MALT1 PROTACS

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 of related applications) This application claims priority and interest to U.S. Provisional Patent Application No. 63 / 314,205, entitled “PROTAC OF MALT1,” filed on 25 February 2022, the disclosure thereof, which is incorporated herein by reference in its entirety for all purposes.

[0002] The present invention relates to the use of targeted proteolytic chimeric (PROTAC) technology for treating diseases or disorders associated with mucosal-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), particularly to compounds for degrading MALT1 and methods thereof. [Background technology]

[0003] Targeted proteolytic chimeric (PROTAC) technology is a recently developed, effective endogenous proteolytic tool that can ubiquitinize target proteins via the ubiquitin-proteasome system (UPS) to achieve effects against tumor growth. Numerous literature reviews on PROTAC technology demonstrate 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 the treatment of prostate and breast cancer, 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 is attracting attention. Based on this, the discovery of new targeted and small molecule inhibitors (SMIs) represents a powerful treatment strategy. In particular, the development of small molecule kinase inhibitors has become one of the most widely pursued areas in the drug discovery process and has achieved great results in cancer treatment (Wu et al., Trends Pharmacol.Sci.2015,36,422-439.doi:10.1016 / j.tips.2015.04.005). However, after success, treatment strategies also face the same problem of drug resistance 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 in cancer treatment and urgently needs to be addressed.

[0005] In recent years, novel strategies targeting disease-related proteins for degradation have attracted considerable attention. Targeted proteolytic chimeras (PROTACs), also known as divalent 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 target protein (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 are that it can compensate for the shortcomings of conventional drug therapies, which are driving its rapid development (Sun and Rao, Biochemistry 2020, 59, 240-249. doi:10.1021 / acs.biochem.9b00848).

[0006] Bifunctional PROTAC molecules consist of a ligand (primarily small molecule inhibitors) for a target protein (POI) and a covalent ligand for an E3 ubiquitin ligase (E3). Upon binding to a POI, the PROTAC can recruit E3 for POI ubiquitination, which is then subjected to proteasome-mediated degradation. PROTACs complement nucleic acid-based gene knockdown / out techniques 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] The PROTAC molecule consists of a ligand for POI (primarily a small molecule inhibitor) and a ligand for E3 ubiquitin ligase (E3), which are covalently interconnected with linkers of 5 to 15 carbon or other atoms. Mechanistically, upon binding to POI, PROTAC can recruit E3 for proximity-induced ubiquitination of POI, which is then subjected to degradation by the endogenous 26S proteasome. Recent X-ray structures of the POI-PROTAC-E3 ternary complex provide strong evidence supporting this mechanism (Gadd MSet 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). Firstly, despite their relatively large molecular weight, PROTACs are more drug-like than RNA / DNA-based protein reducers. By selecting drug-like ligands for POIs and E3s, and subsequently optimizing their medicinal chemistry, PROTACs can possess the good ADME (absorption, distribution, metabolism, and efflux) properties required to become clinically useful drugs. Secondly, because PROTACs can be reused after a single proteolytic degradation, POIs can be quasi-stoichiometrically eliminated. Therefore, the DC50 of a PROTAC may be significantly lower than its binding affinity (or inhibitory IC50) to POIs. For example, low levels of PROTAC, such as 10 pM, can efficiently induce BRD4 degradation (Qin C. et al., J Med Chem. 2018, 61(15), 6685-704). This characteristic offers potentially significant advantages beyond pharmacological protein inhibition. Thirdly, because PROTAC requires only transient binding to POI, it offers an opportunity to overcome mutation-targeted drug resistance. For example, ibrutinib-containing PROTAC MT-802 induced degradation of C481S mutant BTK (which is resistant to ibrutinib) as effectively as wild-type protein and potently inhibited the proliferation of ibrutinib-resistant leukemia cells (Buhimschi AD et al., Biochemistry 2018, 57(26), 3564-75). Fourthly, PROTAC requires only ligands that bind to POI and may not necessarily affect POI function. Therefore, PROTACs can potentially target any protein, including those that are unlikely to be considered drugs. Furthermore, the degradation induced by PROTACs also depends on lysine residues on the POI surface, which represents an additional selectivity requirement.This can 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 with pan inhibitors of protein families.

[0009] Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a protein encoded by the MALT1 gene in humans. It is human paracaspase. Genetic loss and biochemical studies of the paracaspase gene in mice have shown that paracaspase is an important protein for the activation of T lymphocytes and B lymphocytes. It plays a crucial role in the activation of the transcription factor NF-κB, the production of interleukin-2 (IL-2), and the proliferation of T lymphocytes and B lymphocytes. Furthermore, the role of paracaspase has been demonstrated 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. MALT1 downstream NF-κB signaling and activation of protease activity occur in the so-called CBM (CARD-CC / BCL10 / MALT1) signaling complex when BCL10 / MALT1 is recruited to activated CARD-CC family proteins (CAR9, -10, -11, or -14). Paracaspases have been shown to possess proteolytic activity in T lymphocytes via their caspase-like domains. Targeting paracaspase proteolytic activity may allow for the development of novel drugs that could be useful in treating certain lymphomas or autoimmune disorders.

[0010] In summary, approximately 50 PROTACs targeting proteins have been successfully developed to date, and two of these compounds are currently in clinical trials for the treatment of treatment-resistant prostate and breast cancer. Clinical outcomes have not been disclosed. Given these relatively few POIs and clinical candidates, it remains unclear whether these PROTACs can become clinically useful anticancer agents. However, PROTAC technology is not yet fully investigated and developed. It has great potential from the perspective of cancer treatment. There are more than 600 E3 ubiquitin ligases in humans, many of which could be used to design PROTACs (Ottis P. et al, ACS Chem Biol. 2017, 12(10), 2570-8). Success in this area, along with a better understanding of the function and tissue-specific expression of these E3s, could greatly expand the feasibility, usefulness, and selectivity of PROTAC technology. [Overview of the project]

[0011] A first aspect of the present invention relates to a compound of formula (A): [ka] With respect to pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof, During the ceremony, Each X is selected independently 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 rings. Ring B is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl rings. Ring C is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl. M is -CH2-, -C(O)-, -C(O)NRo -, -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 selected from -, -S-, and -S(O)2-; L1 and L2 are a bond, C1-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)<00000z8>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-, respectively independently selected, or M and L2 are both a bond, or L1-M-L2 is a bond, L3 and L4 are a bond, C1-C 12 alkanediyl, C2-C 12 alkenediyl, C2-C 12 alkynediyl, C1-C 12 alkoxylenyl, -((CH2)​​​​​​​​​​​​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- are selected independently from each of them. 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, where alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is one or more R 11 It is sometimes replaced by, Each of R2, R3, and R9 is hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13 A molecule is 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, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 In some cases, it is replaced, Alternatively, two R3s are = O, Each R4, R6, R7, and R 10 These are hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13A molecule is 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, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 It is sometimes replaced by, Each R5 is independently selected from hydrogen and C1-C6 alkyl groups. R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is one or more R 11 It is sometimes replaced by, Each R 11 These are halogen, -OH, -CN, -NO2, and -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 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl. R 12 and R 13 These 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, respectively. 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. However, if t is 0, L4 is a join, However, at least one of L3 and L4 is not a bond, Cycloalkyl groups are saturated or partially unsaturated C3-C3 groups. 10 Monocyclic, C5~C 18 Bicyclic (condensation, cross-linking, or spiro) or C6~C 18 It is a tricyclic (condensed, bridged, or spiro) ring system. Aryls are cyclic aromatic hydrocarbon ring systems containing 1 to 3 aromatic rings. Heterocyclyls are saturated or partially unsaturated 3-10 member monocyclic, 7-12 member bicyclic (condensed, bridging, or spiro-ring), or 11-14 member tricyclic ring systems (condensed, bridging, or spiro-ring) containing 1-7 heteroatoms selected from O, N, S, P, Se, or B. A heteroaryl is a monocyclic or polycyclic aromatic ring system containing 5 to 24 ring atoms, where 1 to 7 of the rectified atoms are heteroatoms selected from N, O, S, P, or B, and the remaining rectified atom is C.

[0012] Another aspect of the present invention relates to a compound of formula (I): [ka] With respect to pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs or tautomers thereof, During the ceremony, Each X is selected independently 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 rings. 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- and is selected, L1 and L2 are a bond, C1-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- are each independently selected, or M and L2 are both a bond, or L1-M-L2 is a bond, L3 and L4 are a bond, C1-C 12 alkylenyl, C2-C 12 alkenedienyl, 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 are each independently selected from -, -S-, and -S(O)2- 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-O-P(O)(OC1-C6 alkyl)2, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 11 in some cases Each R2, R3, and R9 is independently selected from 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 the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is optionally substituted with one or more R 11 in some cases, or two R3s form =O Each R4, R6, R7, and R 10 is independently selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13A molecule is 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, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 It is sometimes replaced by, Each R5 is independently selected from hydrogen and C1-C6 alkyl groups. R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is one or more R 11 It is sometimes replaced by, Each R 11 These are halogen, -OH, -CN, -NO2, and -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 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl. R 12 and R 13 These 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, respectively. 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. However, if t is 0, L4 is a bond. However, at least one of L3 and L4 is not a coupling, Cycloalkyl groups are saturated or partially unsaturated C3-C3 groups. 10 Monocyclic, C5~C 18 Bicyclic (condensation, cross-linking, or spiro) or C6~C 18 It is a tricyclic (condensed, bridged, or spiro) ring system. Aryls are cyclic aromatic hydrocarbon groups having 1 to 3 aromatic rings. Heterocyclyls are saturated or partially unsaturated 3-10 member monocyclic rings, 7-12 member bicyclic rings (condensed, bridging, or spiro-rings), or 11-14 member tricyclic ring systems (condensed, bridging, or spiro-rings) having 1-7 heteroatoms selected from O, N, S, P, Se, or B. A heteroaryl is a monocyclic or polycyclic aromatic radical rectified atom containing 5 to 24 rectified atoms, with 1 to 7 heteroatoms selected from N, O, S, P, or B, and the remaining rectified atom being carbon.

[0013] Another aspect of the present invention relates to a compound of formula (II): [ka] With respect to pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs or tautomers thereof, During the ceremony, Each X is selected independently 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 rings. Ring B is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl rings. 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 Selected from -, -S-, and -S(O)2-, L1 and L2 are bonded, C1~C 12 Alkandiil, C2~C 12 Alkenziel, C2~C 12 Alkynediyl, C3-C8 cycloalkanediyl, C3-C8 cycloalkanediyl-(CH2) p -, C1~C 12 Alkoxyrenyl, -((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- are independently selected, or M and L2 are both conjugates, or L1-M-L2 is a bond, L3 and L4 are bonded, C1~C 12 Alkyrenyl, C2~C 12 Alkenziel, C2~C 12 Alkindil, C1~C 12 Alkoxyrenyl, -((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)2- are selected independently from each of them. 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, where alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is one or more R 11 It is sometimes replaced by, R2 and R9 are hydrogen, halogen, -OH, -CN, -NO2, and -NR respectively. 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, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 It is sometimes replaced by, R4, R6, R7, and R 10 Each of these is hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13A molecule is 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, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 It is sometimes replaced by, Each R5 is independently selected from hydrogen and C1-C6 alkyl groups. R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is one or more R 11 It is sometimes replaced by, Each R 11 These are halogen, -OH, -CN, -NO2, and -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 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl. R 12 and R 13 These 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, respectively. 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. However, if t is 0, L4 is a bond. However, at least one of L3 and L4 is not a coupling, Cycloalkyls are saturated or partially unsaturated C3-C3 10 Monocyclic, C5~C 18 Bicyclic (fusion, bridging, or spiro) or C6~C 18 It is a tricyclic (fused, bridged, or spirocyclic) system. Aryls are cyclic aromatic hydrocarbon ring systems containing 1 to 3 aromatic rings. Heterocyclyls are saturated or partially unsaturated 3-10 member monocyclic, 7-12 member bicyclic (condensed, bridging, or spirocyclic), or 11-14 member tricyclic ring systems (condensed, bridging, or spirocyclic) containing 1-7 heteroatoms selected from O, N, S, P, Se, or B. A heteroaryl is a monovalent monocyclic or polycyclic aromatic ring system containing 5 to 24 ring atoms, where 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 excipients, diluents, or surfactants.

[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 excipients, diluents, or surfactants.

[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 excipients, diluents, or surfactants.

[0017] Another aspect of the present invention relates to a method for treating a disease or disorder related to MALT1. The method comprises administering to a patient in need of treatment for a disease or disorder related to MALT1 an effective amount of the 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 disease or disorder related to MALT1. The method comprises administering to a patient in need of treatment for a disease or disorder related to MALT1 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 disease or disorder related to MALT1. The method comprises administering to a patient in need of treatment for a disease or disorder related to MALT1 an effective amount of the 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. The method comprises administering to a patient in need an effective amount of the 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. The method comprises administering to a patient in need an effective amount of the 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. The method comprises administering to a patient in need an effective amount of the 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 thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of pharmaceuticals for the decomposition of MALT1.

