one of the compounds listed in Table 1.

[0721] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds listed in Table 1.

[0722] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds listed in Table 1.

[0723] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds listed in Table 1.

[0724] In some embodiments, the compound is a salt of citric acid and any one of the compounds listed in Table 1.

[0725] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds listed in Table 1.

[0726] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds listed in Table 1.

[0727] In some embodiments, the compound is a salt of formic acid and any one of the compounds listed in Table 1.

[0728] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds listed in Table 1.

[0729] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0730] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, as well as prodrugs and pharmaceutically acceptable salts thereof.

[0731] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0732] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0733] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1.

[0734] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0735] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0736] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0737] As used herein, the term "isotopic derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of Formula (A) is isotopically enriched or labeled with one or more isotopes compared to the corresponding compound of Formula (A). In some embodiments, an isotopic derivative is 2 H, 13 C. 14 C. 15 N, 18 O. 29 Si, 31 P, and 34 In some embodiments, the isotopic derivatives are deuterium-labeled compounds (i.e., enriched with or labeled with one or more atoms selected from S and S). 2 H).

[0738] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0739] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0740] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds listed in Table 1 and pharmaceutically acceptable salts thereof.

[0741] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1.

[0742] A deuterium-labeled compound is understood to contain deuterium atoms having an abundance of deuterium substantially greater than the natural abundance of deuterium, which is 0.015%.

[0743] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation in each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term "deuterium enrichment factor" refers to the ratio between the deuterium abundance and the natural abundance of deuterium.

[0744] It will be appreciated that deuterium-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein by substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[0745] Compounds of the present disclosure or pharmaceutically acceptable salts or solvates thereof containing the above deuterium atom(s) are within the scope of the present disclosure. 2H) may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0746] In some embodiments, the compound is 18 F-labeled compound.

[0747] In some embodiments, the compound is 123 I-labeled compound, 124 I-labeled compound, 125 I-labeled compound, 129 I-labeled compound, 131 I-labeled compound, 135 I-labeled compounds, or any combination thereof.

[0748] In some embodiments, the compound is 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 S-labeled compounds, or any combination thereof.

[0749] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 It will be appreciated that S-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds are generally prepared using S-labeled compounds instead of non-isotopic labeling reagents. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36It can be prepared by using an S-labeled reagent and by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0750] The above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 Compounds of the present disclosure containing one or more S atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 S) substitution may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0751] For the avoidance of doubt, when a group is qualified herein by "as described herein," it is to be understood that the group encompasses the broadest definition first occurring, as well as each and every specific definition of that group.

[0752] The various functional groups and substituents that make up the compounds of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1100 daltons. More usually, the molecular weight of the compound is less than 1000, for example, less than 900, or less than 800.

[0753] As used herein, the term "isomer" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0754] As used herein, the term "chiral center" refers to a carbon atom bonded to four nonidentical substituents.

[0755] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds with two or more chiral centers can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold, and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0756] As used herein, the term "geometric isomer" refers to diastereomers whose existence results from hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans or Z and E, which indicate that the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0757] It should be understood that the compounds of the present disclosure can be represented as different chiral or geometric isomers. When a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and it should be understood that the name of the compound does not exclude any isomeric form, and not all isomers may have the same level of activity.

[0758] It should be understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof. It should also be understood that not all atropisomers may have the same level of activity.

[0759] As used herein, the term "atropisomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropisomers owe their existence to the restriction of rotation caused by the hindrance of rotation of large groups around a central bond. Such atropisomers typically exist as mixtures, but recent advances in chromatographic techniques have made it possible to separate mixtures of two atropisomers in selected cases.

[0760] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, in which simultaneous electron and hydrogen atom shifts occur. Ring-chain tautomerism occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to give a cyclic (ring-like) form, such as that exhibited by glucose.

[0761] It should be understood that the compounds of the present disclosure can be represented as different tautomeric forms. When a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and it should also be understood that the naming of a compound does not exclude any tautomeric form. It will be understood that certain tautomers may have a higher level of activity than other tautomers.

[0762] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when a compound is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, referred to as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0763] The compounds of the present disclosure may have one or more asymmetric centers, and therefore, such compounds can be prepared as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and their racemic or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or resolution of racemates (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomer centers (E and Z isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers and mixtures thereof that have inflammasome inhibitory activity.

[0764] The present disclosure also includes compounds of the present disclosure as defined herein that contain one or more isotopic substitutions.

[0765] It should be understood that the compounds of any formula described herein include, where applicable, the compounds themselves, as well as their salts and solvates.Salts can be formed, for example, between an anion on the substituted compounds disclosed herein and a positively charged group (e.g., amino).Suitable anions include chloride, bromide, iodide, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0766] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on the substituted compounds disclosed herein and a negatively charged group (e.g., carboxylate). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing quaternary nitrogen atoms.

[0767] It is understood that compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0768] As used herein, the term "solvate" refers to a solvent addition form containing stoichiometric or non-stoichiometric amounts of solvent.Some compounds tend to capture a certain molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate.A hydrate is formed by the combination of one or more molecules of water with one molecule of a substance, where the water retains its molecular state as HO.

[0769] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another but differs slightly in composition (such as the substitution of one atom with an atom of a different element, or in the presence of a particular functional group, or the substitution of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance, but not similar or equivalent in structure or origin to the reference compound.

[0770] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0771] As used herein, the term "bioisomer" refers to a compound resulting from the exchange of an atom or group of atoms with another broadly similar atom or group of atoms. The purpose of bioisosteric substitution is to create a new compound with similar biological properties to the parent compound. Bioisosteric substitution can be physicochemical or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem.Rev.96,3147-3176,1996.

[0772] It should also be understood that any particular compound of any one of the formulas disclosed herein can exist in solvated form as well as unsolvated form, such as hydrated form.Suitable pharmaceutically acceptable solvates are, for example, hydrates such as hemihydrate, monohydrate, dihydrate or trihydrate.It should be understood that the present disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[0773] It should also be understood that any one particular compound of the formula disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof that have inflammasome inhibitory activity.It is generally known that crystalline materials can be analyzed using conventional techniques such as powder X-ray diffraction analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy.The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0774] Compounds of any one of the formulas disclosed herein can exist in many different tautomeric forms, and reference to a compound of formula (I) or (II) includes all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all others are nevertheless encompassed by formula (I) or (II). Examples of tautomeric forms include keto-, enol-, and enolate-forms, such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acinitro. [ka]

[0775] Compounds of any one of the formulas disclosed herein containing an amine functional group can also form N-oxides. Reference herein to compounds of formula (I) or (II) containing an amine functional group also includes N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 1977. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), which involves reacting an amine compound with meta-chloroperbenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0776] The compound of any one of the formulas disclosed herein can be administered in the form of a prodrug, which is decomposed in the human or animal body to release the compound of the present disclosure.Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compound of the present disclosure.Prodrugs can be formed when the compound of the present disclosure contains a suitable group or substituent to which a property-modifying group can be attached.Examples of prodrugs include derivatives of any one of the formulas disclosed herein that contain alkyl or acyl substituents that can be cleaved in vivo on the ester or amide group.

[0777] Therefore, the present disclosure includes any one compound of the formula disclosed herein as defined herein above when it is made available by organic synthesis and when it is made available in the human or animal body by cleavage of its prodrug.Therefore, the present disclosure includes any one compound of the formula disclosed herein that is produced by organic synthesis means, and also includes compounds that are produced in the human or animal body by metabolism of precursor compounds, that is, any one compound of the formula disclosed herein can be a synthetically produced compound or a metabolically produced compound.

[0778] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein are those that are, based on sound medical judgment, suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity. Various forms of prodrugs are described, for example, in the following literature: a) Methods in Enzymology, Vol. 42, pp. 309-396 (edited by K. Widder et al.) (Academic Press, 1985); b) Design of Prodrugs (edited by H. Bundgaard) (Elsevier, 1985); c) A Textbook of Drug Design and Development (edited by Krogsgaard-Larsen and H. Bundgaard) Chapter 5 "Design and Application of Prodrugs" (by H. Bundgaard) pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al. al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Volume 14; and h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0779] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. An in vivo cleavable ester or ether of a compound of any one of the formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include C1-C esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 C1-C alkyl groups such as alkanoyl groups, ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. 10 and alkoxycarbonyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[0780] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a carboxy group include, for example, an in vivo cleavable amide thereof, an amine such as ammonia, a C group such as methylamine, etc. 1~4 They are amides formed with alkylamines, (C1-C4 alkyl)2amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amino acids such as glycine or its esters.

[0781] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example, C1-C acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 and amides formed with alkanoyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0782] The in vivo effect of any one compound of the formula disclosed herein may be partially exerted by one or more metabolic products formed in the human or animal body after administration of any one compound of the formula disclosed herein.As mentioned hereinabove, the in vivo effect of any one compound of the formula disclosed herein may also be exerted by the metabolism of precursor compounds (prodrugs). Method for synthesizing compounds of formula (A)

[0783] The compounds of the invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are illustrated in the schemes provided below.

[0784] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as illustrated in part by the synthetic schemes below. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are used where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage in the compound synthesis, using methods readily apparent to those skilled in the art. The selection process, as well as the reaction conditions and procedures, will recognize whether a stereocenter exists in compounds of formula (I). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis), including not only racemates but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art, see, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0785] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic and / or enzymatic processes.

[0786] The compounds of the present invention can be prepared by many methods well known to those skilled in the art of organic synthesis.For example, the compounds of the present invention can be synthesized using the methods described below, along with synthetic methods known in the field of synthetic organic chemistry, or variations thereof recognized by those skilled in the art.Suitable methods include, but are not limited to, the methods described below.The compounds of the present invention can be synthesized according to the steps outlined in General Procedure A or B, which includes different sequences for assembling intermediates or compounds.Starting materials are commercially available or are prepared by known procedures reported in the literature, or as shown below. General Procedure

[0787] In general, compounds of formula (I) can be prepared using a series of reactions known to those skilled in the art of organic synthesis. The following general schemes illustrate some routes to compounds of formula (I): [ka]

[0788] All reagents may be commercially available compounds themselves or may be synthetic products from commercially available reagents. For each compound in the preparation, a single-step or multi-step synthetic procedure (including but not limited to the procedures described herein in the preparation section) may be used.

[0789] A specific, non-limiting example of a reaction sequence leading to a compound of formula (I) can be illustrated by the preparation of compound 4. [ka]

[0790] A specific, non-limiting example of the reaction sequence leading to compounds of formula (I) can be illustrated by the preparation of compound 15. [ka]

[0791] A specific, non-limiting example of the reaction sequence leading to compounds of formula (I) can be illustrated by the preparation of compound 16. [ka] [ka]

[0792] A specific, non-limiting example of a reaction sequence leading to a compound of formula (I) can be illustrated by the preparation of compound 6. [ka]

[0793] A specific, non-limiting example of the reaction sequence leading to compounds of formula (I) can be illustrated by the preparation of compound 19. [ka]

[0794] Those skilled in the art will readily appreciate that the compounds of formula (I) obtained according to the above procedures may be subject to further transformations and modifications to obtain other compounds of formula (I). Biological assays

[0795] Once compounds designed, selected, and / or optimized by the above methods are produced, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to, the assays described below, to determine whether they have the predicted activity, binding activity, and / or binding specificity.

[0796] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it may be possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques, including but not limited to those described below.

[0797] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein. Pharmaceutical Composition

[0798] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

[0799] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from the combination of the specified ingredients in the specified amounts.