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

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

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

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

[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 diseases associated with MALT1.

[0029] 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 treating or preventing a disease or disorder disclosed herein.

[0030] 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 treating or preventing a disease or disorder disclosed herein.

[0031] 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 treating or preventing a disease or disorder disclosed herein.

[0032] Another aspect of the present invention relates to a method for treating or preventing a disease or disorder disclosed herein in a subject that requires treatment or prevention of the disease or disorder disclosed herein. The method comprises administering to a patient in need of treatment 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 for treating or preventing a disease or disorder disclosed herein in a person requiring treatment or prevention of such disease or disorder. The method comprises administering to a patient requiring treatment 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 for treating or preventing a disease or disorder disclosed herein in a person requiring treatment or prevention of such disease or disorder. The method comprises administering to a patient requiring treatment an effective amount of the 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 thereof, 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 thereof, 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 thereof, 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 related to MALT1, comprising administering a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof to a patient suffering from at least one of the diseases or disorders.

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

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

[0041] This invention provides a PROTAC of MALT1, which is a therapeutic agent for the treatment of diseases and disorders.

[0042] The present invention further provides compounds and compositions having 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 related to MALT1, comprising administering a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof to a patient suffering from at least one of the diseases or disorders.

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

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

[0046] This invention provides a PROTAC of MALT1, which is a therapeutic agent for the treatment of diseases and disorders.

[0047] The present invention further provides a method for 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 a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof to a patient suffering from at least one of the disease or disorder.

[0048] The present invention further provides a method for treating a disease, disorder, or condition selected from immunodeficiency12; lymphoma, mucosal-associated lymphocyte type (MALTOMA); combined immunodeficiency; combined T-cell and B-cell immunodeficiency; or lymphoma, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof to a patient suffering from at least one of the diseases or disorders.

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

[0050] In some embodiments, the present disclosure provides a compound obtainable 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") or obtained thereby.

[0051] In some embodiments, the present disclosure provides an intermediate described herein suitable for use in a method for preparing a compound described herein (e.g., the intermediate is selected from the intermediates described in the section on the synthetic methods of the present disclosure).

[0052] In some embodiments, the present disclosure provides a method for preparing a compound of the present disclosure.

[0053] In some embodiments, the present disclosure provides a method for preparing a compound 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 those generally understood by those skilled in the art to which this disclosure belongs. In this specification, the singular form includes the plural form unless the context clearly indicates otherwise. Similar or equivalent methods and materials to those described herein may be used in the implementation or testing of this disclosure, but suitable methods and materials are listed below. All publications, patent applications, patents, and other references referenced herein are incorporated by reference in their entirety for all purposes. In case of any conflict, this specification, including definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative and not intended to limit the scope. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

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

[0056] [Figure 1] This figure shows bar graphs of the PROTAC activity of compounds 10, 12, and 13 of the present disclosure against MALT1, compared to reference compounds Reference 1 and Reference 2, under the experimental conditions presented in Example C.

[0057] [Figure 2] This figure shows bar graphs of the PROTAC activity of compounds 14, 16, and 17 of the present disclosure against MALT1, compared to reference compound 3, under the experimental conditions shown in Example C. [Modes for carrying out the invention]

[0058] Detailed description of the invention This disclosure provides a method for treating, preventing, or improving a MALT1-related disease or disorder by administering a therapeutically effective amount of one of the compounds disclosed herein to a subject in need of treatment, prevention, or improvement of a MALT1-related disease or disorder.

[0059] Details of this disclosure are described in the attached description below. Similar or equivalent methods and materials may be used in the implementation or testing of this disclosure, but only illustrative methods and materials are described here. Other features, purposes, and advantages of this disclosure will become apparent from the description and the claims. In this specification and the attached claims, singular forms include plural forms unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications referenced herein are incorporated herein by reference in their entirety. definition

[0060] In this disclosure, the articles "a" and "an" are used to refer to one or more (i.e., at least one) grammatical objects of the articles. For example, "element" means one or more elements.

[0061] Unless otherwise specified, the term "and / or" is used in this disclosure to mean either "and" or "or".

[0062] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required) bond to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have one or more substituents other than hydrogen. For example, it may bond to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but is not necessarily required to have further functional groups. Suitable substituents used for optional substitution of the groups described include, but are not limited to, halogens, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1~C6)alkyl, (C1~C6)alkyl, (C1~C6)alkoxy, (C1~C6)haloalkyl, (C1~C 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 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 may be substituted. As used herein, "may be substituted" also means substituted or unsubstituted as described below.

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

[0064] As used herein, the term "unsubstituted" means that a particular group does not have substituents.

[0065] Unless otherwise specifically defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. If it contains two aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group may be linked at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may optionally be substituted at any bonding point with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C1~C6)alkyl, (C1~C6)alkyl, -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~C6)alkyl, -OC(O)O(C1~C6)alkyl, -NH2, -NH((C1~C6)alkyl), -N((C1~C6)alkyl)2, -S(O)2-(C1~C6)alkyl, -S(O)NH(C1~C6)alkyl, and -S(O)N((C1~C6)alkyl)2. The substituents themselves may be substituted depending on the case. Furthermore, when containing two fused rings, the aryl groups as defined herein may have one or more saturated or partially unsaturated rings fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenantrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannerenyl, and the like.

[0066] Unless otherwise specifically defined, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, comprising one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. A polycyclic aromatic radical comprises two or more fused rings, and may further comprise two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specified, “condensation” means two rings sharing two ring atoms. Unless otherwise specified, “spiro-condensation” means two rings sharing one ring atom. A heteroaryl as defined herein also means a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, S, P, or B. A heteroaryl as defined herein also means a tricyclic heteroaromatic group in which one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as defined herein also means a tetracyclic heteroaromatic group comprising one or more ring heteroatoms selected from N, O, S, P, or B. Aromatic radicals are optionally independently substituted 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, benzopyranil, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, flu[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrro [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, chromanil, thiochromanil, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthilidinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthilidinyl, 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]pyridinyl, tetrahydro Pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridine-2-one, flo[3,2-c]pyrimidinyl, flo[2,3-c]pyrimidinyl, 1H-pyrido[3,4-b][1,4]thiadinyl, benzoxazolyl, benzoxazolyl, flo[2,3-b]pyrimidinyl Dinyl, benzothiophenyl, 1,5-naphthilidinyl, flo[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]imidazole-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 include, but are not limited to, [3-b]pyrrolyl, 3H-indolyl, and their derivatives. Furthermore, when comprising 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 comprising three or more fused rings, the saturated or partially unsaturated rings may be further fused with the saturated or partially unsaturated rings described herein. Furthermore, when comprising 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 rings described herein may be optionally substituted with one or more oxos. 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, oxyndryll, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridine-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, and 1,5,6,7-tetrahydrocyclopenta[b]pyrrolidinyl. Examples include lazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidine-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indole-1(2H)-onyl, benzo[c][1,2]oxabolol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrolo[1,2-d][1,4]oxazine-9-onyl, or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrolo[1,2-d][1,4]oxazine]-9'-onyl.

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

[0068] Alkyls refer to straight-chain or branched saturated hydrocarbons 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-chain or branched-chain saturated hydrocarbon containing 1 to 12 carbon atoms, including 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] An "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in its chain. The double bond of the 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. The alkenyl group may be unsubstituted or substituted. Alkenyls can be straight-chain or branched, as defined herein.

[0071] "Alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "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. The alkynyl group may be unsubstituted or substituted.

[0072] The terms "alkylene" or "alkylenyl" refer to a divalent alkyl radical. Any of the monovalent alkyl groups described above may be alkylenes formed by the abstraction of a second hydrogen atom from the alkyl group. As defined herein, alkylenes may be C1-C6 alkylenes. Alkylenes may also be C1-C4 alkylenes. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0073] The term "alkoxylenyl" refers to a divalent alkoxy radical. Any of the monovalent alkoxy groups listed above can be alkoxylenyls formed by abstracting a second hydrogen atom from an alkyl group. Typical alkylene groups include, but are not limited to, -O-CH2-, -O-CH(CH3)-, -OC(CH3)2-, -O-CH2CH2-, -O-CH2CH(CH3)-, -O-CH2C(CH3)2-, -O-CH2CH2CH2-, -O-CH2CH2CH2CH2-, etc.

[0074] "Cycloalkyl" refers to a monocyclic or polycyclic saturated or partially unsaturated carbon ring containing 3 to 18 carbon atoms. Polycyclic cycloalkyls may be condensed bicyclic cycloalkyls, cross-linked bicyclic cycloalkyls, or spiro-condensed bicyclic cycloalkyls. Polycyclic cycloalkyls contain at least one non-aromatic ring. Examples of cycloalkyls 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, heterocyclic, or heterocycloalkyl monocyclic or polycyclic ring comprising 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. The substituents themselves may be 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, oxazolidinyl, and homotropanyl.

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

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

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

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

[0080] "Spirocycloalkyl" or "spirocyclyl" refers to a bicyclic system of bicarbonate in which both rings are linked by a single atom. The rings may differ in size and properties, or they may be identical in size and properties. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both rings within a spiro ring can be fused to a carbocyclic, heterocyclic, aromatic, or heteroaromatic ring of another ring. One or more carbon atoms in a spiro ring can be substituted with heteroatoms (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 carbon atoms may be substituted with heteroatoms.

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

[0082] The term “solvate” refers to a variable stoichiometric complex formed by a solute and a solvent. Such solvents for the purposes of this disclosure cannot 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 a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0083] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. Structural differences can be in composition (geometric isomers) or in the ability to rotate the plane of polarization (stereoisomers). Regarding stereoisomers, the compound of formula (I) may have one or more chiral carbon atoms and may exist as a racemate, a racemic mixture, and as individual enantiomers or diastereomers.

[0084] This disclosure also relates to isotope-labeled compounds of formula I (e.g., 2 H and 14 The intention is to deuterate (i.e., labeled with C). 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 provide certain therapeutic benefits resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced required dose), and therefore may be preferred in some situations. The isotope-labeled compounds of formula I can generally be prepared by procedures similar to those disclosed in the following schemes and / or examples, by using a suitable isotope-labeling reagent instead of a non-isotope-labeling reagent.

[0085] This disclosure also includes pharmaceutical compositions comprising therapeutically effective amounts of the disclosed compound and pharmaceutically acceptable carriers. Typical "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetate, ansonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium, calcium edetate, cansylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estrate, esylate, fumarate, gluceptinate, gluconate, glutamate, glycolyl arsanate, hexafluorophosphate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiocyanate. Examples include nat, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methyl sulfate, mucate, nafilate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theocurate, tosylate, triethiodide, and valerate.

[0086] "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cattle, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus macaque.

[0087] When used in relation to a compound, “effective amount” means an amount effective in treating or preventing the disease described herein.

[0088] As used in this disclosure, the term "carrier" includes carriers, excipients, and diluents, and means materials, compositions, or vehicles such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in the transport or delivery of a pharmaceutical product from one organ or part of the body to another.

[0089] The term "treatment" in relation to the subject refers to improving at least one symptom of the disorder in the subject. Treatment includes curing, improving, or at least partially alleviating the disorder.

[0090] The term “disability” is used in this disclosure to mean, unless otherwise indicated, the terms “disease,” “condition,” or “illness,” and is interchangeable with these terms.

[0091] As used in this disclosure, the terms “administer,” “give administration,” or “give administration” refer to either direct administration of the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound, or administration of a prodrug derivative or analogue of the compound or a pharmaceutically acceptable salt of the compound or composition that can form an equivalent amount of the active compound in the body of the subject.

[0092] As used in this disclosure, the term “prodrug” means a compound that can be converted in vivo to the disclosed compound by metabolic means (e.g., by hydrolysis).

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

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

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

[0096] The amount of compound in the composition described herein required to achieve a therapeutic effect can be determined empirically by conventional procedures for a particular purpose. Generally, for administering a therapeutic agent (e.g., a compound or composition of Formula I described herein (and / or additional agents)) for therapeutic purposes, the therapeutic agent is administered in a pharmacologically effective dose. "Pharmacologically effective dose," "pharmacologically effective dose," "therapeutic effective dose," or "effective dose" refers to an amount sufficient to produce a desired physiological effect or achieve a desired outcome, particularly for treating a disorder or disease. As used herein, an effective dose 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 disease symptoms), reduce or eliminate one or more symptoms or manifestations of a disorder or disease, or reverse the symptoms of a disorder or disease. For example, administration of a therapeutic agent to a subject with cancer provides therapeutic benefits not only if the underlying disease is eradicated or improved, but also if the subject reports a reduction in the severity or duration of disease-related symptoms, such as a reduction in tumor burden, a reduction in circulating tumor cells, or an increase in progression-free survival. Therapeutic benefits also include stopping or slowing the progression of an underlying disease or disability, whether or not improvement is achieved. Compounds of the Disclosure

[0097] In one embodiment, the present disclosure relates to compounds of formula (A) and their salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers: [ka] Provided, 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 in this specification.

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

[0099] In some embodiments, the present disclosure provides compounds of formula (I) as well as 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 the compound 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 be selected from the bases described herein, where applicable: R1, R2, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 Any of the groups described herein for any of X, m, n, t, u, and w, where applicable, are 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 can be combined with any of the remaining one or more of the groups described herein.

[0101] In some embodiments, the present disclosure provides compounds of formula (II) and their salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers. [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 the compound 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 be selected from the bases described herein, where applicable, R1, R2, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 Any of the bases described herein for any of X, m, n, t, u, and w, where applicable, are R1, R2, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 X, m, n, t, u, and w can be combined with any of the remaining one or more of the groups described herein.

[0103] In some compounds having the structure of formula (A), Each X is selected independently 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 rings. Ring B is selected from cycloalkyl, aryl, heterocyclyl, and heteroaryl rings. 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 Selected from -, -S-, and -S(O)2-, L1 and L2 are bonded, C1~C 12 Alkandiil, C2~C 12 Alkenziel, C2~C 12 Alkynediyl, C3-C8 cycloalkanediyl, C3-C8 cycloalkanediyl-(CH2) p -, C1~C 12 Alkoxyrenyl, -((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- are independently selected, or M and L2 are both conjugates, or L1-M-L2 is a bond, L3 and L4 are bonded, C1~C 12 Alkandiil, C2~C 12 Alkenziel, C2~C 12 Alkindil, C1~C 12 Alkoxyrenyl, -((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)2- are selected independently from each of them. 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, where alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is one or more R 11 It is sometimes replaced by, Each of R2, R3, and R9 is hydrogen, halogen, -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, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 In some cases, it is replaced by, or The two R3s are = O, Each R4, R6, R7, and R 10 These are halogen, -OH, -CN, -NO2, and -NR 12 R 13A molecule is 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, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 It is sometimes replaced by, Each R5 is independently selected from hydrogen and C1-C6 alkyl groups. R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is one or more R 11 It is sometimes replaced by, Each R 11 These are halogen, -OH, -CN, -NO2, and -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 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl. R 12 and R 13 These 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 an integer selected from 0, 1, and 2. m and n are integers independently selected from 0, 1, 2, and 3, respectively. 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. However, if t is 0, L4 is a bond. However, at least one of L3 and L4 is not a coupling.

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

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

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

[0107] In some embodiments, at least one of the two X 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 a cycloalkyl group.

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

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

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

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

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

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

[0117] In some embodiments, ring A is condensed C3~C 12 It is a bicyclic cycloalkyl. In some embodiments, ring A is a crosslinked C3-C 12 It is a bicyclic cycloalkyl. In some embodiments, ring A is a spiro-condensed C3-C 12 It is a bicyclic cycloalkyl compound.

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

[0119] In some embodiments, ring A is C6~C 10 It is Ariel.

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

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

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

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

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

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

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

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

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

[0129] In some embodiments, ring A is a four-membered heterocycline containing one or two heteroatoms, where each heteroatom is independently selected from N, O, and S.

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

[0131] In some embodiments, ring A is a five-membered heterocycline containing one or two heteroatoms, where each heteroatom is independently selected from N, O, and S.

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

[0133] In some embodiments, ring A is a six-membered heterocycline containing one, two, or three 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 seven-membered heterocycline containing one, two, or three heteroatoms, where each heteroatom is independently selected from N, O, and S.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0150] In some embodiments, ring A is a six-membered heterocycline containing one, two, three, or four heteroatoms, where each heteroatom is independently selected from N, O, and S.

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

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

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

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

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

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

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

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

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

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

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

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

[0163] In some embodiments, ring B is a cycloalkyl group. In some embodiments, ring B is an aryl group. In some embodiments, ring B is a heterocyclyl group. In some embodiments, ring B is a heteroaryl group.

[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 It is a cycloalkyl that may be substituted depending on the circumstances.

[0168] In some embodiments, ring B is a cycloalkyl group.

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

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

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

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

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

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

[0175] In some embodiments, ring B is condensed C3~C 12 It is a bicyclic cycloalkyl. In some embodiments, ring B is a crosslinked C3-C 12It is a bicyclic cycloalkyl. In some embodiments, ring B is a spiro-condensed C3-C 12 It is a bicyclic cycloalkyl compound.

[0176] In some embodiments, ring B is an aryl ring.

[0177] In some embodiments, ring B is C6~C 10 It is Ariel.

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

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

[0180] In some embodiments, ring B is a heterocyclyl.

[0181] In some embodiments, ring B is a three-membered heterocyclyl.

[0182] In some embodiments, ring B is a three-membered heterocycline containing one heteroatom selected from O and N.

[0183] In some embodiments, ring B is a four-membered heterocyclyl.

[0184] In some embodiments, ring B is a four-membered heterocycline containing one or two heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0185] In some embodiments, ring B is a five-membered heterocyclyl.

[0186] In some embodiments, ring B is a five-membered heterocycline containing one or two heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0187] In some embodiments, ring B is a six-membered heterocyclyl.

[0188] In some embodiments, ring B is a six-membered heterocycline containing one, two, or three 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 seven-membered heterocycline containing one, two, or three heteroatoms, where each heteroatom is independently selected from N, O, and S.

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

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

[0193] In some embodiments, ring B is one or more R 11 It is a heteroaryl that may be substituted depending on the circumstances.

[0194] In some embodiments, ring B is a heteroaryl ring.

[0195] In some embodiments, ring B is a five-membered heteroaryl.

[0196] In some embodiments, ring B is a five-membered heterocycline containing one, two, three, or four 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 six-membered heteroatom containing 1, 2, 3, or 4 heteroatoms. Ariel Here, each heteroatom is independently selected from N, O, and S.

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

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

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

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

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

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

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

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

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

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

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

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

[0211] In some embodiments, ring C is an aryl ring.

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

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

[0214] In some embodiments, ring C is a heterocyclyl.

[0215] In some embodiments, ring C is a bicyclic heterocycline.

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

[0217] In some embodiments, the ring C is a heteroaryl.

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

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

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

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

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

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

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

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

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

[0227] In some embodiments, Y is [ka] That is the case.

[0228] In some embodiments, Y is -NR5C(O)NR5-.

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

[0230] In some embodiments, Y is [ka] That is the case.

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

[0232] In some embodiments, Y is -NR5C(O)-.

[0233] In some embodiments, -NR5C(O)- connects cycles C and L1 as shown herein: (ring C)-NR5C(O)-(L1).

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

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

[0236] In some embodiments, -NHC(O)- connects cycles C and L1 as shown here: (ring C)-NHC(O)-(L1).

[0237] In some embodiments, -NHC(O)- connects cycles 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 It is C(O)-. In some embodiments, M is -NR L C(O)NR L -. In some embodiments, M is -NR L It is C(O)O-. In some embodiments, M is -NR LIt 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)2NR L -. In some embodiments, M is -S-. In some embodiments, M is -S(O)2-.

[0239] In some embodiments, M is -CH2-.

[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 coupling. In some embodiments, L1 is C1~C 12 It is an alkanedyl. In some embodiments, L1 is C2~C 12 It is an alkenzyl. In some embodiments, L1 is C2~C 12 It is an alkinediyl. In some embodiments, L1 is a C3-C8 cycloalkanediyl. In some embodiments, L1 is a C3-C8 cycloalkanediyl-(CH2) p -. In some embodiments, L1 is C1~C 12 It is an alkoxyrenyl. In some embodiments, L1 is -((CH2) 1~6 O) o -(CH2) p -. In some embodiments, L1 is -((CH2)1~6 O) o -(CH2) p -NH-. In some embodiments, L1 is -((CH2) 1~6 O) o -(CH2) p -NH-C(O)-. In some embodiments, L1 is -((CH2) 1~6 O) o -(CH2) p It is -C(O)-NH-.

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

[0256] In some embodiments, L1 is C1~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, L1 is -((CH2) 1~6 O) o -(CH2) p - is

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

[0264] In some embodiments, L1 is -((CH2) 1~6 O) o -(CH2)p - is

[0265] In some embodiments, L1 is -((CH2) 1~6 O) o -(CH2) p It is -NH-.

[0266] In some embodiments, L1 is -((CH2) 1~6 O) o -(CH2) p It is -NH-C(O)-.

[0267] In some embodiments, L1 is -((CH2) 1~6 O) o -(CH2) p It is -C(O)-NH-.

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

[0269] In some embodiments, L1 is [ka] That is the case.

[0270] In some embodiments, L1 is [ka] That is the case.

[0271] In some embodiments, L1 is [ka] That is the case.

[0272] In some embodiments, L1 is [ka] That is the case.

[0273] In some embodiments, L1 is [ka] That is the case.

[0274] In some embodiments, L1 is [ka] That is the case.

[0275] In some embodiments, L1 is [ka] That is the case.

[0276] In some embodiments, L1 is [ka] That is the case.

[0277] In some embodiments, L2 is a coupling. In some embodiments, L2 is C1~C 12 It is an alkanedyl. In some embodiments, L2 is C2~C 12 It is an alkenzyl. In some embodiments, L2 is C2~C 12 It is an alkynediyl. In some embodiments, L2 is a C3-C8 cycloalkanediyl. In some embodiments, L2 is a C3-C8 cycloalkanediyl-(CH2) p -. In some embodiments, L2 is C1~C 12 It is an alkoxyrenyl. In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p -. In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p -NH-. In some embodiments, L2 is -((CH2) 1~6 O) o-(CH2) p -NH-C(O)-. In some embodiments, L2 is -((CH2) 1~6 O) o -(CH2) p It is -C(O)-NH-.

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

[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 - 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 - is

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

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

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

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

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

[0295] In some embodiments, L2 is [ka] That is the case.

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

[0297] In some embodiments, L2 is [ka] That is the case.

[0298] In some embodiments, L2 is [ka] That is the case.

[0299] In some embodiments, L2 is [ka] That is the case.

[0300] In some embodiments, L2 is [ka] That is the case.

[0301] In some embodiments, L2 is [ka] That is the case.

[0302] In some embodiments, L2 is [ka] That is the case.

[0303] In some embodiments, L2 is [ka] That is the case.

[0304] In some embodiments, L2 is [ka] That is the case.

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

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

[0307] In some embodiments, L3 is a coupling. In some embodiments, L3 is C1~C 12 It is an alkanedyl. In some embodiments, L3 is C2~C 12 It is an alkenzyl. In some embodiments, L3 is C2~C 12 It is alkynediyl. In some embodiments, L3 is C1~C 12 It is an alkoxyrenyl. In some embodiments, L3 is -((CH2) 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 It is C(O)-. In some embodiments, L3 is -NR L C(O)NR L -. In some embodiments, L3 is -NR L It is C(O)O-. In some embodiments, L3 is -NR L It 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)2NR L -. In some embodiments, L3 is -S-. In some embodiments, L3 is -S(O)2-.

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

[0309] In some embodiments, L4 is a bond. In some embodiments, L4 is C1~C 12 It is an alkanedyl. In some embodiments, L4 is C2~C 12It is an alkenzyl. In some embodiments, L4 is C2~C 12 It is alkynediyl. In some embodiments, L4 is C1~C 12 It is an alkoxyrenyl. In some embodiments, L4 is -((CH2) 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 It is C(O)-. In some embodiments, L4 is -NR L C(O)NR L -. In some embodiments, L4 is -NR L It is C(O)O-. In some embodiments, L4 is -NR L It 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)2NR 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 - 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, where alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is one or more R 11 It is sometimes replaced.

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

[0317] In some embodiments, R1 is hydrogen.

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

[0319] In some embodiments, R1 is methyl.

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

[0321] In some embodiments, R1 is [ka] That is the case.

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

[0323] In some embodiments, R1 is [ka] That is the case.

[0324] In some embodiments, each R2 is hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13 A molecule is 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, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 It is sometimes replaced.

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

[0326] In some embodiments, at least one R2 is a 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 A molecule is 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, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 It is sometimes replaced.

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

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

[0333] In some embodiments, one R3 is a 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, the two R3s form = O.

[0338] In some embodiments, each R4 is a halogen, -OH, -CN, -NO2, -NR 12 R 13A molecule is 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, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 It is sometimes replaced.

[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 a halogen.

[0343] In some embodiments, R4 is F.

[0344] In some embodiments, w is 1 and R4 is a 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 and C1-C6 alkyl groups.

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

[0353] In some embodiments, each R6 is hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13 A molecule is 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, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 It is sometimes replaced.

[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 a 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 a C1-C6 alkyl group.

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

[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 A molecule is 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, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 It is sometimes replaced.

[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 a halogen.

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

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

[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, R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is one or more R 11 It will be replaced as needed.

[0374] In some embodiments, R8 is H.

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

[0376] In some embodiments, R8 is one or more R 11 These are C1-C6 alkyl groups that may be substituted in some cases.

[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 isopropyl.

[0382] In some embodiments, R8 is butyl.

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

[0384] In some embodiments, R8 is [ka] That is the case.

[0385] In some embodiments, R8 is [ka] That is the case.

[0386] In some embodiments, R8 is a cycloalkyl group.