[0800] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, etc. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0801] The formulation of the present disclosure can be in the form of an aqueous solution containing an aqueous vehicle.The aqueous vehicle component can comprise water and at least one pharmaceutically acceptable excipient.Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonicity agents, viscosity / suspending agents, buffering agents, and pH adjusting agents, and mixtures thereof.

[0802] Any suitable solubility enhancer may be used. Solubility enhancers include cyclodextrins such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly, methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfonated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly, methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0803] Any suitable chelating agent can be used, examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[0804] Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and quaternary ammonium salts such as butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0805] In some embodiments, exemplary preservatives include those selected from the group consisting of benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and quaternary ammonium salts such as butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0806] The aqueous vehicle may also contain an isotonicity agent to adjust the isotonicity (osmotic pressure). The isotonicity agent may be selected from the group consisting of glycols (e.g., propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the isotonicity agent is selected from the group consisting of glycols (e.g., propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0807] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycols (Carbopol-Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, Carbopol 974P, and the like), and mixtures thereof.

[0808] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to a target acceptable pH range. Therefore, it may not be necessary to use both an acid and a base; depending on the formulation, the addition of either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0809] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (e.g., boric acid or salts thereof, including disodium tetraborate), citrate buffers (e.g., citric acid or salts thereof, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0810] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0811] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier.They can be enclosed in gelatin capsules or compressed into tablets.For oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, and the compound in the fluid carrier is orally applied, swallowed, expectorated, or swallowed.Pharmaceutically compatible binding agents and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0812] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined herein above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[0813] In some embodiments, the pharmaceutical compositions described herein may further comprise one or more additional pharmaceutically active agents.

[0814] Compositions of the disclosure may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0815] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0816] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the MLL-associated conditions referred to herein.

[0817] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with the MLL-associated conditions referred to herein.

[0818] The size of a dose of a compound of formula (I) for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration, in accordance with well-known medical principles. How to use

[0819] In some aspects, the present disclosure provides methods for degrading MALT1 (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0820] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0821] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0822] In some embodiments, the disease or disorder is associated with MALT1. In some embodiments, the disease or disorder is a disease or disorder in which MALT1 is implicated.

[0823] The compounds of the present invention are PROTACs of MALT1.

[0824] The compounds of the present invention are also useful for treating diseases associated with MALT1. For example, diseases and conditions treatable according to the methods of the present invention include immunodeficiency 12; lymphoma, mucosal-associated lymphoid type (MALTOMA); combined immunodeficiency; combined immunodeficiency of T and B cells; or lymphoma.

[0825] In some embodiments, the disease or disorder is lymphoma.

[0826] In some embodiments, the disease or disorder is lymphoma, mucosa-associated lymphocytic type (MALTOMA).

[0827] In some embodiments, the disease or disorder is an immunodeficiency.

[0828] In some embodiments, the disease or disorder is combined immunodeficiency.

[0829] In some embodiments, the disease or disorder is a combined T-cell and B-cell immunodeficiency.

[0830] In some aspects, the present disclosure provides a method of treating or preventing lymphoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0831] In some aspects, the present disclosure provides a method for treating or preventing immunodeficiency 12 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0832] In some aspects, the present disclosure provides a method of treating or preventing lymphoma, mucosa-associated lymphocyte type (MALTOMA) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0833] In some aspects, the present disclosure provides a method of treating or preventing combined immune deficiency in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0834] In some aspects, the present disclosure provides a method of treating or preventing combined T-cell and B-cell immunodeficiency in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0835] In some aspects, the present disclosure provides a method of treating lymphoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0836] In some aspects, the present disclosure provides a method for treating an immune deficiency 12 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0837] In some aspects, the present disclosure provides a method of treating lymphoma, mucosa-associated lymphocyte type (MALTOMA) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0838] In some aspects, the present disclosure provides a method of treating combined immune deficiency in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0839] In some aspects, the present disclosure provides a method of treating a combined T-cell and B-cell immune deficiency in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0840] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the degradation of MALT1 (e.g., in vitro or in vivo).

[0841] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or disorder disclosed herein.

[0842] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0843] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing lymphoma in a subject in need thereof.

[0844] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing immunodeficiency 12 in a subject in need thereof.

[0845] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing lymphoma, mucosa-associated lymphocyte type (MALTOMA) in a subject in need thereof.

[0846] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing combined immune deficiency in a subject in need thereof.

[0847] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a combined T-cell and B-cell immunodeficiency in a subject in need thereof.

[0848] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating lymphoma in a subject in need thereof.

[0849] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating an immune deficiency 12 in a subject in need thereof.

[0850] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating lymphoma, mucosa-associated lymphocyte type (MALTOMA) in a subject in need of such treatment.

[0851] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a combined immune deficiency in a subject in need thereof.

[0852] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a combined T-cell and B-cell immunodeficiency in a subject in need thereof.

[0853] In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for degrading MALT1 (e.g., in vitro or in vivo).

[0854] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0855] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0856] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing lymphoma in a subject in need thereof.

[0857] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing lymphoma, mucosa-associated lymphocyte type (MALTOMA) in a subject in need thereof.

[0858] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing immunodeficiency 12 in a subject in need thereof.

[0859] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing combined immune deficiency in a subject in need thereof.

[0860] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing combined T-cell and B-cell immunodeficiency in a subject in need thereof.

[0861] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating lymphoma in a subject in need thereof.

[0862] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating lymphoma, mucosa-associated lymphocyte type (MALTOMA) in a subject in need thereof.

[0863] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating immune deficiency 12 in a subject in need thereof.

[0864] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating combined immune deficiency in a subject in need thereof.

[0865] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a combined T-cell and B-cell immunodeficiency in a subject in need thereof.

[0866] The present disclosure provides compounds that function as PROTACs for MALT1 (e.g., in vitro or in vivo). Accordingly, the present disclosure provides methods for degrading MALT1 in vitro or in vivo, the methods comprising contacting a cell with a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt thereof.

[0867] In some embodiments, the MALT1 PROTAC is a compound of the present disclosure.

[0868] The efficacy of the compounds of the present disclosure can be determined by industry-accepted assays / disease models according to standard practices for elucidating the same as described in the art and found in current general knowledge.

[0869] The present disclosure also provides a method for treating a disease or disorder in which MALT1 is implicated in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0870] In some embodiments, the subject is a mammal, hi some embodiments, the subject is a human. Route of administration

[0871] The compounds of the present disclosure or pharmaceutical compositions containing these compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, at the desired site of action).

[0872] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (e.g., including patches, bandages, etc.); transmucosal (e.g., including patches, bandages, etc.); intranasal (e.g., by nasal spray); ophthalmic (e.g., eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via an aerosol, e.g., used through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; e.g., by implantation of a depot or reservoir subcutaneously or intramuscularly.

[0873] Abbreviations used in the examples below and elsewhere in this specification are as follows: JPEG2025507758000436.jpg234170JPEG2025507758000437.jpg46170(Example) General Synthetic Procedures and Examples for the Preparation of Compounds. Building Block Synthesis Synthesis of 7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (P4) [ka] Preparation 1. Ethyl 3-cyclopentyl-3-oxopropanoate (P1) 1) Carbonyldiimidazole (10.91 g, 67.25 mmol) was added in small portions to a mixture of tetrahydrofuran-2-carboxylic acid (7.1 g, 61.14 mmol) and anhydrous EtOAc (100 mL). The mixture was stirred at 50° C. for 3 hours. 2) MgCl2 (23.3 g, 122.28 mmol) was added portionwise to a mixture of potassium 3-ethoxy-3-oxopropanoate (20.81 g, 122.28 mmol) and anhydrous EtOAc (300 mL). The mixture was stirred at 50 °C for 3 hours. The solution from step (1) was added dropwise to the suspension from step (2), and the mixture was stirred at reflux overnight. The mixture was cooled in an ice bath and acidified to pH = 3 with 4 M HCl (140 mL). The mixture was warmed to ambient temperature, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water, brine, and dried (Na2SO4). Concentration and purification by chromatography on silica gel gave compound P1 (8.5 g, 75%). 1 H NMR(400MHz,CDCl3),δ:4.40(dd,J=8.3,6.5Hz,1H),4.21(q,J=7.1Hz,2H),3.93(dd,J=9.6,3.9Hz,2H),3.5 9(s,2H),2.21(ddd,J=15.4,12.6,7.1Hz,1H),2.13-2.00(m,1H),1.98-1.85(m,2H),1.26(t,J=7.1Hz,3H).

[0874] Preparation 2. Ethyl (2Z)-3-(dimethylamino)-2-(tetrahydrofuran-2-ylcarbonyl)acrylate (P2) A solution of compound P1 (10.6 g, 56.9 mmol) and N,N-dimethylformamide dimethyl acetal (75 mL, 569.0 mmol) was stirred at reflux overnight. The mixture was evaporated to dryness, and the residue was purified by silica gel column chromatography. Yield of compound P2 (11.2 g, 82%). 1H NMR(400MHz,DMSO-d6),δ:7.59(d,J=8.7Hz,1H),4.80(dd,J=8.0,5.4Hz,1H),4.08(q,J=7.1Hz,2H),3.71(t,J=6.8Hz, 2H),3.31(s,6H),1.99(dq,J=12.2,7.7Hz,1H),1.87(dt,J=12.1,6.4Hz,1H),1.81-1.66(m,2H),1.21(t,J=7.1Hz,3H).

[0875] Preparation 3. Ethyl 7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (P3) To a solution of compound P2 (9.5 g, 39.3 mmol) in 200 mL of EtOH, 1H-pyrazol-5-amine (4.0 g, 47.2 mmol) was added. The mixture was stirred at reflux overnight. The mixture was evaporated, and the residue was purified by silica gel column chromatography. Yield of compound P3 (9.0 g, 88%). 1 H NMR(400MHz,DMSO-d6),δ:8.60(s,1H),8.36(d,J=2.3Hz,1H),6.86(t,J=3.9Hz,1H),5.70(t,J=7.2Hz,1H),4.41-4.32(m,1H),4 .31-4.22(m,1H),3.97(dd,J=14.3,7.1Hz,1H),3.93-3.83(m,1H),2.67-2.54(m,1H),2.24-1.94(m,3H),1.32(t,J=7.1Hz,3H).

[0876] Preparation 4. 7-(Tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (P4) A mixture of compound P3 (9.0 g, 34.4 mmol) and NaOH (2.1 g, 51.6 mmol) in 200 mL of EtOH and 50 mL of HO was stirred at 60 °C for 15 h and evaporated. The residue was diluted with water and acidified with 6 M HCl to pH = 3-4. The solid formed was filtered off and dried. Yield of compound P4 (6.9 g, 86%). 1H NMR(400MHz,DMSO-d6),δ:13.37(s,1H),8.57(d,J=10.1Hz,1H),7.96(t,J=9.5Hz,1H),6.34(t,J=8.3Hz,1H ),5.49(dd,J=9.0,4.4Hz,1H),4.06-3.59(m,2H),2.42-2.22(m,1H),1.93-1.78(m,2H),1.77-1.68(m,1H). Synthesis of ethyl 6-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P9) [ka]

[0877] Preparation 5. 3-Methyl-5-nitropyridine-2-carbonitrile (P5) A mixture of 2-chloro-3-methyl-5-nitro-pyridine (5.0 g, 29.0 mmol), zinc cyanide (2.7 g, 23.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.3 g, 1.45 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) in 1-methyl-2-pyrrolidinone (30 mL) was heated to 130-135 °C for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL), and filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over NaSO and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P5 (4.0 g, 85%). 1 H NMR (400MHz, DMSO-d6) δ 9.32 (s, 1H), 8.83 (s, 1H), 2.64 (s, 3H).

[0878] Preparation 6. N'-Hydroxy-3-methyl-5-nitropyridine-2-carboximidamide (P9) To a solution of hydroxylamine hydrochloride (8.6 g, 122.5 mmol) in 150 mL of H2O was added Na2CO3 (6.5 g, 61.3 mmol). The mixture was stirred at ambient temperature for 0.5 hours. Compound P5 (4.0 g, 24.5 mmol) was dissolved in EtOH and added to the mixture, and the reaction mixture was stirred at ambient temperature for 14 hours. EtOH was evaporated. The formed solid was filtered off and dried. Yield of compound P6 (4.0 g, 83%). 1 H NMR (400MHz, DMSO-d6) δ10.30 (d, J = 1.7 Hz, 1H), 9.20 (s, 1H), 8.52 (s, 1H), 5.95 (s, 2H), 2.61 (s, 3H).

[0879] Preparation 7. Ethyl 7-({[(1Z)-amino(3-methyl-5-nitropyridin-2-yl)methylene]amino}oxy)-7-oxoheptanoate (P7) To a solution of 7-ethoxy-7-oxo-heptanoic acid (0.50 g, 2.7 mmol) in 20 mL of DCM was added TEA (1.1 mL, 8.1 mmol). The mixture was stirred at room temperature for 10 minutes. After this, TBTU (10.8 g, 3.3 mmol) and compound P6 (0.52 g, 2.7 mmol) were added, and the mixture was stirred at ambient temperature for 15 hours. The mixture was washed with 20% K2CO3 (aq), dried over Na2SO4, and evaporated. The residue (P7) was used in the next step without further purification. LCMS ESI (m / z): 367.4 ([M+1] + ),197.3,179.3.

[0880] Preparation 8. Ethyl 6-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P8) A solution of compound P7 in 50 mL of dioxane was refluxed with stirring for 96 hours. The mixture was evaporated and purified by column chromatography on silica gel. The yield of compound P8 over the two steps (Preparation 7 and Preparation 8) was 0.56 g (61%). LCMS ESI (m / z): 349.5 ([M+1] + ),303.5.

[0881] Preparation 9. Ethyl 6-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P9) To a solution of compound P8 (0.56 g, 1.6 mmol) in 20 mL of acetic acid was added Fe powder (0.9 g, 16 mmol). The suspension was stirred at 70° C. for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL) and filtered through Celite. The filtrate was evaporated. The residue was diluted with saturated NaHCO3 (aq) and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P9 (0.44 g, 86%). LCMS ESI (m / z): 319.4 ([M+1] + ),149.4. Synthesis of 6-(3-{3-methyl-5-[({[7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl]amino}carbonyl)amino]pyridin-2-yl}-1,2,4-oxadiazol-5-yl)hexanoic acid (P11) [ka]

[0882] Preparation 10. Ethyl 6-(3-{3-methyl-5-[({[7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl]amino}carbonyl)amino]pyridin-2-yl}-1,2,4-oxadiazol-5-yl)hexanoate (P10) To a solution of compound P4 (0.30 g, 1.3 mmol) in 20 mL of toluene, TEA (0.7 mL, 5.2 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Then, DPPA (0.34 mL, 1.56 mmol) was added. The mixture was stirred at room temperature for 1 hour, and compound P9 (0.40 g, 1.3 mmol) was added. The resulting mixture was stirred at 90° C. for 14 hours. The mixture was evaporated and purified by column chromatography on silica gel. Yield of compound P10 (0.38 g, 54%). LCMS ESI (m / z): 549.7 ([M+1] +),345.1.

[0883] Preparation 11. 6-(3-{3-methyl-5-[({[7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl]amino}carbonyl)amino]pyridin-2-yl}-1,2,4-oxadiazol-5-yl)hexanoic acid (P11) A mixture of compound P10 (0.38 g, 0.7 mmol), NaOH (0.05 g, 1.05 mmol) in 10 mL of EtOH and 2 mL of HO was stirred at 60 °C for 15 h and evaporated. The residue was diluted with water and acidified with 6 M HCl to pH = 3-4. The solid formed was filtered off and dried. Yield of compound P11 (0.36 g, 99%). LCMS ESI (m / z): 521.7 ([M+1] + ),317.1. Synthesis of 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid (P18) [ka]

[0884] Preparation 12. 3-Chloro-5-nitropyridine-2-carbonitrile (P12) Zinc cyanide (1.83 g, 15.55 mmol) was added to a solution of 2,3-dichloro-5-nitropyridine (5.0 g, 25.91 mmol) in 20 mL of N-methyl-2-pyrrolidone. The flask was purged with argon and heated to 135 °C. In a separate flask, tris(dibenzylideneacetone)dipalladium(0) (1.19 g, 1.30 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.75 g, 1.30 mmol) were suspended in 15 mL of N-methyl-2-pyrrolidone, and the mixture was purged with argon and then heated to 80 °C. The suspension was added to the first flask under argon. The reaction mixture was stirred at 135 °C for 1 hour. Upon completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through Celite. The solution in ethyl acetate was washed with water, dried over Na2SO4 and evaporated. The product was purified by column chromatography on silica gel. Eluent - hexane / ethyl acetate = 40 / 1. The product P12 was obtained as a solid (3.92 g, 82%). 1 H NMR (400MHz, DMSO-d6), δ: 9.46 (d, J = 2.2 Hz, 2H), 9.17 (d, J = 2.2 Hz, 2H).

[0885] Preparation 13. 3-Chloro-N'-hydroxy-5-nitropyridine-2-carboximidamide (P13) A solution of 3-chloro-5-nitropyridine-2-carbonitrile P12 (3.92 g, 21.4 mmol) in 40 mL of ethanol was added dropwise to a solution of hydroxylamine hydrochloride (5.94 g, 85.4 mmol) and Na2CO3 (4.53 g, 42.7 mmol) in 110 mL of water. The mixture was stirred at 90 °C for 12 h. The reaction mass was cooled to room temperature and filtered to give 3-chloro-N'-hydroxy-5-nitropyridine-2-carboximidamide P13 (4.41 g, 90%). The precipitate was used for further reactions without further purification. 1 H NMR (400MHz, DMSO-d6), δ:10.22(s,1H),9.31(d,J=2.2Hz,1H),8.77(d,J=2.2Hz,1H),6.00(s,2H).

[0886] Preparation 14. Ethyl 7-{[(E)-(3-chloro-5-nitropyridin-2-yl)(hydroxyimino)methyl]amino}-7-oxoheptanoate (P14) To a solution of 7-ethoxy-7-oxoheptanoic acid (0.37 g, 1.94 mmol) in 40 mL of dioxane was added N-ethyl-N-isopropylpropan-2-amine (0.30 g, 2.33 mmol). The solution was stirred for 5 minutes, and then P13 (0.42 g, 1.94 mmol) was added, and the mixture was stirred for 10 minutes. 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.93 g, 2.91 mmol, 50 wt% solution in EtOAc) was poured into the reaction flask, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under vacuum, dissolved in ethyl acetate, washed with water, and evaporated. The residue (P14) was used in the next step without further purification. LCMS ESI (m / z): 387.4 ([M+1] + ),217.4.

[0887] Preparation 15. Ethyl 6-[3-(3-chloro-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P15). Ethyl 7-{[(E)-(3-chloro-5-nitropyridin-2-yl)(hydroxyimino)methyl]amino}-7-oxoheptanoate P14 (1.79 g, 4.61 mmol) was dissolved in 50 mL of 1,4-dioxane. The solution was refluxed for 96 h. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated in vacuo. The residue was purified on silica gel eluting with 1:10 EtOAc / hexane to give ethyl 6-[3-(3-chloro-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate P15 (0.62 g). The yield was 37% for the two steps (Preparations 14 and 15). LCMS ESI (m / z): 369.1 ([M+1] + ),323.5.

[0888] Preparation 16. Ethyl 6-[3-(5-amino-3-chloropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P16). Ethyl 6-[3-(3-chloro-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate P15 (0.62 g, 1.69 mmol) was dissolved in 50 mL of a solvent consisting of ethanol and acetic acid in equal amounts. The mixture was heated to 40 °C, and 5 equivalents of Fe powder (0.47 g, 8.45 mmol) was added. Stirring was continued at this temperature until complete conversion of the starting material was achieved, as indicated by TLC. The mixture was cooled to ambient temperature and passed through Celite. The filtrate was evaporated, and the residue was dissolved in ethyl acetate, washed with water, and concentrated. The mixture was then dissolved in methylene chloride, washed with an aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated to give ethyl 6-[3-(5-amino-3-chloropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate P16 (0.46 g, 80%). 1 H NMR(400MHz,DMSO-d6),δ:7.99(d,J=2.3Hz,1H),7.09(d,J=2.3Hz,1H),6.19(s,2H),4.03(q,J=7.1Hz,2H),2.97(t,J=7 .4Hz,2H),2.28(t,J=7.3Hz,2H),1.83-1.69(m,2H),1.67-1.49(m,2H),1.37(m,2H),1.26(m,2H),1.10(t,J=7.1Hz,3H).

[0889] Preparation 17. Ethyl 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate (P17). Triethylamine (0.548 g, 5.4 mmol) was added to a suspension of 7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.31 g, 1.35 mmol) in 40 mL of toluene. The mixture was stirred for 5 minutes. DPPA (0.48 g, 1.62 mmol) was then added and stirred at room temperature for 60 minutes. After this time, ethyl 6-[3-(5-amino-3-chloropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate P16 (0.458 g, 1.35 mmol) was added, and the mixture was refluxed for 12 hours. The reaction was monitored by LCMS. The mixture was quenched with water, and the separated toluene was dried over Na2SO4 and evaporated. The residue was purified on silica gel eluting with hexane / ethyl acetate 1:1 to give ethyl 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate P17 (0.55 g, 72%). LCMS ESI (m / z): 567.5 ([M+1] + ).

[0890] Preparation 18. 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid (P18). Aqueous NaOH (0.08 g, 1.94 mmol) was added to a solution of ethyl 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate P17 (0.55 g, 0.97 mmol) in 10 ml of ethanol. The mixture was stirred at 50° C. for 12 hours. After complete hydrolysis of the ester, the mixture was cooled to ambient temperature. The ethanol was evaporated, the reaction mixture was acidified to pH=7 with hydrochloric acid, and the product was then extracted with ethyl acetate. The solution of the product in ethyl acetate was dried over Na2SO4 and evaporated. 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid P18 (0.378 g, 72%) was obtained as a solid. LCMS ESI (m / z): 539.5 ([M+1] + ),431.5. Synthesis of 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoic acid (P26) [ka]

[0891] Preparation 19. 3-Methyl-5-nitropyridine-2-carboxylic acid (P19). In a 25 mL microwave vial, 3-methyl-5-nitropyridine-2-carbonitrile P5 (1.75 g, 10.7 mmol) was dissolved in a mixture of EtOH (5 mL) and concentrated H2SO4 (15 mL). The vial was sealed and heated to 120 °C in a microwave oven for 60 min. Upon completion, the reaction mixture was cooled to room temperature and concentrated to dryness. The resulting residue was dissolved in THF, and 1 N NaOH was slowly added until pH = 9. The resulting mixture was stirred at 50 °C for 1 h. The mixture was then diluted with water, acidified to pH 4-5 with 1 N HCl, and then extracted with EtOAc. The EtOAc layer was washed with brine (10 mL), dried (Na2SO4), and concentrated to give the crude product, which was used in the next step without purification. The yield of 3-methyl-5-nitropyridine-2-carboxylic acid P19 was 1.05 g (53%). 1 H NMR (400MHz, DMSO-d6), δ: 11.90 (br.s, 1H), 9.46-8.99 (m, 1H), 8.60 (d, J = 17.4Hz, 1H), 2.54 (s, 3H).