[0387] In some embodiments, R8 is C3~C 12 It is a cycloalkyl group.

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

[0389] In some embodiments, R8 is a 3-membered cycloalkyl group. In some embodiments, R8 is a 4-membered cycloalkyl group. In some embodiments, R8 is a 5-membered cycloalkyl group. In some embodiments, R8 is a 6-membered cycloalkyl group. In some embodiments, R8 is a 7-membered cycloalkyl group.

[0390] In some embodiments, R8 is [ka] That is the case.

[0391] In some embodiments, R8 is [ka] That is the case.

[0392] In some embodiments, R8 is [ka] That is the case.

[0393] In some embodiments, R8 is [ka] That is the case.

[0394] In some embodiments, the ring R8 is condensed C5~C 12 It is a bicyclic cycloalkyl. In some embodiments, R8 is a crosslinked C5-C 12 It is a bicyclic cycloalkyl. In some embodiments, ring R8 is spiro-condensed C5~C 12 It is a bicyclic cycloalkyl compound.

[0395] In some embodiments, R8 is an arrow.

[0396] In some embodiments, R8 is C6~C 10 It is Ariel.

[0397] In some embodiments, R8 is phenyl.

[0398] In some embodiments, R8 is [ka] That is the case.

[0399] In some embodiments, R8 is a heterocycline.

[0400] In some embodiments, R8 is a 3- to 10-membered heterocycline.

[0401] In some embodiments, R8 is a 3-membered heterocycline. In some embodiments, R8 is a 4-membered heterocycline. In some embodiments, R8 is a 5-membered heterocycline. In some embodiments, R8 is a 6-membered heterocycline. In some embodiments, R8 is a 7-membered heterocycline.

[0402] In some embodiments, R8 is a three-membered heterocycline.

[0403] In some embodiments, R8 is a three-membered heterocycline containing one heteroatom selected from O and N.

[0404] In some embodiments, R8 is a four-membered heterocycline.

[0405] In some embodiments, R8 is a four-membered heterocycline containing one or two heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0406] In some embodiments, R8 is a five-membered heterocycline.

[0407] In some embodiments, R8 is a five-membered heterocycline containing one or two heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0408] In some embodiments, R8 is a six-membered heterocycline.

[0409] In some embodiments, R8 is a six-membered heterocycline containing one, two, or three heteroatoms, where each heteroatom is independently selected from N, O, and S.

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

[0411] In some embodiments, R8 is a seven-membered heterocycline containing one, two, or three heteroatoms, where each heteroatom is independently selected from N, O, and S.

[0412] In some embodiments, R8 is [ka] That is the case.

[0413] In some embodiments, R8 is [ka] That is the case.

[0414] In some embodiments, R8 is [ka] That is the case.

[0415] In some embodiments, R8 is a heteroaryl compound.

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

[0417] In some embodiments, R8 is [ka] That is the case.

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

[0419] In some embodiments, R9 is hydrogen.

[0420] In some embodiments, R9 is a cycloalkyl group.

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

[0422] In some embodiments, R9 is [ka] That is the case.

[0423] In some embodiments, R 10 These are halogen, -OH, -CN, -NO2, and -NR 12 R 13 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, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are one or more R 11 It is sometimes replaced.

[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 It is a halogen.

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

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

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

[0430] In some embodiments, R 10 These are C1-C6 alkyl groups.

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

[0432] Several embodiments, each R 11 These are halogen, -OH, -CN, -NO2, and -NR 12 R 13、 A molecule can be 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 molecules.

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

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

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

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

[0437] In some embodiments, R 11 These are C1-C6 alkyl groups.

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

[0439] Several embodiments, each R L The element is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.

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

[0441] In some embodiments, R L These are C1-C6 alkyl groups.

[0442] In some embodiments, R 12 and R 13 Each of these is 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 These are hydrogen atoms, respectively.

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

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

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

[0447] In some embodiments, R 12 and R 13 These are both ethyl compounds.

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

[0449] In some embodiments, the compound is of formula (II): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0450] In some embodiments, the compound is of formula (I-II): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0451] In some embodiments, the compound is of formula (I-III): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0452] In some embodiments, the compound is of formula (IIH): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0453] In some embodiments, the compound is of formula (I-II-H): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0454] In some embodiments, the compound is of formula (IIO): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0455] In some embodiments, the compound is of formula (I-II-O): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0456] In some embodiments, the compound is of formula (II'): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0457] In some embodiments, the compound is of formula (I-II'): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0458] In some embodiments, the compound is of formula (IIA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0459] In some embodiments, the compound is of formula (IIA-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0460] In some embodiments, the compound is of formula (IIA-1-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0461] In some embodiments, the compound is of formula (IIA-1-a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0462] In some embodiments, the compound is of formula (IIA-1-a-1-I): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0463] In some embodiments, the compound is of formula (IIA-1-a-1-IA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0464] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where n is selected from 0 and 1, where each R3 is H or two R3s form = O, and all other variables are as defined herein.

[0465] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1-I): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where n is selected from 0 and 1, where each R3 is H or two R3s form = O, and all other variables are as defined herein.

[0466] In some embodiments, the compound is of formula (I-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0467] In some embodiments, the compound is of formula (I-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0468] In some embodiments, the compound is of formula (I-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

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

[0470] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0471] In some embodiments, the compound is of formula (I-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

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

[0473] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0474] In some embodiments, the compound is formula (I-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0475] In some embodiments, the compound is of formula (I-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0476] In some embodiments, the compound is of formula (I-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

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

[0478] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0479] In some embodiments, the compound is of formula (I-11): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0480] In some embodiments, the compound is formula (I-12): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0481] In some embodiments, the compound is formula (I-13): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0482] In some embodiments, the compound is formula (I-14): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3This forms = O, and the remaining variables are as defined herein.

[0483] In some embodiments, the compound is formula (I-15): [ka] (I-15) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0484] In some embodiments, the compound is formula (I-16): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where n is an integer selected from 0 and 1, and where both R3 are either H or two R 3 This forms = O, and the remaining variables are as defined herein.

[0485] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1-IA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where n is an integer selected from 0 and 1, and where each R3 is either H or two R3s 3 This forms = O, and all other variables are as defined herein.

[0486] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1-IA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each R3 is either H or two R 3 The expression forms = O, where n is selected from 0 and 1, and all other variables are as defined herein.

[0487] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1-IA-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each R3 is either H or two R 3 The equation forms = O, where w, u, and n are each independently selected from 0 and 1, and all other variables are as defined herein.

[0488] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1-IA-1-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where 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 is of 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, where 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 is of formula (IIA-1-a-1-IA-1-IA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where each R3 is H or two R3s form =O, n is selected from 0 and 1, and all other variables are as defined herein.

[0491] In some embodiments, the compound is of 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 is of 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 is of formula (IIA-1-a-1-IA-1-IA-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where each R3 is H or two R3s form = O, n is selected from 0 and 1, and all other variables are as defined herein.

[0494] In some embodiments, the compound is of 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 is of 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 is of 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 is of formula (IIA-1-a-1-IA-1-IB-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where each R3 is H or two R3s form = O, n is selected from 0 and 1, and all other variables are as defined herein.

[0498] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1-IB-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each of w, u, and n is independently selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

[0499] In some embodiments, the compound is of 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, where 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 is of 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, where 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 is of formula (IIA-1-a-1-IA-1-IB-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where each R3 is H or two R3s form = O, n is selected from 0 and 1, and all other variables are as defined herein.

[0502] In some embodiments, the compound is of 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 is of 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 is of formula (IIA-1-a-1-IA-1-IB-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where each R3 is H or two R3s form = O, n is selected from 0 and 1, and all other variables are as defined herein.

[0505] In some embodiments, the compound is of 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 is of 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 is of 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 is of formula (IIA-1-a-1-IA-1-IC-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each R3 is H or two R3s 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 is of formula (IIA-1-a-1-IA-1-IC-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each of w, u, and n is independently selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

[0510] In some embodiments, the compound is of 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, where 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 is of 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, where 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 is of formula (IIA-1-a-1-IA-1-IC-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each of w, u, and n is independently selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

[0513] In some embodiments, the compound is of 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, where 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 is of 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, where 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 is of formula (IIA-1-a-1-IA-1-IC-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each of w, u, and n is independently selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

[0516] In some embodiments, the compound is of 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, where 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 is of 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, where 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 is of formula (IIA-1-a-1-IA-1-IC-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where n is selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

[0519] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1-IC-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each x is independently selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

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

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

[0522] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1-IC-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where n is selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

[0523] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1-IC-3-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each x is independently selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

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

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

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

[0527] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1-ID-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each R3 is H or two R3s 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 is of formula (IIA-1-a-1-IA-1-ID-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each of w, u, and n is independently selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

[0529] In some embodiments, the compound is of 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, where 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 is of 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, where 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 is of formula (IIA-1-a-1-IA-1-ID-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each of w, u, and n is independently selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

[0532] In some embodiments, the compound is of 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, where 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 is of the formula (IIA-1-a-1-IA-1-ID-1-bO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where x is independently selected from 0 and 1, and all other variables are as defined herein.

[0534] In some embodiments, the compound is of formula (IIA-1-a-1-IA-1-ID-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each x is independently selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

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

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

[0537] In some embodiments, the compound is of formula (IIA-2): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0538] In some embodiments, the compound is of formula (IIA-2-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0539] In some embodiments, the compound is of formula (IIA-2-a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0540] In some embodiments, the compound is of formula (IIA-2-a-1-I): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0541] In some embodiments, the compound is of formula (IIA-2-a-1-IA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0542] In some embodiments, the compound is of formula (IIB): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0543] In some embodiments, the compound is of formula (IIB-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0544] In some embodiments, the compound is of formula (IIB-1-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0545] In some embodiments, the compound is of formula (IIB-1-a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0546] In some embodiments, the compound is of formula (IIB-1-a-1-I): [ka] (IIB-1-a-1-I) or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0547] In some embodiments, the compound is of formula (IIB-1-a-1-IA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0548] In some embodiments, the compound is of formula (IIB-2): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0549] In some embodiments, the compound is of formula (IIB-2-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0550] In some embodiments, the compound is of formula (IIB-2-a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0551] In some embodiments, the compound is of formula (IIB-2-a-1-I): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0552] In some embodiments, the compound is of formula (IIB-2-a-1-IA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0553] In some embodiments, the compound is of 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 is of 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 is of 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 is of formula (IIB-2-a-1-IA-1-IC-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where n is selected from 0 and 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

[0557] In some embodiments, the compound is of formula (IIB-2-a-1-IA-1-IC-3-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each R3 is H or two R3s are = O, and all other variables are as defined herein.

[0558] In some embodiments, the compound is of the formula (IIB-2-a-1-IA-1-IC-3-aH): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0559] In some embodiments, the compound is of the formula (IIB-2-a-1-IA-1-IC-3-aO): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0560] In some embodiments, the compound is of formula (I-II-A): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0561] In some embodiments, the compound is of formula (I-II-A-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0562] In some embodiments, the compound is of formula (I-II-A-1-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0563] In some embodiments, the compound is of formula (I-II-A-1-a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0564] In some embodiments, the compound is of formula (I-II-A-1-a-1-I): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0565] In some embodiments, the compound is of formula (I-II-A-1-a-1-IA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0566] In some embodiments, the compound is of 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 is of 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 is of the 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 is of formula (I-II-A-1-a-1-IA-1-IC-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where n is 0 or 1, each R3 is H, or two R3s are = O, and all other variables are as defined herein.

[0570] In some embodiments, the compound is of formula (I-II-A-1-a-1-IA-1-IC-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where each R3 is H or two R3s are = O, and all other variables are as defined herein.