[0892] Preparation 20. tert-Butyl 2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazinecarboxylate (P20). To a solution of 3-methyl-5-nitropyridine-2-carboxylic acid P19 (1.56 g, 8.57 mmol) in 30 ml of N,N-dimethylformamide, N-[(dimethylamino)(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methylene]-N-methylmethanaminium hexafluorophosphate (4.89 g, 12.85 mmol) was added and the solution was mixed for 5 minutes. tert-Butyl carbazate (1.36 g, 10.28 mmol) and triethylamine (1.73 g, 17.14 mmol) were then added at room temperature. The reaction mixture was stirred at that temperature for 2 hours. The mixture was then diluted with water and extracted with EtOAc. The EtOAc layer was washed with brine (10 mL), dried (Na2SO4) and concentrated to give tert-butyl 2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazinecarboxylate (1.78 g, 70%). 1 H NMR (400MHz, CDCl3), δ:9.46(s,1H),9.20(s,1H),8.42(s,1H),6.69(s,1H),2.90-2.80(m,3H),1.52(s,9H).

[0893] Preparation 21. 3-Methyl-5-nitropyridine-2-carbohydrazide (P21). tert-Butyl 2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazinecarboxylate P20 (1.76 g, 5.94 mmol) was dissolved in 20 mL of 1,4-dioxane. Hydrogen chloride, a 3N solution in 1,4-dioxane (20 ml) was added. The solution was stirred at room temperature for 12 hours. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated in vacuo and the residue was dissolved in methanol. Potassium carbonate was added, and the mixture was stirred for 5 minutes, filtered off, and concentrated to give 3-methyl-5-nitropyridine-2-carbohydrazide P21 (460 mg, 40%). LCMS ESI (m / z): 197.2 ([M+1] + ).

[0894] Preparation 22. Ethyl 7-{2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazino}-7-oxoheptanoate (P22). 7-Ethoxy-7-oxoheptanoic acid (0.44 g, 2.35 mmol) and N,N-carbonyldiimidazole (0.456 g, 2.82 mmol) were stirred in 20 mL of 1,4-dioxane at 50 °C for 3 h. 3-Methyl-5-nitropyridine-2-carbohydrazide P21 (0.46 g, 2.35 mmol) was then added and stirred at this temperature for an additional 12 h. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over NaSO and evaporated. The residue was purified by column chromatography on silica gel (eluent—EtOAc / hexane, 5:1) to give ethyl 7-{2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazino}-7-oxoheptanoate P22 (0.23 g, 27%). LCMS ESI(m / z): 367.5([M+1] + ).

[0895] Preparation 23. Ethyl 6-[5-(3-methyl-5-nitropyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate (P23). To a solution of iodine (40.9 mg, 0.16 mmol) in DCM at 0-5 °C, triphenylphosphine was added portionwise (42.2 mg, 0.16 mmol). Ethyl 7-{2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazino}-7-oxoheptanoate P22 (118 mg, 0.32 mmol) was then added, followed by EtN (32.6 mg, 0.32 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was washed with 10% sodium thiosulfate solution, dried over NaSO, and evaporated. The residue was purified by column chromatography on silica gel to give ethyl 6-[5-(3-methyl-5-nitropyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate P23 (51 mg, 45%). LCMS ESI(m / z):349.5([M+1] + ).

[0896] Preparation 24. Ethyl 6-[5-(5-amino-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate (P24) Ethyl 6-[5-(3-methyl-5-nitropyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate P23 (0.2 g, 0.57 mmol) was dissolved in 20 mL of an equal volume of a solvent consisting of ethanol and acetic acid. The mixture was heated to 40 °C, and Fe powder (0.16 g, 2.85 mmol) was added. Stirring was continued at this temperature until complete conversion of the starting material was achieved, as indicated by TLC. The mixture was cooled to ambient temperature and passed through Celite. The filtrate was evaporated, and the residue was dissolved in ethyl acetate, washed with water, and concentrated. The mixture was then dissolved in methylene chloride, washed with an aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated to give ethyl 6-[5-(5-amino-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate P24 (0.15 g, 82%). LCMS ESI(m / z): 319.5([M+1] + ).

[0897] Preparation 25. Ethyl 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoate (P25). Triethylamine (0.189 g, 1.87 mmol) was added to a suspension of 7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.108 g, 0.46 mmol) in 20 ml of toluene. The mixture was stirred for 5 minutes. DPPA (0.15 g, 0.56 mmol) was then added and stirred at room temperature for 60 minutes. After this time, ethyl 6-[5-(5-amino-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate P24 (0.189 g, 0.56 mmol) was added, and the mixture was refluxed for 12 hours. The reaction was monitored by LCMS. The mixture was quenched with water, and the separated toluene layer was dried over Na2SO4 and evaporated. The residue was purified on silica gel eluting with hexane / ethyl acetate 1:1 to give ethyl 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoate P25 (0.165 g, 62%). LCMS ESI (m / z): 547.6 ([M+1] + ).

[0898] Preparation 26. 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoic acid (P26). Aqueous NaOH (8.2 mg, 0.2 mmol) was added to a solution of ethyl 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoate P25 (56 mg, 0.1 mmol) in 10 ml of ethanol. The mixture was stirred at 50° C. for 12 hours. After complete hydrolysis of the ester, the mixture was cooled to ambient temperature. The ethanol was evaporated, the reaction mixture was acidified to pH=7 with hydrochloric acid, and the product was then extracted with ethyl acetate. The solution of the product in ethyl acetate was dried over Na2SO4 and evaporated. 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoic acid P26 (47.6 mg, 90%) was obtained as a solid. LCMS ESI (m / z): 519.6 ([M+1] + ). Synthesis of 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoic acid (P32) [ka]

[0899] Preparation 27. 3-Methyl-5-nitro-2-[(trimethylsilyl)ethynyl]pyridine (P27). To a suspension of 2-chloro-3-methyl-5-nitropyridine (3.0 g, 13.78 mmol), tetrakis(triphenylphosphine)palladium(0) (2.01 g, 1.74 mmol), and CuI powder (0.66 g, 3.48 mmol) in triethylamine (100 mL) was added ethynyltrimethylsilane (2.56 g, 26.08 mmol). The flask was purged with argon and heated at 80 °C for 12 h. Upon completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through Celite. The filtrate was washed with saturated aqueous solutions of NaHCO and NaCl, dried over NaSO, and concentrated. The product was purified by column chromatography on silica gel. Eluent—hexane / ethyl acetate, 80:1. 3-Methyl-5-nitro-2-[(trimethylsilyl)ethynyl]pyridine P27 (1.14 g, 28%) was obtained as a solid. 1 H NMR (400MHz, CDCl3) δ9.23(d,J=2.2Hz,1H),8.33(d,J=2.0Hz,1H),2.57(s,3H),0.33(s,9H).

[0900] Preparation 28. 5-Methyl-6-[(trimethylsilyl)ethynyl]pyridin-3-amine (P28). 3-Methyl-5-nitro-2-[(trimethylsilyl)ethynyl]pyridine P27 (1.13 g, 4.82 mmol) was dissolved in 50 mL of a solvent consisting of equal volumes of ethanol and acetic acid. The mixture was heated to 40 °C, and 5 equivalents of Fe powder (1.35 g, 24.1 mmol) was added. Stirring was continued at this temperature until complete conversion of the starting material was achieved, as indicated by TLC. The mixture was cooled to ambient temperature and passed through Celite. The filtrate was evaporated, and the residue was dissolved in ethyl acetate, washed with water, and concentrated. The mixture was then dissolved in methylene chloride, washed with an aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated to give 5-methyl-6-[(trimethylsilyl)ethynyl]pyridin-3-amine P28 (0.87 g, 88%). 1H NMR (400MHz, CDCl3), δ:7.92(d,J=2.3Hz,1H),7.00(br.s,2H),6.80(d,J=2.0Hz,1H),2.35(s,3H),0.26(s,9H).

[0901] Preparation 29. N-(7-Cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-{5-methyl-6-[(trimethylsilyl)ethynyl]pyridin-3-yl}urea (P29). Triethylamine (1.44 g, 14.2 mmol) was added to a suspension of 7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.82 g, 3.55 mmol) in 40 mL of toluene. The mixture was stirred for 5 minutes. DPPA (1.17 g, 4.26 mmol) was then added and stirred at room temperature for 60 minutes. After this time, 5-methyl-6-[(trimethylsilyl)ethynyl]pyridin-3-amine P28 (0.87 g, 4.26 mmol) was added and the mixture was refluxed for 12 hours. The reaction was monitored by LCMS. The mixture was quenched with water, and the separated toluene was dried over Na2SO4 and evaporated. The residue was purified on silica gel eluting with hexane / ethyl acetate, 1:1, to give N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[(trimethylsilyl)ethynyl]pyridin-3-yl}urea P29 (0.47 g, 30%). 1 H NMR(400MHz,DMSO-d6),δ:9.22(s,1H),8.45(br.s,3H),8.22(d,J=2.4Hz,1H),7.87(s,1H),6.74(d,J=2.2Hz ,1H),3.97-3.74(m,1H),2.34(s,3H),2.36-2.32(m,2H),1.99(s,2H),1.85(s,2H),1.70(s,2H),0.25(s,9H).

[0902] Preparation 30. N-(7-Cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-(6-ethynyl-5-methylpyridin-3-yl)urea (P30). N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[(trimethylsilyl)ethynyl]pyridin-3-yl}urea P29 (0.24 g, 0.56 mmol) was dissolved in equal amounts in 20 mL of a solvent consisting of methanol and dichloromethane. Potassium fluoride (0.097 g, 1.67 mmol) was added to the flask, which was stirred at room temperature for 2 hours. After completion of the reaction as indicated by TLC, the reaction mass was diluted with water and extracted with ethyl acetate. N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(6-ethynyl-5-methylpyridin-3-yl)urea P30 (0.186 g, 93%) was concentrated and used in the next step without purification. LCMS ESI (m / z): 361.5 ([M+H] + ).

[0903] Preparation 31. Ethyl 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoate (P31). N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(6-ethynyl-5-methylpyridin-3-yl)urea P30 (0.186 g, 0.52 mmol) and ethyl 7-azidoheptanoate (0.103 g, 0.52 mmol) were dissolved in equal amounts in 20 mL of a solvent consisting of tetrahydrofuran and water. Copper(II) acetate (0.009 g, 0.05 mmol) and sodium ascorbate (0.01 g, 0.05 mmol) were added to the flask, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction as indicated by LCMS, the product was extracted with ethyl acetate and concentrated. The residue was purified on silica gel eluting with ethyl acetate to give ethyl 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoate P31 (0.149 g, 51%). 1H NMR(400MHz,DMSO-d6),δ:9.12(s,1H),8.53(s,1H),8.47(s,1H),8.46(s,1H),8 .42(s,1H),8.23(d,J=2.4Hz,1H),4.40(t,J=7.2Hz,2H),4.03(q,J=7.1Hz,2H), 3.87(s,1H),2.60(s,3H),2.33(s,2H),2.26(t,J=7.3Hz,2H),1.99(s,2H),1.86 (s,4H),1.70(s,2H),1.50(d,J=7.8Hz,2H),1.28(s,4H),1.16(t,J=7.1Hz,3H).

[0904] Preparation 32. 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoic acid (P32). Aqueous NaOH (0.021 g, 0.53 mmol) was added to a solution of ethyl 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoate P31 (0.149 g, 0.27 mmol) in 10 ml of ethanol. The mixture was stirred at 50° C. for 12 hours. After complete hydrolysis of the ester, the mixture was cooled to ambient temperature. The ethanol was evaporated, the reaction mixture was acidified to pH=7 with hydrochloric acid, and the product was then extracted with ethyl acetate. The solution of the product in ethyl acetate was dried over Na2SO4 and evaporated. 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoic acid P32 (0.138 g, 97%) was obtained as a solid. LCMS ESI (m / z): 532.3 ([M+H] + ). Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrido[3,2-d]pyrimidine (P36) [ka]

[0905] Preparation 33. Ethyl 3-cyclopentyl-3-oxopropanoate (P33). 1) To a mixture of cyclopentanecarboxylic acid (8.0 g, 70.10 mmol) and anhydrous EtOAc (100 mL), carbonyldiimidazole (12.5 g, 77.11 mmol) was added in portions. The mixture was stirred at 50° C. for 3 hours. 2) MgCl (26.7 g, 280.4 mmol) was added in portions to a mixture of potassium 3-ethoxy-3-oxopropanoate (23.86 g, 140.2 mmol) and anhydrous EtOAc (300 mL). The mixture was stirred at 50° C. for 3 hours. The solution from step (1) was added dropwise to the suspension from step (2), and the mixture was stirred at reflux overnight. The mixture was cooled in an ice bath and acidified to pH=3 with 4 M HCl (140 mL). The mixture was warmed to ambient temperature, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water, brine, and dried (Na2SO4). Concentration and purification by silica gel chromatography gave compound P33 (10.1 g, 78%). 1 H NMR (400MHz, CDCl3), δ:4.18(q,J=7.1Hz,2H),3.48(s,2H),3.13-2.90(m,1H),2.00-1.70(m,4H),1.72-1.50(m,4H),1.27(t,J=7.1Hz,3H).

[0906] Preparation 34. Ethyl (2Z)-2-(cyclopentylcarbonyl)-3-(dimethylamino)acrylate (P34). A solution of compound P33 (10.1 g, 54.8 mmol) and N,N-dimethylformamide dimethyl acetal (73 mL, 548.0 mmol) was stirred under reflux overnight. The mixture was evaporated to dryness, and the residue was purified by silica gel column chromatography. Yield of compound P34 (11.0 g, 84%). 1H NMR(400MHz,DMSO-d6),δ:1H NMR(400MHz,DMSO-d6),δ:7.55(s,1H),4.09(q,J=7.1Hz,2H),2.83(br.s,6H),1.87-1.37(m,9H),1.21(t,J=7.1Hz,3H).

[0907] Preparation 35. Ethyl 7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylate (P35). To a solution of P34 (11.0 g, 46.0 mmol) in 200 mL of EtOH, 1H-pyrazol-5-amine (4.6 g, 55.2 mmol) was added. The mixture was stirred at reflux overnight. The mixture was evaporated, and the residue was purified by silica gel column chromatography. Yield of compound P35 (11.0 g, 84%). 1 H NMR(400MHz,CDCl3),δ:8.81(d,J=7.0Hz,1H),8.17(d,J=2.1Hz,1H),6.70(d,J=2.0Hz,1H),4.76-4.56(m,1H),4.43(q,J=7.1H) z,2H),2.61-2.39(m,2H),2.25-2.06(m,2H),1.94(dt,J=11.4,8.3Hz,2H),1.80(dt,J=10.0,4.5Hz,2H),1.44(t,J=7.1Hz,3H).

[0908] Preparation 36. 7-Cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (P36). A mixture of compound P35 (9.2 g, 35.5 mmol) and NaOH (2.2 g, 53.2 mmol) in 200 mL of EtOH and 50 mL of HO was stirred at 60 °C for 14 h and evaporated. The residue was diluted with water and acidified with 6 M HCl to pH = 3-4. The solid formed was filtered off and dried. Yield of compound P36 (8.1 g, 98%). 1H NMR(400MHz,DMSO-d6),δ:13.62(s,1H),8.78(d,J=1.1Hz,1H),8.35(d,J=2.1Hz,1H),6.80(s,1H) ,4.63(dd,J=17.8,9.0Hz,1H),2.39(br.s,2H),2.03(br.s,2H),1.85(br.s,2H),1.72(br.s,2H). Synthesis of ethyl 4-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]butanoate (P39) [ka]

[0909] Preparation 37. Ethyl 5-({[(1Z)-amino(3-methyl-5-nitropyridin-2-yl)methylene]amino}oxy)-5-oxopentanoate (P37) To a solution of 5-ethoxy-5-oxo-pentanoic acid (0.50 g, 3.1 mmol) in 20 mL of DCM, TEA (1.3 mL, 9.3 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Then, TBTU (0.94 g, 3.7 mmol) and compound P6 (0.61 g, 3.1 mmol) were added, and the mixture was stirred at ambient temperature for 14 hours. The mixture was washed with 20% K2CO3 (aq), dried over Na2SO4, and evaporated. The residue (P37) was used in the next step without further purification. LCMS ESI (m / z): 339.4 ([M+1] + ),197.4,179.4.

[0910] Preparation 38. Ethyl 4-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]butanoate (P38) A solution of compound P37 in 50 mL of dioxane was refluxed with stirring for 96 hours. The mixture was evaporated and purified by column chromatography on silica gel. Yield of compound P38 over the two steps (preparations 37 and 38) was 0.37 g (37%). LCMS ESI (m / z): 321.5 ([M+1] + ),275.4,179.3.

[0911] Preparation 39. Ethyl 4-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]butanoate (P39) To a solution of compound P38 (0.37 g, 1.15 mmol) in 20 mL of acetic acid was added Fe powder (0.65 g, 11.5 mmol). The suspension was stirred at 70° C. for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL), and filtered through Celite. The filtrate was evaporated. The residue was diluted with saturated NaHCO (aq) and extracted with ethyl acetate. The combined organic extracts were dried over Na SO and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P39 (0.30 g, 89%). LCMS ESI (m / z): 291.4 ([M+1] + ),149.6. Synthesis of 4-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}butanoic acid (P41) [ka]

[0912] Preparation 40. Ethyl 4-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}butanoate (P40). To a solution of compound P36 (0.24 g, 1.0 mmol) in 20 mL of toluene was added EtN (0.6 mL, 4.0 mmol). The mixture was stirred at room temperature for 10 minutes. After this, DPPA (0.27 mL, 1.2 mmol) was added. The mixture was stirred at room temperature for 1 hour, and compound P39 (0.30 g, 1.0 mmol) was added. The resulting mixture was stirred at 90° C. for 14 hours. The mixture was evaporated and purified by column chromatography on silica gel to give compound P40 (0.35 g, 65%). LCMS ESI (m / z): 519.5 ([M+1] + ),431.6.

[0913] Preparation 41. 4-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}butanoic acid (P41). A mixture of compound P40 (0.35 g, 0.7 mmol) and NaOH (0.04 g, 1.05 mmol) in 10 mL of EtOH and 2 mL of HO was stirred at 60 °C for 14 h and evaporated. The residue was diluted with water and acidified with 6 M HCl to pH = 3-4. The solid formed was filtered off and dried. Yield of compound P41 (0.27 g, 82%). 1 H NMR(400MHz,DMSO-d6),δ:9.42(s,1H),8.63(s,1H),8.56(s,1H),8.48(s,1H),8.23(t,J=3.7Hz,1H),8.00(s,1H),6.74(dd,J=6.8,2.3Hz,1H ),4.01-3.76(m,1H),3.04(t,J=7.4Hz,2H),2.48(s,3H),2.40(t,J=7.2Hz,2H),2.35(br.s,3H),2.09-1.94(m,4H),1.87(s,2H),1.71(s,2H). LCMS ESI(m / z):491.5([M+1] + ). Synthesis of ethyl 3-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]propanoate (P44) [ka]

[0914] Preparation 42. Ethyl 4-({[(1Z)-amino(3-methyl-5-nitropyridin-2-yl)methylene]amino}oxy)-4-oxobutanoate (P42). To a solution of 4-ethoxy-4-oxo-butanoic acid (0.50 g, 3.4 mmol) in 20 mL of DCM was added EtN (1.4 mL, 10.2 mmol). The mixture was stirred at room temperature for 10 minutes. After this, TBTU (1.0 g, 4.1 mmol) and compound P6 (0.67 g, 3.4 mmol) were added, and the mixture was stirred at ambient temperature for 14 hours. The mixture was washed with 20% KCO (aq), dried over NaSO, and evaporated. The residue (P42) was used in the next step without further purification. LCMS ESI (m / z): 325.5 ([M+1] + ),197.4,179.4.

[0915] Preparation 43. Ethyl 3-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]propanoate (P43). A solution of compound P42 in 50 mL of dioxane was refluxed with stirring for 96 hours. The mixture was evaporated and purified by column chromatography on silica gel. Yield of compound P43 for the two steps (P42 and P43) was 0.56 g (53%). LCMS ESI (m / z): 307.5 ([M+1] + ),261.4,233.1.

[0916] Preparation 44. Ethyl 3-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]propanoate (P44). To a solution of compound P43 (0.56 g, 1.8 mmol) in 20 mL of acetic acid was added Fe powder (1.0 g, 18.0 mmol). The suspension was stirred at 70° C. for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL), and filtered through Celite. The filtrate was evaporated. The residue was diluted with saturated NaHCO (aq) and extracted with ethyl acetate. The combined organic extracts were dried over Na SO and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P44 (0.46 g, 91%). LCMS (m / z): 277.4 ([M+1] + ),149.4. Synthesis of 3-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}propanoic acid (P46) [ka]

[0917] Preparation 45. Ethyl 3-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}propanoate (P45). To a solution of compound P36 (0.39 g, 1.7 mmol) in 20 mL of toluene was added EtN (1.0 mL, 6.8 mmol). The mixture was stirred at room temperature for 10 minutes. After this, DPPA (0.44 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 1 hour, and compound P44 (0.46 g, 1.7 mmol) was added. The resulting mixture was stirred at 90° C. for 14 hours. The mixture was evaporated and purified by column chromatography on silica gel. Yield of compound P45 (0.41 g, 48%). LCMS ESI (m / z): 505.5 ([M+1] + ),431.6.