[0571] In some embodiments, the compound is of the formula (I-II-A-1-a-1-IA-1-IC-1-aH): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0572] In some embodiments, the compound is of the formula (I-II-A-1-a-1-IA-1-IC-1-aO): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0573] In some embodiments, the compound is of formula (I-II-A-2): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0574] In some embodiments, the compound is of formula (I-II-A-2-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0575] In some embodiments, the compound is of formula (I-II-A-2-a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0576] In some embodiments, the compound is of formula (I-II-A-2-a-1-I): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0577] In some embodiments, the compound is of formula (I-II-A-2-a-1-IA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0578] In some embodiments, the compound is of formula (I-II-B): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0579] In some embodiments, the compound is of formula (I-II-B-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0580] In some embodiments, the compound is of formula (I-II-B-1-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0581] In some embodiments, the compound is of formula (I-II-B-1-a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0582] In some embodiments, the compound is of formula (I-II-B-1-a-1-I): [ka] (I-II-B-1-a-1-I) or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0583] In some embodiments, the compound is of formula (I-II-B-1-a-1-IA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0584] In some embodiments, the compound is of formula (I-II-B-2): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0585] In some embodiments, the compound is of formula (I-II-B-2-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0586] In some embodiments, the compound is of formula (I-II-B-2-a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0587] In some embodiments, the compound is of formula (I-II-B-2-a-1-I): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0588] In some embodiments, the compound is of formula (I-II-B-2-a-1-IA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0589] In some embodiments, the compound is of formula (II-A): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0590] In some embodiments, the compound is of formula (II-AI): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0591] In some embodiments, the compound is of formula (II-AIa): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0592] In some embodiments, the compound is of formula (II-AIa-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0593] In some embodiments, the compound is of formula (II-AIa-1-I): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0594] In some embodiments, the compound is of formula (II-AIa-1-IA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0595] In some embodiments, the compound is of formula (II-AIa-1-IA-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0596] In some embodiments, the compound is of formula (II-B): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0597] In some embodiments, the compound is of formula (II-BI): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0598] In some embodiments, the compound is of formula (II-BIa): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0599] In some embodiments, the compound is of formula (II-BIa-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0600] In some embodiments, the compound is of formula (II-BIa-1-I): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0601] In some embodiments, the compound is of formula (II-BIa-1-IA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0602] In some embodiments, the compound is of formula (II-BIa-1-IA-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0603] In some embodiments, the compound is given by formula (AI): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0604] In some embodiments, the compound is of formula (AI-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0605] In some embodiments, the compound is of formula (AI-1-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0606] In some embodiments, the compound is of formula (AI-1-aI): [ka] (AI-1-aI) or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0607] In some embodiments, the compound is of formula (AI-1-aIA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0608] In some embodiments, the compound is of formula (AI-1-aIA-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0609] In some embodiments, the compound is of formula (AI-1-aIA-1-a): [ka] (AI-1-aIA-1-a) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-1-a-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-1-a-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-1-a-1-a-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-1-a-1-a-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-1-a-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-1-a-1-b-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-1-a-1-b-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of 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, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is represented by formula (AI-1-aIA-1-a-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-2-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-2-a-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-2-a-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-2-a-1-a-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is represented by formula (AI-1-aIA-1-a-2-a-1-a-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-2-a-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-2a-1-b-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-2-a-1-b-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is represented by formula (AI-1-aIA-1-a-2a-1-b-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-1-a-3): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0633] In some embodiments, the compound is of formula (AI-1-aIA-1-b): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0634] In some embodiments, the compound is of formula (AI-1-aIA-1-b-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0635] In some embodiments, the compound is of formula (AI-1-aIA-1-b-1-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0636] In some embodiments, the compound is of the formula (AI-1-aIA-1-b-1-a*): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0637] In some embodiments, the compound is of formula (AI-1-aIA-1-b-1-a**): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0638] In some embodiments, the compound is of the formula (AI-1-aIA-1-b-1-a***): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0639] In some embodiments, the compound is of the formula (AI-1-aIA-1-b-1-a****): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0640] In some embodiments, the compound is of formula (AI-1-aIA-1-b-2): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0641] In some embodiments, the compound is of formula (AI-1-aIA-1-b-2-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0642] In some embodiments, the compound is of formula (AI-1-aIA-1-b-2a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0643] In some embodiments, the compound is of the formula (AI-1-aIA-1-b-2a-1*): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0644] In some embodiments, the compound is of the formula (AI-1-aIA-1-b-2a-1**): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0645] In some embodiments, the compound is of the formula (AI-1-aIA-1-b-2a-1***): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0646] In some embodiments, the compound is of the formula (AI-1-aIA-1-b-2a-1****): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0647] In some embodiments, the compound is of formula (AI-1-aIA-1-b-2-a-2): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0648] In some embodiments, the compound is of the formula (AI-1-aIA-1-b-2-a-2*): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0649] In some embodiments, the compound is of formula (AI-1-aIA-1-b-2-a-2**): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0650] In some embodiments, the compound is of the formula (AI-1-aIA-1-b-2-a-2***): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0651] In some embodiments, the compound is of the formula (AI-1-aIA-1-b-2-a-2****): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0652] In some embodiments, the compound is of formula (AI-1-aIA-1-c): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0653] In some embodiments, the compound is of formula (AI-1-aIA-2): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0654] In some embodiments, the compound is of formula (AI-1-aIA-2-a): [ka] (AI-1-aIA-2-a) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-3): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0656] In some embodiments, the compound is of formula (AI-1-aIA-3-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-3-b): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0658] In some embodiments, the compound is of 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 is of 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 is of formula (AI-1-aIA-4a-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 is of formula (AI-1-aIA-4a-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 is of 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 is of 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 is of formula (AI-1-aIA-5a-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 is of formula (AI-1-aIA-5a-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 is of 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 is of formula (AI-1-aIA-6-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-6a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-6a-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-1-aIA-7): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0671] In some embodiments, the compound is of formula (AI-1-aIA-7-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0672] In some embodiments, the compound is of formula (AI-1-aIA-7a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0673] In some embodiments, the compound is of formula (AI-1-aIA-7a-1-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0674] In some embodiments, the compound is of formula (AI-1-a-II): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0675] In some embodiments, the compound is of formula (AI-1-b): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0676] In some embodiments, the compound is of formula (AI-1-bI): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0677] In some embodiments, the compound is of formula (AI-1-bIA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0678] In some embodiments, the compound is of formula (AI-1-bIA-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0679] In some embodiments, the compound is of formula (AI-1-bIA-1-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0680] In some embodiments, the compound is of formula (AI-1-bIA-1-a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0681] In some embodiments, the compound is of formula (AI-1-c): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0682] In some embodiments, the compound is of formula (AI-1-cI): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0683] In some embodiments, the compound is of formula (AI-1-cIA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0684] In some embodiments, the compound is of formula (AI-1-cIA-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0685] In some embodiments, the compound is of formula (AI-1-cIA-1-a): [ka] (AI-1-cIA-1-a) or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0686] In some embodiments, the compound is of formula (AI-1-cIA-1-a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0687] In some embodiments, the compound is of formula (AI-1-cIA-1-a-1-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0688] In some embodiments, the compound is of formula (AI-1-cIA-2): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0689] In some embodiments, the compound is of formula (AI-1-cIA-2-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0690] In some embodiments, the compound is of formula (AI-1-cIA-2a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where 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 is of formula (AI-2): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0692] In some embodiments, the compound is of formula (A-II): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0693] In some embodiments, the compound is of formula (A-II-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0694] In some embodiments, the compound is of formula (A-II-1-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0695] In some embodiments, the compound is of formula (A-II-1-aI): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0696] In some embodiments, the compound is of formula (A-II-1-aIA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0697] In some embodiments, the compound is of formula (A-II-1-aIA-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0698] In some embodiments, the compound is of formula (A-II-1-aIA-1-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0699] In some embodiments, the compound is of formula (A-II-1-aIA-1-a-1): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0700] In some embodiments, the compound is of formula (A-II-2): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0701] In some embodiments, the compound is of formula (A-II-2-a): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0702] In some embodiments, the compound is of formula (A-II-2-aI): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0703] In some embodiments, the compound is of formula (A-II-2-aIA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0704] In some embodiments, the compound is of formula (A-II-2-aIA): [ka] or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

[0705] In some embodiments, the compound is of formula (A-II-2-aIA-1): [ka] (A-II-2-aIA-1) or any pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof, all of which are as defined herein.

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

[0707] Any compound of any of the formulas disclosed herein and any pharmaceutically acceptable salt thereof will be understood to include stereoisomers of all isomeric forms of the compound, mixtures of stereoisomers, and polymorphs.

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

[0709] In some embodiments, the compounds are selected from the compounds listed in Table 1, as well as their prodrugs and pharmaceutically acceptable salts.

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

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

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

[0713] JPEG0007879629000357.jpg236170JPEG0007879629000358.jpg225170JPEG0007879629000359.jpg225170JPEG0007879629000360.jpg210170JP EG0007879629000361.jpg203170JPEG0007879629000362.jpg196170JPEG0007879629000363.jpg204170JPEG0007879629000364.jpg242170JPEG0 007879629000365.jpg203170JPEG0007879629000366.jpg243170JPEG0007879629000367.jpg246170JPEG0007879629000368.jpg245170JPEG000 7879629000369.jpg241170JPEG0007879629000370.jpg200170JPEG0007879629000371.jpg242170JPEG0007879629000372.jpg219170JPEG000787 9629000373.jpg240170JPEG0007879629000374.jpg244170JPEG0007879629000375.jpg225170JPEG0007879629000376.jpg248170JPEG0007879629000377.jpg236170JPEG0007879629000378.jpg220170JPEG0007879629000379.jpg239170JPEG0007879629000380.jpg240170JPEG00078796290 00381.jpg243170JPEG0007879629000382.jpg233170JPEG0007879629000383.jpg242170JPEG0007879629000384.jpg247170JPEG0007879629000385.jpg237170JPEG0007879629000386.jpg246170JPEG0007879629000387.jpg237170JPEG0007879629000388.jpg233170JPEG0007879629000389.jpg203170JPEG0007879629000390.jpg179170JPEG0007879629000391.jpg214170JPEG0007879629000392.jpg182170JPEG0007879629000393.jpg212170JPEG0007879629000394.jpg222170JPEG0007879629000395.jpg247170JPEG0007879629000396.jpg226170JPEG0007879629000397.jpg188170JPEG0007879629000398.jpg186170JPEG0007879629000399.jpg213170JPEG0007879629000400.jpg223170JPEG0007879629000401.jpg222170JPEG0007879629000402.jpg217170JPEG0007879629000403.jpg237170JPEG0007879629000404.jpg202170JPEG0007879629000405.jpg240170JPEG0007879629000406.jpg182170JPEG0007879629000407.jpg224170JPEG0007879629000408.jpg245170JPEG0007879629000409.jpg218170JPEG0007879629000410.jpg244170JPEG0007879629000411.jpg241170JPEG0007879629000412.jpg216170JPEG0007879629000413.jpg208170JPEG0007879629000414.jpg246170JPEG0007879629000415.jpg232170JPEG0007879629000416.jpg240170JPEG0007879629000417.jpg211170JPEG0007879629000418.jpg238170JPEG0007879629000419.jpg232170JPEG0007879629000420.jpg247170JPEG0007879629000421.jpg237170JPEG0007879629000422.jpg248170JPEG0007879629000423.jpg242170JPEG0007879629000424.jpg159170.

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

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

[0716] In some embodiments, the compound is a 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 and any one of the compounds listed in Table 1.

[0718] JPEG0007879629000425.jpg251170JPEG0007879629000426.jpg70170

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

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

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

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

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

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

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

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

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

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

[0729] In some embodiments, the present disclosure provides compounds that are isotopic derivatives (e.g., isotope-labeled compounds) of any one of the compounds of the formulas disclosed herein.

[0730] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1, as well as its prodrug and pharmaceutically acceptable salt.

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

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

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

[0734] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by using an isotopic labeling reagent instead of a non-isotopic labeling reagent.

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

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

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

[0738] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds listed in Table 1, as well as its prodrug and pharmaceutically acceptable salt.

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

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

[0742] It is understood that deuterium-labeled compounds contain deuterium atoms with a deuterium abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

[0743] In some embodiments, the deuterium-labeled compound has a deuterium concentration factor 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) for each deuterium atom. As used herein, the term “deuterium concentration factor” means the ratio between the deuterium abundance and the naturally occurring abundance of deuterium.

[0744] It is understood that deuterium-labeled compounds can be prepared using any of the various techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by using a deuterium-labeled reagent instead of a non-deuterium-labeled reagent.

[0745] Compounds of the disclosure containing the above-mentioned deuterium atoms (or multiple deuterium atoms) or their pharmaceutically acceptable salts or solvates are within the scope of the disclosure. Furthermore, deuterium (i.e., 2Substitution with H) may provide certain therapeutic benefits resulting from greater metabolic stability, such as an increased in vivo half-life or a reduced required dose.

[0746] In some embodiments, the compound is 18 It is an 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 This is an S-labeled compound, 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 is understood that S-labeled compounds can be prepared using any of the various techniques recognized in the art. For example, deuterium-labeled compounds are generally prepared using non-isotope labeling reagents instead of 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 performing 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 Disclosure containing one or more S atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the Disclosure. Furthermore, isotopes (e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 Substitution with S) may result in certain therapeutic benefits stemming from greater metabolic stability, such as an increased in vivo half-life or a reduced required dose.

[0751] To avoid misunderstanding, where a group is limited by "as described herein" in this specification, it should be understood that the group includes the broadest definition that first arises, as well as each and all of the specific definitions of that group.

[0752] The various functional groups and substituents constituting the compound of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1100 daltons. More commonly, 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 a compound having the same molecular formula but differing in the order of its atomic bonding or the arrangement of its atoms in space. Isomers that differ in the arrangement of their atoms in space are called “stereoisomers.” Stereoiomers that are not mirror images of each other are called “diastereoisomers,” and stereoisomers that are mirror images of each other but cannot be superimposed are called “enantiomers” or sometimes “optical isomers.” A mixture containing equal amounts of individual enantiomer forms with opposite chirality is called a “racemic mixture.”

[0754] As used herein, the term “chiral center” refers to a carbon atom bonded to four non-identical substituents.