[0918] Preparation 46. 3-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}propanoic acid (P46). A mixture of compound P45 (0.41 g, 0.8 mmol), NaOH (0.05 g, 1.2 mmol) in 10 mL of EtOH and 2 mL of HO was stirred at 60 °C for 14 h and evaporated. The residue was diluted with water and acidified with 6 M HCl to pH = 3-4. The solid formed was filtered off and dried. Yield of compound P46 (0.32 g, 83%). 1 H NMR(400MHz,DMSO-d6),δ:12.30(br.s,1H),9.41(s,1H),8.62(s,1H),8.55(s,1H),8.48(s,1H),8.23(d,J=2.3Hz,1H),8.00(s,1H),6.75(d,J =2.3Hz,1H),3.98-3.81(m,1H),3.19(t,J=6.8Hz,2H),2.84(t,J=6.8Hz ,2H),2.46(s,3H),2.35(s,2H),1.99(s,2H),1.86(s,2H),1.71(s,2H). LCMS ESI(m / z):477.3([M+1] + ). Synthesis of ethyl 5-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]pentanoate (P49) [ka]

[0919] Preparation 47. Ethyl 6-({[(1Z)-amino(3-methyl-5-nitropyridin-2-yl)methylene]amino}oxy)-6-oxohexanoate (P47) To a solution of 6-ethoxy-6-oxo-hexanoic acid (0.60 g, 3.4 mmol) in 20 mL of DCM was added EtN (1.5 mL, 10.2 mmol). The mixture was stirred at room temperature for 10 minutes. Then TBTU (1.03 g, 4.1 mmol) and P6 (0.67 g, 3.4 mmol) were added, and the mixture was stirred at ambient temperature for 14 hours. The mixture was washed with 20% KCO (aq), dried over NaSO, and evaporated. The residue was used in the next step without further purification. LCMS (m / z): 353.4 ([M+1] + ),197.3,179.3.

[0920] Preparation 48. Ethyl 5-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]pentanoate (P48). A solution of compound P47 in 50 mL of dioxane was refluxed with stirring for 96 hours. The mixture was evaporated and purified by column chromatography on silica gel. Yield of compound P48 for the two steps (P47 and P48) was 0.58 g (51%). LCMS ESI (m / z): 335.5 ([M+1] + ),289.3.

[0921] Preparation 49. Ethyl 5-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]pentanoate (P49). To a solution of compound P48 (0.58 g, 1.7 mmol) in 20 mL of acetic acid was added Fe powder (1.0 g, 17 mmol). The suspension was stirred at 70 °C for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL) and filtered through Celite. The filtrate was evaporated. The residue was diluted with saturated NaHCO3 (aq) and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P49 (0.47 g, 84%). LCMS ESI (m / z): 305.5 ([M+1] + ),149.4. Synthesis of 5-formyl-4-methyl-1H-indole-2-carbonitrile N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(5-oxopentyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P53) [ka]

[0922] Preparation 50. Ethyl 5-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}pentanoate (P50). To a solution of compound P36 (0.36 g, 1.6 mmol) in 20 mL of toluene was added EtN (0.9 mL, 6.4 mmol). The mixture was stirred at room temperature for 10 minutes. Then DPPA (0.4 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 1 hour, and compound P49 (0.47 g, 1.6 mmol) was added. The resulting mixture was stirred at 90° C. for 14 hours. The mixture was evaporated and purified by column chromatography on silica gel. Yield of compound P50 (0.52 g, 63%). LCMS ESI (m / z): 533.5 ([M+1] + ),377.5.

[0923] Preparation 51. 5-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}pentanoic acid (P51). A mixture of compound P50 (0.52 g, 1.0 mmol), NaOH (0.06 g, 1.5 mmol) in 10 mL of EtOH and 2 mL of HO was stirred at 60 °C for 14 h and evaporated. The residue was diluted with water and acidified with 6 M HCl to pH = 3-4. The solid formed was filtered off and dried. Yield of compound P51 (0.45 g, 92%). LCMS (m / z): 505.5 ([M+1] + ).

[0924] Preparation 52. N-(7-Cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-{6-[5-(5-hydroxypentyl)-1,2,4-oxadiazol-3-yl]-5-methylpyridin-3-yl}urea (P52). To a solution of compound P51 (0.45 g, 0.9 mmol) in 10 mL of THF was added EtN (0.16 mL, 1.17 mmol). The mixture was stirred at room temperature for 10 minutes. After this, ethyl chloroformate (0.11 mL, 1.17 mmol) was added at 0-5°C. The mixture was stirred at room temperature for 1 hour. The formed solid was filtered off, and the filtrate was added dropwise to a solution of sodium borohydride (0.17 g, 4.5 mmol) in water (10 mL) at 0-5°C. The resulting mixture was stirred at ambient temperature for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over NaSO and evaporated. The residue was purified by silica gel column chromatography. Yield of compound P52 (0.34 g, 78%). LCMS (m / z): 491.4 ([M+1] + ).

[0925] Preparation 53. N-(7-Cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-{5-methyl-6-[5-(5-oxopentyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P53). A solution of dimethyl sulfoxide (0.14 mL, 1.88 mmol) in DCM (0.1 mL) was added to a stirred solution of trifluoroacetic anhydride (0.2 mL, 1.37 mmol) in DCM (10 mL) at -70 °C. A solution of compound P52 (0.28 g, 0.57 mmol) in DCM (1.0 mL) was added dropwise to the solution prepared above over 15 min, and the mixture was stirred for an additional 3.5 h. Triethylamine (0.5 mL, 3.42 mmol) was added dropwise with stirring over 15 min, and the whole was allowed to warm to room temperature. The mixture was diluted with DCM, washed with saturated NaHCO3 (aq), dried over Na2SO4, and evaporated. The residue (P53) was used in the next step without further purification. LCMS ESI (m / z): 489.4 ([M+1] + ). Synthesis of N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(3-oxopropyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P55) [ka]

[0926] Preparation 54. N-(7-Cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-{6-[5-(3-hydroxypropyl)-1,2,4-oxadiazol-3-yl]-5-methylpyridin-3-yl}urea (P54). To a solution of compound P46 (0.4 g, 0.8 mmol) in 10 mL of THF was added EtN (0.16 mL, 1.04 mmol). The mixture was stirred at room temperature for 10 minutes. After this time, ethyl chloroformate (0.1 mL, 1.04 mmol) was added at 0-5°C. The mixture was stirred at room temperature for 1 hour. The formed solid was filtered off, and the filtrate was added dropwise to a solution of sodium borohydride (0.16 g, 4.0 mmol) in water (10 mL) at 0-5°C. The resulting mixture was stirred at ambient temperature for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over NaSO and evaporated. The residue was purified by column chromatography on silica gel to give compound P54 (0.22 g, 57%). 1 H NMR(400MHz,DMSO-d6),δ:9.39(s,1H),8.62(d,J=2.1Hz,1H),8.54(s,1H),8 .48(s,1H),8.23(d,J=2.2Hz,1H),7.99(s,1H),6.75(d,J=2.2Hz,1H),4.63( br.s,1H),3.86(dd,J=18.0,9.1Hz,1H),3.51(t,J=6.1Hz,2H),3.03(t,J=7. 5Hz, 2H), 2.47 (s, 3H), 2.35 (s, 2H), 2.11-1.78 (m, 6H), 1.70 (d, J = 5.1Hz, 2H). LCMS ESI(m / z):463.7([M+1] + ).

[0927] Preparation 55. N-(7-Cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-{5-methyl-6-[5-(3-oxopropyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P55). A solution of DMSO (0.03 mL, 0.43 mmol) in DCM (0.1 mL) was added to a stirred solution of trifluoroacetic anhydride (0.045 mL, 0.31 mmol) in DCM (10 mL) at -70 °C. A solution of compound P54 (0.06 g, 0.13 mmol) in DCM (1.0 mL) was added dropwise to the solution prepared above over 15 min, and the mixture was stirred for an additional 3.5 h. Triethylamine (0.11 mL, 0.78 mmol) was added dropwise with stirring over 15 min, and the whole was allowed to warm to room temperature. The mixture was diluted with DCM, washed with saturated NaHCO3 (aq), dried over Na2SO4, and evaporated. The residue (P55) was used in the next step without further purification. LCMS ESI (m / z): 461.4 ([M+1] + ). Synthesis of N-(3-chloro-7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(3-oxopropyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P56) [ka]

[0928] Preparation 56. N-(3-Chloro-7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-{5-methyl-6-[5-(3-oxopropyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P56). A solution of DMSO (0.06 mL, 0.80 mmol) in DCM (0.1 mL) was added to a stirred solution of oxalyl chloride (0.05 mL, 0.53 mmol) in DCM (10 mL) at -70 °C. A solution of compound P54 (0.1 g, 0.24 mmol) in DCM (1.0 mL) was added dropwise to the solution prepared above over 15 min, and the mixture was stirred for an additional 3.5 h. Triethylamine (0.20 mL, 1.44 mmol) was added dropwise with stirring over 15 min, and the whole was allowed to warm to room temperature. The mixture was diluted with CHCl, washed with saturated NaHCO (aq), dried over NaSO, and evaporated. The residue was used in the next step without further purification. LCMS ESI (m / z): 495.4 ([M+1] + ). Synthesis of N-(3-chloro-7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(4-oxobutyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P58) [ka]

[0929] Preparation 57. N-(7-Cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-{6-[5-(4-hydroxybutyl)-1,2,4-oxadiazol-3-yl]-5-methylpyridin-3-yl}urea (P57). To a solution of compound P41 (0.27 g, 0.55 mmol) in 10 mL of THF was added EtN (0.1 mL, 0.72 mmol). The mixture was stirred at room temperature for 10 minutes. Then, ethyl chloroformate (0.07 mL, 0.72 mmol) was added at 0-5°C. The mixture was stirred at room temperature for 1 hour. The formed solid was filtered off, and the filtrate was added dropwise to a solution of sodium borohydride (0.1 g, 2.75 mmol) in water (10 mL) at 0-5°C. The resulting mixture was stirred at ambient temperature for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over NaSO and evaporated. The residue was purified by silica gel column chromatography. Yield of compound P57: 0.20 g, 76%. LCMS ESI (m / z): 477.6 ([M+1] + ),377.4.

[0930] Preparation 58. N-(3-Chloro-7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-{5-methyl-6-[5-(4-oxobutyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P58). A solution of DMSO (0.05 mL, 0.66 mmol) in DCM (0.1 mL) was added to a stirred solution of oxalyl chloride (0.045 mL, 0.48 mmol) in DCM (10 mL) at -70 °C. A solution of compound P57 (0.1 g, 0.2 mmol) in DCM (1.0 mL) was added dropwise to the solution prepared above over 15 min, and the mixture was stirred for an additional 3.5 h. Triethylamine (0.2 mL, 1.20 mmol) was added dropwise with stirring over 15 min, and the whole was allowed to warm to room temperature. The mixture was diluted with DCM, washed with saturated NaHCO3 (aq), dried over Na2SO4, and evaporated. The residue (P58) was used in the next step without further purification. LCMS ESI (m / z): 509.4 ([M+1] + ). Synthesis of N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(4-oxobutyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P59) [ka]

[0931] Preparation 59. N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(4-oxobutyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P59) A solution of DMSO (0.025 mL, 0.33 mmol) in DCM (0.1 mL) was added to a stirred solution of trifluoroacetic anhydride (0.036 mL, 0.24 mmol) in DCM (10 mL) at -70 °C. A solution of compound P57 (0.05 g, 0.1 mmol) in DCM (1.0 mL) was added dropwise to the solution prepared above over 15 min, and the mixture was stirred for an additional 3.5 h. Triethylamine (0.09 mL, 0.60 mmol) was added dropwise with stirring over 15 min, and the whole was allowed to warm to room temperature. The mixture was diluted with DCM, washed with saturated NaHCO3 (aq), dried over Na2SO4, and evaporated. The residue (P59) was used in the next step without further purification. LCMS ESI (m / z): 475.4 ([M+1] + ). Synthesis of ethyl 6-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P8) - Second option [ka]

[0932] Preparation 60. Ethyl 7-{[(E)-(hydroxyimino)(3-methyl-5-nitropyridin-2-yl)methyl]amino}-7-oxoheptanoate (P60) To a solution of 7-ethoxy-7-oxoheptanoic acid (0.78 g, 4.2 mmol) in 40 mL of 1,4-dioxane was added N-ethyl-N-isopropylpropan-2-amine (0.645 g, 4.98 mmol). The solution was stirred for 5 minutes, and then N'-hydroxy-3-methyl-5-nitropyridine-2-carboximidamide P6 (0.816 g, 4.2 mmol) was added, and the mixture was stirred for 10 minutes. 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (1.98 g, 6.3 mmol, 50 wt% solution in EtOAc) was poured into the reaction flask, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, washed with water, and evaporated. The residue (P60) was used in the next step without further purification. LCMS(m / z): 366.3 ([M+1] + ).