[0755] As used herein, the term “chiral isomer” means a compound having at least one chiral center. Compounds having two or more chiral centers may exist as individual diastereomers or as a mixture of diastereomers called a “diastereomer mixture.” Where a single chiral center is present, the stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. 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” means a diastereomer whose existence is due to an impediment to rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by the prefixes cis and trans or Z and E, which indicate that the group is on the same side or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rule.

[0757] It should be understood that the compounds of this disclosure may be represented as different chiral or geometric isomers. Where a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of this disclosure, and it should be understood that the naming of the compounds 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 of their atropisomers. 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 spatially distinct. The existence of atropisomers is due to rotational limitations caused by the obstruction of the rotation of the large group around the central bond. Such atropisomers typically exist as a mixture, but as a result of recent advances in chromatography techniques, it has been possible to separate a mixture of two atropisomers when selected.

[0760] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion results in a formal transfer of hydrogen atoms, involving the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer 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 can be interconverted by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. Keto-enol tautomerism involves a simultaneous shift of electrons and hydrogen atoms. Ring tautomerism results from the reaction of an aldehyde group (-CHO) in a sugar molecule with one of the hydroxyl groups (-OH) in the same molecule, giving it a cyclic (ring-shaped) form, such as that exhibited by glucose.

[0761] It should be understood that the compounds of this disclosure may be represented as different tautomers. Where a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this disclosure, and the naming of the compounds does not exclude any tautomer forms. It will be understood that certain tautomers may have higher levels of activity than others.

[0762] Compounds that have the same molecular formula but differ in the bonding properties or arrangement of their atoms or 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 mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, if a compound is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral center and are described by Cahn and Prelog's R and S sequencing rules, or by the rotation of the plane of polarization of the molecule, in a manner called 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 this disclosure may have one or more chiral centers, and therefore such compounds may be prepared as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the descriptions or nomenclature of specific compounds in the specification and claims are intended to include both individual enantiomers and their racemates 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 by separation 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 this disclosure may have geometric isomer centers (E and Z isomers). It should be understood that this disclosure encompasses all optical isomers, diastereoisomers and geometric isomers, as well as mixtures thereof, that have inflammasome inhibitory activity.

[0764] This disclosure also includes compounds of the disclosure as defined herein, which include one or more isotopic substitutions.

[0765] It should be understood that any compound of any formula described herein includes, where applicable, the compound itself, as well as its salts and solvates. Salts can be formed, for example, between an anion on a substituted compound disclosed herein and a positively charged group (e.g., amino). Suitable anions include chlorides, bromides, iodides, bisulfates, sulfamates, nitrates, phosphates, citrates, methanesulfonates, trifluoroacetates, glutamates, glucuronates, glutarates, malatates, maleates, succinates, fumarates, tartrates, tosylates, salicylates, lactates, naphthalenesulfonates, and acetates (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 a substituted compound disclosed herein and a negatively charged group (e.g., a carboxylate). Suitable cations include sodium, potassium, magnesium, calcium ions, and ammonium cations, such as tetramethylammonium or diethylamine ions. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0767] It should be understood that the compounds of this disclosure, for example, salts of the compounds, can exist in hydrated or unhydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvate, acetone solvate, etc.

[0768] As used herein, the term “solvate” means a solvent-added form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to capture a certain molar ratio of solvent molecules in a crystalline solid state and thus form solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one or more molecules of water and one molecule of a substance in which water retains its molecular state as H2O.

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

[0770] As used herein, the term “derivative” refers to a compound having a common core structure and being substituted with one of the various groups described herein.

[0771] As used herein, the term “biological equivalent” 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 biological equivalent substitution is to create a new compound that has similar biological properties to the parent compound. Biological equivalent substitution can be physicochemical or topological. Examples of carboxylic acid biological equivalents 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 be understood that any particular compound of any of the formulas disclosed herein may exist in solvated and non-solvated forms, such as hydrated forms. Suitable pharmaceutically acceptable solvates are hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this disclosure encompasses all such solvated forms having inflammasome inhibitory activity.

[0773] It should be understood that any particular compound of any one of the formulas disclosed herein may exhibit polymorphism, and that this disclosure encompasses all such forms or mixtures thereof that have inflammasome inhibitory activity. Crystalline materials are generally known to be analyzeable using conventional techniques such as powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, 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] Any compound of any one of the formulas disclosed herein may exist in a number of different tautomers, and references to compounds of formula (I) or (II) include all such forms. To avoid misunderstanding, if a compound may exist in one of several tautomers and only one is specifically described or shown, all others are nevertheless encompassed by formula (I) or (II). Examples of tautomers include, for example, the keto-, enol-, and enolate-types such as the following tautomer pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / acinitro. [ka]

[0775] Compounds of any one of the formulas disclosed herein that contain an amine functional group may also form an N-oxide. References herein to compounds of formula (I) or (II) containing an amine functional group also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are 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., a peroxycarboxylic acid); see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of LWDeady (Syn Comm. 1977, 7, 509-514), in which an amine compound is reacted with meta-chloroperbenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0776] Any compound of any of the formulas disclosed herein may be administered in the form of a prodrug, which is broken down in the body of a human or animal to release the compound disclosed herein. Prodrugs can be used to alter the physical and / or pharmacokinetic properties of the compounds disclosed herein. Prodrugs can be formed when the compounds disclosed herein contain a suitable group or substituent to which a characterizing group can be attached. Examples of prodrugs include derivatives of any ester or amide group of any of the formulas disclosed herein, which contain an alkyl or acyl substituent that can be cleaved in vivo.

[0777] Accordingly, this disclosure includes any one compound of any of the formulas disclosed herein as defined herein, when made available by organic synthesis and when made available in the body of a human or animal by cleavage of its prodrug. Accordingly, this disclosure includes any one compound of any of the formulas disclosed herein produced by organic synthesis means and also includes compounds produced in the body of a human or animal by metabolism of precursor compounds, i.e., any one compound of any of the formulas disclosed herein may be a synthetically produced compound or a metabolically produced compound.

[0778] A suitable pharmaceutically acceptable prodrug of any one compound of the formulas disclosed herein is based on reasonable medical judgment that it is suitable for administration to the human or animal body without undesirable pharmacological activity and excessive toxicity. Various forms of prodrugs are described in the following literature, for example: a) Methods in Enzymology, Vol. 42, pp. 309-396 (K. Widder, et al., eds.) (Academic Press, 1985); b) Design of Pro-drugs (H. Bundgaard, ed.) (Elsevier, 1985); c) A Textbook of Drug Design and Development (Krogsgaard-Larsen and H. Bundgaard, eds.) Chapter 5 "Design and Application of Pro-drugs" (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] A suitable pharmaceutically acceptable prodrug of any one compound of any of the formulas disclosed herein having a hydroxyl group is, for example, its in vivo cleavable ester or ether. An in vivo cleavable ester or ether of any one compound of any of the formulas disclosed herein containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the body of a human or animal to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include inorganic esters such as phosphate esters (including phosphoramide cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include C1-C such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 C1-C6 alkyl groups such as alkanoyl groups, ethoxycarbonyl groups, N,N-(C1-C6 alkyl)2-carbamoyl groups, 2-dialkylaminoacetyl groups, and 2-carboxyacetyl groups. 10 Examples include alkoxycarbonyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxyl groups include acetoxymethyl and α-acyloxyalkyl groups such as pivaloyloxymethyl.

[0780] A suitable pharmaceutically acceptable prodrug of any one of the compounds of the formulas disclosed herein having a carboxyl group is, for example, its in vivo cleavable amide, such as an amine such as ammonia, or a C such as methylamine. 1~4 These are amides formed from amino acids such as alkylamines, (C1-C4 alkyl)2 amines 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 glycine or its esters.

[0781] A suitable pharmaceutically acceptable prodrug of any one compound of the formulas disclosed herein having an amino group is, for example, its in vivo cleavable amide derivative. Suitable pharmaceutically acceptable amides from an amino group include, for example, C1-C compounds such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 Examples of amides formed with an alkanoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0782] The in vivo effect of any one compound of any of the formulas disclosed herein may be partially exerted by one or more metabolites formed in the body of a human or animal after administration of any one compound of any of the formulas disclosed herein. As stated above herein, the in vivo effect of any one compound of any of the formulas disclosed herein may also be exerted by the metabolism of a precursor compound (prodrug). Method for synthesizing the compound of formula (A)

[0783] The compounds of the present invention can be prepared by various methods, including standard chemistry. A suitable synthesis route is shown in the scheme below.

[0784] Compounds of formula (I) can be prepared by methods known in the field of organic synthesis, partially shown by the following synthetic scheme. In the scheme described below, it will be understood that protecting groups for sensitive or reactive groups are used where necessary according to general principles or chemistry. Protecting groups are handled according to standard methods of organic synthesis (TW Greene and PGMWuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of compound synthesis using methods readily apparent to those skilled in the art. The selection process, as well as the reaction conditions and order to those skilled in the art, will recognize whether a stereocenter exists in the compound of formula (I). Thus, the present invention includes both possible stereoisomers (unless specified in synthesis) and includes not only racemic compounds but also individual enantiomers and / or diastereomers. If the compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by the division of the final product or any convenient intermediate. The resolution of the final product, intermediate, or starting material may be affected by any suitable method known in the art. For example, see "Stereochemistry of Organic Compounds" by ELEliel, S. Wilen, and LNMander (Wiley-Interscience, 1994).

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

[0786] The compounds of the present invention can be prepared by a number of 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 include intermediates or different sequences for assembling the compounds. Starting materials are commercially available or prepared by known procedures in reported 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 scheme illustrates several routes to compounds of formula (I): [ka]

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

[0789] A specific, non-limiting example of the sequence of reactions yielding the compound of formula (I) can be demonstrated by the preparation of compound 4. [ka]

[0790] A specific, non-limiting example of the sequence of reactions yielding the compound of formula (I) can be demonstrated by the preparation of compound 15. [ka]

[0791] A specific, non-limiting example of the sequence of reactions yielding the compound of formula (I) can be demonstrated by the preparation of compound 16. [ka] [ka]

[0792] A specific, non-limiting example of the sequence of reactions yielding the compound of formula (I) can be demonstrated by the preparation of compound 6. [ka]

[0793] A specific, non-limiting example of the sequence of reactions yielding the compound of formula (I) can be demonstrated by the preparation of compound 19. [ka]

[0794] Those skilled in the art will readily understand that the compound of formula (I) obtained by the above procedure may be subject to further transformation and modification to obtain other compounds of formula (I). Biological assays

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

[0796] Furthermore, high-throughput screening can be used to speed up analyses 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 may 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 this disclosure. These in vitro or in vivo biological assays may include, but are 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 embodiments, the Disclosure provides pharmaceutical compositions comprising the compounds of the Disclosure as active ingredients. In some embodiments, the 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 Disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

[0799] As used herein, the term “composition” is intended to encompass products containing specified amounts of specified components, as well as any products resulting directly or indirectly from combinations of specified components in specified amounts.

[0800] The compounds of this disclosure may be formulated for oral administration in the form of tablets, capsules (including sustained-release and time-release formulations, respectively), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of this disclosure may 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 skilled in the pharmaceutical art.

[0801] The formulations of this disclosure may be in the form of aqueous solutions comprising an aqueous vehicle. The aqueous vehicle component may 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, isotonic agents, viscosity / suspensioning agents, buffers, and pH adjusters, as well as mixtures thereof.

[0802] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins, such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly selected from the group consisting of 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 selected from the group consisting of 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, disodium edetate, trisodium edetate and tetrasodium edetate, and mixtures thereof.

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

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

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

[0807] The aqueous vehicle may also contain a viscous / suspending agent. Suitable viscous / 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 glycol (Carbopol-Carbopol934, Carbopol934P, Carbopol971, Carbopol974, Carbopol974P, etc.), and mixtures thereof.

[0808] To adjust the formulation to an acceptable pH (typically within the ranges of 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 pH adjusters. The pH adjusters are typically mineral acids or metal hydroxide bases selected from the group consisting of potassium hydroxide, sodium hydroxide, 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 the target acceptable pH range. Therefore, it may not be necessary to use both acids and bases, and 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] Aqueous vehicles may also contain buffers to stabilize the pH. When used, buffers are 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, as well as mixtures thereof.

[0810] The formulation may further contain 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, polyoxyethylene-sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyroxapole), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, as well as mixtures thereof.

[0811] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable food-grade carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of 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, in which case the compound in the fluid carrier is applied orally, swallowed, spit out, or ingested. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring.

[0812] A further aspect of this disclosure provides a pharmaceutical composition comprising a compound of the disclosure as defined herein 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] The compositions of this disclosure may be in forms 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 fine powders or liquid aerosols), administration by blowing (e.g., as fine powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

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

[0816] A therapeutically effective dose of the compounds of this disclosure for use in treatment is sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the MLL-related symptoms referred to herein.

[0817] A therapeutically effective dose of the compounds of this disclosure for use in treatment is sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with the MLL-related symptoms referred to herein.

[0818] The size of the dose of the compound of formula (I) for therapeutic or prophylactic purposes varies naturally according to well-known medical principles, depending on the nature and severity of the symptoms, the age and sex of the animal or subject, and the route of administration. How to use

[0819] In some embodiments, the Disclosure provides a method for degrading MALT1 (e.g., in vitro or in vivo) comprising contacting cells with a therapeutically effective amount of the Compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0820] In some embodiments, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject requiring treatment or prevention of such disease or disorder, comprising administering a therapeutically effective amount of the Compounds Disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject.

[0821] In some embodiments, the Disclosure provides a method for treating a disease or disorder disclosed herein in a subject requiring treatment of such disease or disorder, comprising administering a therapeutically effective amount of the Compounds Disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject.

[0822] In some embodiments, the disease or disorder is related to MALT1. In some embodiments, the disease or disorder is a disease or disorder in which MALT1 is involved.

[0823] The compound of the present invention is a protac of MALT1.

[0824] The compounds of the present invention are also useful in treating diseases associated with MALT1. For example, diseases and conditions that can be treated according to the methods of the present invention include immunodeficiency12; lymphoma, mucosal-associated lymphocyte type (MALTOMA); combined immunodeficiency; combined T-cell and B-cell immunodeficiency; or lymphoma.

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

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

[0827] In some embodiments, the disease or disorder is immunodeficiency 12.

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

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

[0830] In some embodiments, the Disclosure provides a method for treating or preventing lymphoma in a subject requiring treatment or prevention of lymphoma, comprising administering a therapeutically effective amount of the Compounds of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Pharmaceuticals of the Disclosure, to a subject.

[0831] In some embodiments, the Disclosure provides a method for treating or prophylactically treating immunodeficiency 12 in a subject requiring treatment or prophylactic treatment of immunodeficiency 12, comprising administering a therapeutically effective amount of the Compounds of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0832] In some embodiments, the Disclosure provides a method for treating or prophylactically treating lymphoma, mucosal-associated lymphoma (MALTOMA) in subjects requiring treatment or prophylactic care for lymphoma, mucosal-associated lymphoma (MALTOMA), comprising administering a therapeutically effective amount of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof, or a pharmaceutical composition of the Pharmaceuticals of the Disclosure, to a subject.

[0833] In some embodiments, the Disclosure provides a method for treating or preventing combined immunodeficiency in a subject requiring treatment or prevention of combined immunodeficiency, comprising administering a therapeutically effective amount of the Compounds of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0834] In some embodiments, the Disclosure provides a method for treating or preventing combined T-cell and B-cell immunodeficiency in subjects requiring treatment or prevention of combined T-cell and B-cell immunodeficiency, comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0835] In some embodiments, the Disclosure provides a method for treating lymphoma in a subject requiring treatment for lymphoma, comprising administering a therapeutically effective amount of the Compounds of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0836] In some embodiments, the Disclosure provides a method for treating immunodeficiency 12 in a subject requiring treatment of immunodeficiency 12, comprising administering a therapeutically effective amount of the Compounds of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0837] In some embodiments, the Disclosure provides a method for treating lymphoma, mucosal-associated lymphoma (MALTOMA) in subjects requiring treatment for MALTOMA, comprising administering a therapeutically effective amount of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0838] In some embodiments, the Disclosure provides a method for treating combined immunodeficiency in a subject requiring treatment of combined immunodeficiency, comprising administering a therapeutically effective amount of the Compounds of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0839] In some embodiments, the Disclosure provides a method for treating combined T-cell and B-cell immunodeficiency in subjects requiring treatment of combined T-cell and B-cell immunodeficiency, comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0840] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the degradation of MALT1 (e.g., in vitro or in vivo).

[0841] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating or preventing diseases or disorders disclosed herein.

[0842] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating diseases or disorders disclosed herein.

[0843] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating or prophylactically treating lymphoma in subjects requiring treatment or prophylaxis of lymphoma.

[0844] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating or prophylactically treating immunodeficiency 12 in subjects requiring treatment or prophylaxis of immunodeficiency 12.

[0845] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating or prophylactically treating lymphoma, mucosal-associated lymphocytes (MALTOMA) in subjects requiring treatment or prophylactic care for lymphoma, mucosal-associated lymphocytes (MALTOMA).

[0846] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating or prophylacticizing combined immunodeficiency in subjects requiring treatment or prophylactic treatment of combined immunodeficiency.

[0847] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating or prophylactic T-cell and B-cell combined immunodeficiency in subjects requiring treatment or prophylaxis of T-cell and B-cell combined immunodeficiency.

[0848] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating lymphoma in subjects requiring treatment for lymphoma.

[0849] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating immunodeficiency 12 in subjects requiring treatment of immunodeficiency 12.

[0850] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating lymphoma, mucosal-associated lymphocyte (MALTOMA) in subjects requiring treatment of lymphoma, mucosal-associated lymphocyte (MALTOMA).

[0851] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating combined immunodeficiency in subjects requiring treatment of combined immunodeficiency.

[0852] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in treating combined T-cell and B-cell immunodeficiency in subjects requiring treatment of combined T-cell and B-cell immunodeficiency.

[0853] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the degradation of MALT1 (e.g., in vitro or in vivo).

[0854] In some aspects, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicinal product for treating or preventing a disease or disorder disclosed herein.

[0855] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicinal product for the treatment of a disease or disorder disclosed herein.

[0856] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical product for treating or preventing lymphoma in a subject requiring treatment or prevention of lymphoma.

[0857] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment or prevention of lymphoma, mucosal-associated lymphocytes (MALTOMA) in subjects requiring treatment or prevention of lymphoma, mucosal-associated lymphocytes (MALTOMA).

[0858] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical product for treating or prophylactically treating immunodeficiency 12 in subjects requiring treatment or prophylactic care for immunodeficiency 12.

[0859] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical product for treating or preventing combined immunodeficiency in subjects requiring treatment or prevention of combined immunodeficiency.

[0860] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for treating or prophylactic T-cell and B-cell combined immunodeficiency in subjects requiring treatment or prophylactic treatment of T-cell and B-cell combined immunodeficiency.

[0861] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical product for the treatment of lymphoma in a subject requiring treatment for lymphoma.

[0862] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment of lymphoma, mucosal-associated lymphocytes (MALTOMA) in subjects requiring treatment of lymphoma, mucosal-associated lymphocytes (MALTOMA).

[0863] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical product for treating immunodeficiency 12 in subjects requiring treatment of immunodeficiency 12.

[0864] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical product for treating combined immunodeficiency in subjects requiring treatment of combined immunodeficiency.

[0865] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for treating combined T-cell and B-cell immunodeficiency in subjects requiring treatment of combined T-cell and B-cell immunodeficiency.

[0866] This disclosure provides compounds that function as PROTACs for MALT1 (e.g., in vitro or in vivo). Accordingly, this disclosure provides a method for degrading MALT1 in vitro or in vivo, the method comprising contacting cells with a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, as defined herein.

[0867] In some embodiments, the PROTAC of MALT1 is a compound of the present disclosure.

[0868] The efficacy of the compounds disclosed herein can be determined by industry-accepted assays / disease models, in accordance with standard practices for elucidating them as described in the Art, and as found in current general knowledge.

[0869] This disclosure also provides a method for treating a disease or disorder relating to a subject requiring such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein.

[0870] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Route of administration

[0871] The compounds of this disclosure or pharmaceutical compositions containing these compounds may be administered to a subject by any convenient route of administration, whether systemic, peripheral, or topical (i.e., 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); ocular (e.g., eye drops); pulmonary (e.g., by aerosol, by inhalation or inhalation therapy used, for example, through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral injections, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; and, for example, by depot or reservoir implantation into the subcutaneous or intramuscular region.

[0873] The abbreviations used in the following examples and elsewhere in this specification are as follows: JPEG0007879629000435.jpg234170 JPEG0007879629000436.jpg46170 (Example) General synthetic procedures and examples for the preparation of compounds. Combining building blocks 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) Carbonyl diimidazole (10.91 g, 67.25 mmol) was added in fractions to a mixture of tetrahydrofuran-2-carboxylic acid (7.1 g, 61.14 mmol) and anhydrous butyl (100 mL). The mixture was stirred at 50°C for 3 hours. 2) MgCl2 (23.3 g, 122.28 mmol) was added in part to a mixture of potassium 3-ethoxy-3-oxo-propanoate (20.81 g, 122.28 mmol) and anhydrous HCl (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 under 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 HCl, and the combined organic layers were washed with water and brine and dried (Na2SO4). Compound P1 (8.5 g, 75%) was obtained by concentration and purification by chromatography on silica gel. 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 dimethylacetal (75 mL, 569.0 mmol) was stirred overnight under reflux. 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) 1H-pyrazole-5-amine (4.0 g, 47.2 mmol) was added to a 200 mL solution of compound P2 (9.5 g, 39.3 mmol) in EtOH. The mixture was stirred overnight under reflux. 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 of 4.7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (P4) Compound P3 (9.0 g, 34.4 mmol) and NaOH (2.1 g, 51.6 mmol) were mixed in 200 mL of EtOH and 50 mL of H2O, stirred at 60°C for 15 hours, and evaporated. The residue was diluted with water and acidified to pH 3-4 with 6 M HCl. The resulting solid 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-methylpyridine-2-yl)-1,2,4-oxadiazole-5-yl]hexanoate (P9) [ka]

[0877] Preparation 5.3-methyl-5-nitropyridine-2-carbonitrile (P5) A mixture of 2-chloro-3-methyl-5-nitropyridine (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-pyrrolidinene (30 mL) was heated at 130-135°C for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with ELISA (100 mL), and filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na₂SO₄ and evaporated. The residue was purified by silica gel column chromatography. 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-carboxymidamide (P9) Na2CO3 (6.5 g, 61.3 mmol) was added to 150 mL of a hydroxylamine hydrochloride (8.6 g, 122.5 mmol) solution in H2O. 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. The reaction mixture was stirred at ambient temperature for 14 hours. The EtOH was evaporated. The resulting solid was filtered and dried. Yield of compound P6 (4.0 g, 83%). 1 H NMR (400MHz, DMSO-d6) δ 10.30 (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-nitropyridine-2-yl)methylene]amino}oxy)-7-oxoheptanoate (P7) To 20 mL of a DCM solution of 7-ethoxy-7-oxo-heptanoic acid (0.50 g, 2.7 mmol), TEA (1.1 mL, 8.1 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Then, 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 (aqueous solution), 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-nitropyridine-2-yl)-1,2,4-oxadiazole-5-yl]hexanoate (P8) A 50 mL solution of compound P7 in dioxane was refluxed with stirring for 96 hours. The mixture was evaporated and purified by column chromatography using silica gel. The yield of compound P8 in 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-methylpyridine-2-yl)-1,2,4-oxadiazole-5-yl]hexanoate (P9) To a 20 mL solution of compound P8 (0.56 g, 1.6 mmol) in acetic acid, Fe powder (0.9 g, 16 mmol) was added. The suspension was stirred at 70°C for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (100 mL), and filtered through Celite. The filtrate was evaporated. The residue was diluted with saturated NaHCO3 (aqueous solution) and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography. 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]pyrimidine-6-yl]amino}carbonyl)amino]pyridine-2-yl}-1,2,4-oxadiazole-5-yl)hexanoic acid (P11) [ka]