[0933] Preparation 8a. Ethyl 6-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P8) Ethyl 7-{[(E)-(hydroxyimino)(3-methyl-5-nitropyridin-2-yl)methyl]amino}-7-oxoheptanoate P60 (0.815 g, 4.16 mmol) was dissolved in 50 mL of 1,4-dioxane. The solution was refluxed for 96 hours. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated in vacuo. The residue was purified on silica gel eluting with 1:10 EtOAc / hexane to give ethyl 6-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate P8 (0.55 g). The yield was 38% for both steps (Preparation 60 and Preparation 8a). 1H NMR(400MHz,DMSO-d6),δ:9.34(d,J=2.4Hz,1H),8.72(d,J=2.5Hz,1H),4.04(q,J=7.1Hz,2H),3.06(t,J=7.5Hz,2H) ,2.64(s,3H),2.30(t,J=7.3Hz,2H),1.90-1.71(m,2H),1.67-1.52(m,2H),1.50-1.29(m,2H),1.16(t,J=7.1Hz,3H). Synthesis of 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid (P62) [ka]

[0934] Preparation 61. Ethyl 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate (P61). Triethylamine (0.166 g, 1.64 mmol) was added to a suspension of 7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.095 g, 0.41 mmol) in 40 mL of toluene. The mixture was stirred for 5 minutes. DPPA (1.136 g, 0.49 mmol) was then added and stirred at room temperature for 60 minutes. After this time, ethyl 6-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate P9 (0.13 g, 0.41 mmol) was added and the mixture was refluxed for 12 hours. The reaction was monitored by LCMS. The mixture was quenched with water, and the separated toluene was dried over Na2SO4 and evaporated. The residue was purified on silica gel eluting with hexane / ethyl acetate, 1:1, to give ethyl 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate P61 (0.129 g, 57%). 1 H NMR(400MHz,DMSO-d6),δ:9.35(s,1H),8.62(d,J=2.2Hz,1H),8.51(s,1H),8.48(s,1H),8.23(d,J=2.3 Hz,1H),8.00(s,1H),6.75(d,J=2.3Hz,1H),4.04(q,J=7.1Hz,2H),3.94-3.78(m,1H),3.00(t,J=7.5Hz ,2H),2.47(s,3H),2.34(d,J=11.0Hz,2H),2.30(t,J=7.3Hz,2H),1.99(s,2H),1.86(s,2H),1.78(dd,J =15.4,7.5Hz,2H),1.71(s,2H),1.57(dd,J=15.3,7.3Hz,2H),1.44-1.33(m,2H),1.16(t,J=7.1Hz,3H).

[0935] Preparation 62. 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid (P62). Aqueous NaOH (0.026 g, 0.46 mmol) was added to a solution of ethyl 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate P61 (0.127 g, 0.23 mmol) in 10 ml of ethanol. The mixture was stirred at 50° C. for 12 hours. After complete hydrolysis of the ester, the mixture was cooled to ambient temperature. The ethanol was evaporated, the reaction mixture was acidified to pH=7 with hydrochloric acid, and the product was then extracted with ethyl acetate. The solution of the product in ethyl acetate was dried over Na2SO4 and evaporated. 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid P62 (0.102 g, 84%) was obtained as a solid. 1 H NMR(400MHz,DMSO-d6),δ:11.99(s,1H),9.36(s,1H),8.62(d,J=2.2Hz,1H),8.51(s,1H),8.48(s,1H),8 .23(d,J=2.3Hz,1H),7.99(s,1H),6.75(d,J=2.3Hz,1H),4.03(q,J=7.1Hz,1H),3.94-3.77(m,1H),3.00( t,J=7.4Hz,2H),2.47(s,3H),2.34(d,J=8.5Hz,2H),2.22(t,J=7.3Hz,2H),1.99(s,2H),1.92-1.83(m,2H) ),1.78(dd,J=15.1,7.5Hz,2H),1.71(s,2H),1.54(dd,J=15.1,7.4Hz,2H),1.39(dd,J=14.8,8.0Hz,2H). Synthesis of tert-butyl (4-azidobutoxy) acetate (P64) [ka]

[0936] Preparation 63. tert-Butyl {4-[(methylsulfonyl)oxy]butoxy}acetate (P63). Methanesulfonyl chloride (0.673 g, 5.87 mmol) was added to a solution of tert-butyl(4-hydroxybutoxy)acetate (1.0 g, 4.9 mmol) and triethylamine (0.743 g, 7.4 mmol) in dry DCM (30 mL) at 0 °C. The mixture was stirred overnight and then washed with water, 1 M hydrochloric acid, 5% aqueous sodium bicarbonate solution, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to give tert-butyl {4-[(methylsulfonyl)oxy]butoxy}acetate P63 (1.0 g, 72%). 1 H NMR(400MHz,DMSO-d6),δ:4.22(t,J=6.4Hz,2H),3.93(d,J=9.5Hz,2H),3.46(t,J=6.2Hz, 2H), 3.16(d,J=7.3Hz,3H),1.82-1.67(m,2H),1.59(dt,J=12.7,6.3Hz,2H),1.42(s,9H).

[0937] Preparation 64. tert-Butyl (4-azidobutoxy) acetate (P64). Sodium azide (1.15 g, 17.5 mmol) was added to a solution of tert-butyl {4-[(methylsulfonyl)oxy]butoxy}acetate in DMF (30 ml). The mixture was stirred with heating at 80° C. for 18 hours. Upon completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The product was purified by column chromatography on silica gel. Eluent: hexane / ethyl acetate, 40:1. tert-Butyl (4-azidobutoxy)acetate (0.395 g) was obtained in 48% yield. 1 H NMR (400MHz, DMSO-d6), δ:3.94(s,2H),3.45(t,J=5.9Hz,2H),3.35(t,J=6.6Hz,2H),1.68-1.49(m,4H),1.42(s,9H). Synthesis of (4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetic acid (P66) [ka]

[0938] Preparation 65. tert-Butyl (4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetate (P65). N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(6-ethynyl-5-methylpyridin-3-yl)urea P30 (0.232 g, 0.64 mmol) and tert-butyl (4-azidobutoxy)acetate (0.147 g, 0.64 mmol) were dissolved in equal amounts in 20 mL of a solvent consisting of tetrahydrofuran and water. Copper(II) acetate (0.012 g, 0.06 mmol) and sodium ascorbate (0.013 g, 0.06 mmol) were added to the flask, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction as indicated by LCMS, the product was extracted with ethyl acetate and concentrated. The residue was purified on silica gel eluting with 40:1 EtOAc / MeOH to give tert-butyl (4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetate P65 (0.157 g, 41%). LCMS ESI (m / z): 590.5 ([M+1] + ),534.3.

[0939] Preparation 66. (4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetic acid (P66). tert-Butyl (4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetate P65 (0.157 g, 0.27 mmol) was dissolved in 10 ml of DCM containing TFA (0.303 g, 2.66 mmol). The solution was stirred at room temperature for 15 h. TLC control. The product was concentrated using vacuum and evaporated with dioxane saturated with HCl. (4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetic acid hydrochloride P66 (0.15 g) was obtained in 98% yield. LCMS ESI (m / z): 534.5 ([M+1] + ). Synthesis of [4-(benzoyloxy)butoxy]acetic acid (P68) [ka]

[0940] Preparation 67. 4-(2-Tert-butoxy-2-oxoethoxy)butylbenzoate (P67). To a solution of tert-butyl 2-(4-hydroxybutoxy)acetate (1.0 g, 4.9 mmol) in 20 mL of DCM was added EtN (1.7 mL, 12.3 mmol). Benzoyl chloride (0.7 mL, 5.9 mmol) was then added at 0-5°C. The mixture was stirred at room temperature for 14 hours. The mixture was diluted with DCM, washed with saturated NaHCO (aq), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography. Yield of compound P67: 1.0 g, 68%. 1H NMR(400MHz,DMSO-d6),δ:8.03-7.88(m,2H),7.66(t,J=7.4Hz,1H),7.53(t,J=7.7Hz,2H),4.30(t,J =6.5Hz,2H),3.95(s,2H),3.49(t,J=6.3Hz,2H),1.86-1.71(m,2H),1.71-1.54(m,2H),1.41(s,9H).

[0941] Preparation 68. [4-(Benzoyloxy)butoxy]acetic acid (P68). To a solution of compound P67 (1.0 g, 3.3 mmol) in 15 mL of DCM was added TFA (2.6 mL, 33.0 mmol). The mixture was stirred at room temperature for 14 hours. The mixture was evaporated. Yield of compound P68: 0.84 g, 99%. 1 H NMR(400MHz,DMSO-d6),δ:12.56(s,1H),7.97(d,J=7.2Hz,2H),7.66(t,J=7.4Hz,1H),7.53(t,J=7.7Hz,2H) ,4.30(t,J=6.5Hz,2H),3.98(s,2H),3.50(t,J=6.3Hz,2H),1.87-1.71(m,2H),1.65(dt,J=13.2,6.5Hz,2H). Synthesis of 4-{[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]methoxy}butylbenzoate (P70) [ka]

[0942] Preparation 69. 4-{[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]methoxy}butylbenzoate (P69) To a solution of compound P68 (0.84 g, 3.3 mmol) in 20 mL of dioxane was added CDI (0.6 g, 3.7 mmol). The mixture was stirred at 60° C. for 4 hours. Then, compound P6 (0.65 g, 3.3 mmol) was added, and the mixture was stirred at reflux for 72 hours. The mixture was evaporated. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P69: 0.25 g, 18%. LCMS ESI (m / z): 413.5 ([M+1] + ),291.5.

[0943] Preparation 70. 4-{[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]methoxy}butylbenzoate (P70). To a solution of compound P69 (0.25 g, 0.6 mmol) in 10 mL of acetic acid was added Fe powder (0.3 g, 6.0 mmol). The suspension was stirred at 70° C. for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL), and filtered through Celite. The filtrate was evaporated. The residue was diluted with saturated NaHCO (aq) and extracted with ethyl acetate. The combined organic extracts were dried over Na SO and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P70: 0.14 g, 60%. LCMS ESI (m / z): 383.5 ([M+1] + ). Synthesis of N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(5-methyl-6-{5-[(4-oxobutoxy)methyl]-1,2,4-oxadiazol-3-yl}pyridin-3-yl)urea (P73) [ka]

[0944] Preparation 71. 4-({3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}methoxy)butylbenzoate (P71). To a solution of compound P36 (0.08 g, 0.035 mmol) in 10 mL of toluene was added EtN (0.2 mL, 0.140 mmol). The mixture was stirred at room temperature for 10 minutes. Then DPPA (0.09 mL, 0.042 mmol) was added. The mixture was stirred at room temperature for another hour, and compound P70 (0.13 g, 0.035 mmol) was added. The resulting mixture was stirred at 90° C. for 14 hours. The mixture was evaporated and purified by column chromatography on silica gel. Yield of compound P71: 0.13 g, 58%. LCMS ESI (m / z): 611.5 ([M+1] + ).

[0945] Preparation 72. N-(7-Cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-(6-{5-[(4-hydroxybutoxy)methyl]-1,2,4-oxadiazol-3-yl}-5-methylpyridin-3-yl)urea (P72). To a solution of compound P71 (0.13 g, 0.21 mmol) in 5 mL of MeOH was added K2CO3 (0.12 g, 0.84 mmol). The mixture was stirred at 60 °C for 4 h. The mixture was evaporated. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. Yield of compound P72: 0.085 g, 80%. LCMS ESI (m / z): 507.5 ([M+1] + ).

[0946] Preparation 73. N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(5-methyl-6-{5-[(4-oxobutoxy)methyl]-1,2,4-oxadiazol-3-yl}pyridin-3-yl)urea (P73) A solution of dimethyl sulfoxide (0.04 mL, 0.5 mmol) in DCM (0.1 mL) was added to a stirred solution of oxalyl chloride (0.032 mL, 0.36 mmol) in DCM (10 mL) at -70°C. A solution of compound P72 (0.078 g, 0.15 mmol) in DCM (1.0 mL) was added dropwise to the solution prepared above over 15 minutes, and the mixture was stirred for an additional 3.5 hours. Triethylamine (0.13 mL, 0.90 mmol) was added dropwise with stirring over 15 minutes, and the whole was allowed to warm to room temperature. The mixture was diluted with DCM, washed with saturated NaHCO3 (aq), dried over Na2SO4, and evaporated. The residue (P73) was used in the next step without further purification. LCMS ESI (m / z): 505.4 ([M+1] + ). Synthesis of 3-[2-(benzoyloxy)ethoxy]propanoic acid (P75) [ka]

[0947] Preparation 74. 2-(3-Tert-butoxy-3-oxopropoxy)ethyl benzoate (P74). To a solution of tert-butyl 3-(2-hydroxyethoxy)propanoate (1.0 g, 5.3 mmol) in 20 mL of DCM was added EtN (1.9 mL, 13.3 mmol). Benzoyl chloride (0.7 mL, 5.9 mmol) was then added at 0-5°C. The mixture was stirred at room temperature for 14 hours. The mixture was diluted with DCM, washed with saturated NaHCO (aq), dried over NaSO, and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P74: 1.2 g, 80%. 1 H NMR(400MHz,DMSO-d6),δ:7.96(d,J=7.8Hz,2H),7.66(t,J=7.4Hz,1H),7.53(t,J=7.6Hz,2H),4.38(d,J =4.5Hz,2H),3.73(d,J=4.5Hz,2H),3.66(t,J=6.1Hz,2H),2.43(t,J=6.1Hz,2H),1.37(d,J=13.7Hz,9H).

[0948] Preparation 75. 3-[2-(benzoyloxy)ethoxy]propanoic acid (P75). To a solution of compound P74 (1.2 g, 4.1 mmol) in 15 mL of DCM was added TFA (3.2 mL, 41.0 mmol). The mixture was stirred at room temperature for 14 hours. The mixture was evaporated. Yield of compound P75: 0.96 g, 99%. 1 H NMR(400MHz,DMSO-d6),δ:12.87-11.46(m,1H),8.08-7.91(m,2H),7.66(t,J=7.4Hz,1H),7.53(t,J=7.7Hz,2 H),4.47-4.29(m,2H),3.76-3.71(m,2H),3.68(t,J=6.3Hz,2H),2.50(d,J=1.7Hz,4H),2.46(t,J=6.3Hz,2H). Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2-phenylethyl)quinozoline (P78) [ka]

[0949] Preparation 76. 2-[3-({[(1E)-amino(3-methyl-5-nitropyridin-2-yl)methylene]amino}oxy)-3-oxopropoxy]ethyl benzoate (P76). To a solution of compound P75 (0.48 g, 2.0 mmol) in 20 mL of DCM was added EtN (0.9 mL, 6.0 mmol). The mixture was stirred at room temperature for 10 minutes. Then, TBTU (0.6 g, 2.4 mmol) and compound P6 (0.40 g, 2.0 mmol) were added, and the mixture was stirred at ambient temperature for 14 hours. The mixture was washed with 20% KCO (aq), dried over NaSO, and evaporated. The residue (P76) was used in the next step without further purification. LCMS ESI (m / z): 417.6 ([M+1] + ),179.3,149.4.

[0950] Preparation 77. 2-{2-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]ethoxy}ethyl benzoate (P77). A solution of compound P76 in 50 mL of dioxane was refluxed with stirring for 96 hours. The mixture was evaporated and purified by column chromatography on silica gel. Yield of compound P77: 0.5 g, 62% over two steps (Preparation 76 and Preparation 77). 1 H NMR(400MHz,DMSO-d6),δ:9.31(d,J=2.4Hz,1H),8.69(d,J=1.9Hz,1H),7.92-7.82(m,2H),7.58(t,J=7.4Hz,1H),7. 43(t,J=7.8Hz,2H),4.40-4.34(m,2H),3.98(t,J=6.1Hz,2H),3.83-3.75(m,2H),3.35(t,J=6.0Hz,2H),2.58(s,3H).

[0951] Preparation 78. 2-{2-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]ethoxy}ethyl benzoate (P78). To a solution of compound P77 (0.5 g, 1.3 mmol) in 10 mL of acetic acid was added Fe powder (0.7 g, 13.0 mmol). The suspension was stirred at 70° C. for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL), and filtered through Celite. The filtrate was evaporated. The residue was diluted with saturated NaHCO (aq) and extracted with ethyl acetate. The combined organic extracts were dried over Na SO and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P78: 0.42 g, 91%. LCMS ESI (m / z): 369.1 ([M+1] + ),149.4. Synthesis of N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(5-methyl-6-{5-[2-(2-oxoethoxy)ethyl]-1,2,4-oxadiazol-3-yl}pyridin-3-yl)urea (P81) [ka]

[0952] Preparation 79. 2-(2-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}ethoxy)ethyl benzoate (P79). To a solution of compound P36 (0.29 g, 1.3 mmol) in 20 mL of toluene was added EtN (0.7 mL, 5.2 mmol). The mixture was stirred at room temperature for 10 minutes. Then DPPA (0.32 mL, 1.6 mmol) was added. The mixture was stirred at room temperature for 1 hour, and compound P78 (0.42 g, 1.3 mmol) was added. The resulting mixture was stirred at 90° C. for 14 hours. The mixture was evaporated and purified by column chromatography on silica gel. Yield of compound P79: 0.5 g, 66%. LCMS ESI (m / z): 597.3 ([M+1] + ).

[0953] Preparation 80. N-(7-Cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-(6-{5-[2-(2-hydroxyethoxy)ethyl]-1,2,4-oxadiazol-3-yl}-5-methylpyridin-3-yl)urea (P80). To a solution of compound P79 (0.23 g, 0.4 mmol) in 5 mL of MeOH was added K2CO3 (0.16 g, 1.2 mmol). The mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. Yield of compound P80: 0.1 g, 54%. LCMS ESI (m / z): 493.6 ([M+1] + ).

[0954] Preparation 81. N-(7-Cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N´-(5-methyl-6-{5-[2-(2-oxoethoxy)ethyl]-1,2,4-oxadiazol-3-yl}pyridin-3-yl)urea (P82). A solution of DMSO (0.08 mL, 1.2 mmol) in DCM (0.1 mL) was added to a stirred solution of oxalyl chloride (0.08 mL, 0.86 mmol) in DCM (10 mL) at -70°C. A solution of compound P81 (0.18 g, 0.36 mmol) in DCM (1.0 mL) was added dropwise to the solution prepared above over 15 minutes, and the mixture was stirred for an additional 3.5 hours. Triethylamine (0.3 mL, 2.16 mmol) was added dropwise with stirring over 15 minutes, and the whole was allowed to warm to room temperature. The mixture was diluted with DCM, washed with saturated NaHCO3 (aq), dried over Na2SO4, and evaporated. The residue (P82) was used in the next step without further purification. LCMS ESI (m / z): 491.4 ([M+1] + ). Synthesis of 6-{3-[5-({[(5-cyclopentylimidazo[1,2-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid (P82) [ka]

[0955] Preparation 82. 6-{3-[5-({[(5-cyclopentylimidazo[1,2-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid (P82). Aqueous NaOH (0.015 g, 0.37 mmol) was added to a solution of compound P61 (0.101 g, 0.23 mmol) in 10 ml of ethanol. The mixture was stirred at 50° C. for 12 hours. After complete hydrolysis of the ester, the mixture was cooled to ambient temperature. The ethanol was evaporated, the reaction mixture was acidified to pH=7 with hydrochloric acid, and the product was then extracted with ethyl acetate. The solution of the product in ethyl acetate was dried over Na2SO4 and evaporated. Compound P82 (0.086 g, 90%) was obtained as a solid. LCMS ESI (m / z): 519.3 ([M+1] + ). Synthesis of 5-methoxy-3,3-dimethyl-5-oxope...

Claims

1. Compound of formula (I-IA-1-a-1-IA): 【Chemistry 1】 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, During the ceremony, Ring A is a 5-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms, where each heteroatom is independently selected from N, O, and S; Ring B is a 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms, where each heteroatom is independently selected from N, O, and S; M is -CH ２ -, -C(O)-, L1 is a bond; L 2 is selected from a bond, —CH 2 —, —CH 2 CH 2 —, C 3 -C 8 cycloalkanediyl-(CH 2 ) p —; Each R 3 and R ９ is hydrogen or or two R's ３ is =O, Each R ４ , R ６ , R ７ , and R １０ is halogen, -OH, -CN, -NO ２ , -NR １２ R １３ , C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are independently selected from one or more R １１ and optionally substituted with R ８ is H, C １ ~C ６ selected from alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein said alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is selected from one or more R １１ and optionally substituted with Each R １１ is halogen, -OH, -CN, -NO ２ , -NR １２ R １３、 C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ independently selected from haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl; R １２ and R １３ is hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C １ ~C ６ each independently selected from hydroxyalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl; m and n are integers independently selected from 0, 1, 2, and 3; p is an integer selected from 0 and 1; u is an integer selected from 0, 1 and 2; w is an integer selected from 0, 1 and 2; A compound of formula (IIA-1-a-1-IA) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof:

2. The compound has formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-11), (I-12), (I-13), (I-14), or (I-16): 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 Things, or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, wherein in each of formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-11), (I-12), (I-13), (I-14), and (I-16), n is an integer selected from 0 and 1; The compound of claim 1.

3. A compound selected from: or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

4. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

5. 5. The pharmaceutical composition of claim 4, further comprising an additional pharmaceutically active agent.

6. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to any one of claims 4 or 5 for use in the manufacture of a medicament for degrading MALT1, wherein the compound or the pharmaceutical composition is administered to a subject.

7. 10. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to any one of claims 4 or 5 for use in the manufacture of a medicament for treating a disease or disorder associated with MALT1, wherein the compound or pharmaceutical composition is administered to a subject.

8. 10. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to any one of claims 4 or 5 for use in the manufacture of a medicament for treating a disease or disorder selected from lymphoma and immunodeficiency, wherein said compound or said pharmaceutical composition is administered to a subject in need of treatment.

9. The use according to claim 6, wherein the subject is a mammal.

10. The use according to claim 9, wherein the subject is a human.

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