[0882] Preparation 10. Ethyl 6-(3-{3-methyl-5-[({[7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidine-6-yl]amino}carbonyl)amino]pyridine-2-yl}-1,2,4-oxadiazole-5-yl)hexanoate (P10) To a 20 mL solution of compound P4 (0.30 g, 1.3 mmol) in 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 using 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]pyrimidine-6-yl]amino}carbonyl)amino]pyridine-2-yl}-1,2,4-oxadiazole-5-yl)hexanoic acid (P11) Compound P10 (0.38 g, 0.7 mmol) and NaOH (0.05 g, 1.05 mmol) were mixed in 10 mL of EtOH and 2 mL of H2O, stirred at 60°C for 15 hours, and evaporated. The residue was diluted with water and acidified to pH=3-4 with 6 M HCl. The resulting solid was filtered 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]pyrimidine-6-yl)amino]carbonyl}amino)pyridine-2-yl]-1,2,4-oxadiazole-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 20 mL of 2,3-dichloro-5-nitropyridine (5.0 g, 25.91 mmol) in N-methyl-2-pyrrolidone solution. The flask was purged with argon and heated to 135°C. In another 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. 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. After the reaction was complete (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 using silica gel. Eluent - hexane / ethyl acetate = 40 / 1. 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-carboxymidamide (P13) A 40 mL solution of 3-chloro-5-nitropyridine-2-carbonitrile P12 (3.92 g, 21.4 mmol) in ethanol was added dropwise to 110 mL of aqueous solutions of hydroxylamine hydrochloride (5.94 g, 85.4 mmol) and Na2CO3 (4.53 g, 42.7 mmol). The mixture was stirred at 90°C for 12 hours. The reaction mixture was cooled to room temperature and filtered to obtain 3-chloro-N'-hydroxy-5-nitropyridine-2-carboximidoamide P13 (4.41 g, 90%). The precipitate was used in 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-nitropyridine-2-yl)(hydroxyimino)methyl]amino}-7-oxoheptanoate (P14) To a 40 mL solution of 7-ethoxy-7-oxoheptanoic acid (0.37 g, 1.94 mmol) in dioxane, N-ethyl-N-isopropylpropan-2-amine (0.30 g, 2.33 mmol) was added. The solution was stirred for 5 minutes, 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-trioxatriphosfinan 2,4,6-trioxide (0.93 g, 2.91 mmol, 50 wt% solution in ethylethanol) was poured into the reaction flask, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete as shown 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-nitropyridine-2-yl)-1,2,4-oxadiazole-5-yl]hexanoate (P15). Ethyl 7-{[(E)-(3-chloro-5-nitropyridine-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 hours. After the completion of the reaction as shown by TLC, the reaction mixture was concentrated under vacuum. The residue was purified with silica gel eluted with ethyl 6-[3-(3-chloro-5-nitropyridine-2-yl)-1,2,4-oxadiazole-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-chloropyridine-2-yl)-1,2,4-oxadiazole-5-yl]hexanoate (P16). Ethyl 6-[3-(3-chloro-5-nitropyridine-2-yl)-1,2,4-oxadiazole-5-yl]hexanoate P15 (0.62 g, 1.69 mmol) was dissolved in equal volumes in 50 mL of solvent consisting of ethanol and acetic acid. The mixture was heated to 40°C and 5 equivalents of Fe powder (0.47 g, 8.45 mmol) were added. Stirring was continued at this temperature until the starting materials were completely converted, as shown by TLC. The mixture was cooled to ambient temperature and passed through Celite. The filtrate was evaporated, the residue was dissolved in ethyl acetate, washed with water, and concentrated. The mixture was then dissolved in methylene chloride, washed with aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated to obtain ethyl 6-[3-(5-amino-3-chloropyridine-2-yl)-1,2,4-oxadiazole-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]pyrimidine-6-yl)amino]carbonyl}amino)pyridine-2-yl]-1,2,4-oxadiazole-5-yl}hexanoate (P17). Triethylamine (0.548 g, 5.4 mmol) was added to a 40 mL suspension of 7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.31 g, 1.35 mmol) in toluene. The mixture was stirred for 5 minutes. Then, DPPA (0.48 g, 1.62 mmol) was added and the mixture was stirred at room temperature for 60 minutes. After that, ethyl 6-[3-(5-amino-3-chloropyridine-2-yl)-1,2,4-oxadiazole-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 LC-MS. The mixture was quenched with water, and the separated toluene was dried over Na2SO4 and evaporated. The residue was purified with silica gel eluted with hexane / ethyl acetate 1:1 to obtain ethyl 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)pyridine-2-yl]-1,2,4-oxadiazole-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]pyrimidine-6-yl)amino]carbonyl}amino)pyridine-2-yl]-1,2,4-oxadiazole-5-yl}hexanoic acid (P18). A 0.08 g (1.94 mmol) aqueous solution of NaOH was added to a 10 ml solution of ethyl 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)pyridine-2-yl]-1,2,4-oxadiazole-5-yl}hexanoate P17 (0.55 g, 0.97 mmol) in 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 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]pyrimidine-6-yl)amino]carbonyl}amino)pyridine-2-yl]-1,2,4-oxadiazole-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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,3,4-oxadiazole-2-yl}hexanoic acid (P26) [ka]

[0891] Preparation of 19.3-methyl-5-nitropyridine-2-carboxylic acid (P19). In a 25 mL microwave vial, 3-methyl-5-nitropyridine-2-carbonitride 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 in a microwave oven at 120°C for 60 minutes. After completion, the reaction mixture was cooled to room temperature, concentrated, and dried. The resulting residue was dissolved in THF and 1 N NaOH was slowly added to pH=9. The resulting mixture was stirred at 50°C for 1 hour. The mixture was then diluted with water, acidified to pH 4-5 with 1 N HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine (10 mL), dried, and concentrated to obtain 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-nitropyridine-2-yl)carbonyl]hydrazine carboxylate (P20). To a 30 ml solution of 3-methyl-5-nitropyridine-2-carboxylic acid P19 (1.56 g, 8.57 mmol) in N,N-dimethylformamide, N-[(dimethylamino)(3-oxide-1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)methylene]-N-methylmethaneaminium hexafluorophosphate (4.89 g, 12.85 mmol) was added, and the solution was mixed for 5 minutes. Then, tert-butylcarbazate (1.36 g, 10.28 mmol) and triethylamine (1.73 g, 17.14 mmol) were 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 ethylethanol. The alkyl ethyl acetate layer was washed with brine (10 mL), dried, and concentrated to obtain tert-butyl 2-[(3-methyl-5-nitropyridine-2-yl)carbonyl]hydrazine carboxylate (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). 1.76 g, 5.94 mmol of tert-butyl 2-[(3-methyl-5-nitropyridine-2-yl)carbonyl]hydrazine carboxylate P20 was dissolved in 20 mL of 1,4-dioxane. 20 mL of 3N hydrogen chloride solution in 1,4-dioxane was added. The solution was stirred at room temperature for 12 hours. After the reaction was complete as shown by LC-MS, the reaction mixture was concentrated under vacuum, and the residue was dissolved in methanol. Potassium carbonate was added, the mixture was stirred for 5 minutes, filtered, and concentrated to obtain 3-methyl-5-nitropyridine-2-carbohradazide P21 (460 mg, 40%). LC-MS ESI (m / z): 197.2 ([M+1] + ).

[0894] Preparation 22. Ethyl 7-{2-[(3-methyl-5-nitropyridine-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 mixed in 20 mL of 1,4-dioxane and stirred at 50°C for 3 hours. Then, 3-methyl-5-nitropyridine-2-carbohdrazide P21 (0.46 g, 2.35 mmol) was added and the mixture was stirred at this temperature for a further 12 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (eluent-siRNA-siRNA / hexane, 5:1) to obtain ethyl 7-{2-[(3-methyl-5-nitropyridine-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-nitropyridine-2-yl)-1,3,4-oxadiazole-2-yl]hexanoate (P23). Triphenylphosphine was added in fractions (42.2 mg, 0.16 mmol) to a solution of iodine (40.9 mg, 0.16 mmol) in DCM at 0-5°C. Then, ethyl 7-{2-[(3-methyl-5-nitropyridine-2-yl)carbonyl]hydrazino}-7-oxoheptanoate P22 (118 mg, 0.32 mmol) was added, followed by the addition of Et3N (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 Na2SO4, and evaporated. The residue was purified by silica gel column chromatography to obtain ethyl 6-[5-(3-methyl-5-nitropyridine-2-yl)-1,3,4-oxadiazole-2-yl]hexanoate P23 (51 mg, 45%). LCMS ESI(m / z):349.5([M+1] + ).

[0896] Preparation 24. Ethyl 6-[5-(5-amino-3-methylpyridine-2-yl)-1,3,4-oxadiazole-2-yl]hexanoate (P24) Ethyl 6-[5-(3-methyl-5-nitropyridine-2-yl)-1,3,4-oxadiazole-2-yl]hexanoate P23 (0.2 g, 0.57 mmol) was dissolved in 20 mL of a solvent consisting of ethanol and acetic acid in equal volumes. 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 the starting materials were completely converted, as shown by TLC. The mixture was cooled to ambient temperature and passed through Celite. The filtrate was evaporated, 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 obtain ethyl 6-[5-(5-amino-3-methylpyridine-2-yl)-1,3,4-oxadiazole-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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,3,4-oxadiazole-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. Then, DPPA (0.15 g, 0.56 mmol) was added and the mixture was stirred at room temperature for 60 minutes. After that, ethyl 6-[5-(5-amino-3-methylpyridine-2-yl)-1,3,4-oxadiazole-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 LC-MS. The mixture was quenched with water, and the separated toluene layer was dried over Na2SO4 and evaporated. The residue was purified with silica gel eluted in hexane / ethyl acetate in a 1:1 ratio to obtain ethyl 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,3,4-oxadiazole-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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,3,4-oxadiazole-2-yl}hexanoic acid (P26). An aqueous solution of NaOH (8.2 mg, 0.2 mmol) was added to a 10 ml solution of ethyl 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,3,4-oxadiazole-2-yl}hexanoate P25 (56 mg, 0.1 mmol) in ethanol. The mixture was stirred at 50°C for 12 hours. After the hydrolysis of the ester was complete, 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 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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,3,4-oxadiazole-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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-1-yl}heptanoic acid (P32) [ka]

[0899] Preparation 27.3-methyl-5-nitro-2-[(trimethylsilyl)ethynyl]pyridine (P27). Ethynyltrimethylsilane (2.56 g, 26.08 mmol) was added 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). The flask was purged with argon and heated at 80 °C for 12 hours. After the reaction was complete (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 NaHCO₃ and NaCl, dried over Na₂SO₄, and concentrated. The product was purified by column chromatography using 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 of 28,5-methyl-6-[(trimethylsilyl)ethynyl]pyridine-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) were added. Stirring was continued at this temperature until the starting materials were completely converted, as shown by TLC. The mixture was cooled to ambient temperature and passed through Celite. The filtrate was evaporated, the residue was dissolved in ethyl acetate, washed with water, and concentrated. The mixture was then dissolved in methylene chloride, washed with aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated to obtain 5-methyl-6-[(trimethylsilyl)ethynyl]pyridine-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]pyrimidine-6-yl)-N'-{5-methyl-6-[(trimethylsilyl)ethinyl]pyridine-3-yl}urea (P29). Triethylamine (1.44 g, 14.2 mmol) was added to a 40 mL suspension of 7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.82 g, 3.55 mmol) in toluene. The mixture was stirred for 5 minutes. Then, DPPA (1.17 g, 4.26 mmol) was added and the mixture was stirred at room temperature for 60 minutes. After that, 5-methyl-6-[(trimethylsilyl)ethynyl]pyridine-3-amine P28 (0.87 g, 4.26 mmol) was added and the mixture was refluxed for 12 hours. The reaction was monitored by LC-MS. The mixture was quenched with water, and the separated toluene was dried over Na2SO4 and evaporated. The residue was purified with silica gel eluted in hexane / ethyl acetate in a 1:1 ratio to obtain N-(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)-N'-{5-methyl-6-[(trimethylsilyl)ethynyl]pyridine-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]pyrimidine-6-yl)-N'-(6-ethynyl-5-methylpyridine-3-yl)urea (P30). N-(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)-N'-{5-methyl-6-[(trimethylsilyl)ethynyl]pyridine-3-yl}urea P29 (0.24 g, 0.56 mmol) was dissolved in equal volumes in 20 mL of a solvent consisting of methanol and dichloromethane. Potassium fluoride (0.097 g, 1.67 mmol) was added to the flask and stirred at room temperature for 2 hours. After the reaction was complete as shown by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate. N-(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)-N'-(6-ethynyl-5-methylpyridine-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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-1-yl}heptanoate (P31). N-(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)-N'-(6-ethynyl-5-methylpyridine-3-yl)urea P30 (0.186 g, 0.52 mmol) and ethyl 7-azidoheptanoate (0.103 g, 0.52 mmol) were dissolved in equal volumes in 20 mL of 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 the completion of the reaction as shown by LC-MS, the product was extracted with ethyl acetate and concentrated. The residue was purified with silica gel that elutes with ethyl acetate to obtain ethyl 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-1-yl}heptanoic acid (P32). A 0.021 g, 0.53 mmol aqueous solution of NaOH was added to a 10 ml solution of ethyl 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-1-yl}heptanoate P31 (0.149 g, 0.27 mmol) in ethanol. The mixture was stirred at 50°C for 12 hours. After the hydrolysis of the ester was complete, 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 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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-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) Carbonyl diimidazole (12.5 g, 77.11 mmol) was added in fractions to a mixture of cyclopentanecarboxylic acid (8.0 g, 70.10 mmol) and anhydrous sorbate (100 mL). The mixture was stirred at 50°C for 3 hours. 2) MgCl2 (26.7 g, 280.4 mmol) was added in portions to a mixture of potassium 3-ethoxy-3-oxo-propanoate (23.86 g, 140.2 mmol) and anhydrous siRNA (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 overnight under reflux. The mixture was cooled in an ice bath and acidified to pH=3 with 4M HCl (140 mL). The mixture was warmed to ambient temperature, and the layers were separated. The aqueous layer was extracted with phenylethylamine, and the combined organic layers were washed with water and brine and dried (Na₂SO₄). The mixture was concentrated and purified by silica gel chromatography to obtain 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 dimethylacetal (73 mL, 548.0 mmol) was stirred overnight under reflux. 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 200 mL solution of P34 (11.0 g, 46.0 mmol) in EtOH, 1H-pyrazole-5-amine (4.6 g, 55.2 mmol) was added. The mixture was stirred overnight under reflux. 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 of 36,7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (P36). Compound P35 (9.2 g, 35.5 mmol) and NaOH (2.2 g, 53.2 mmol) were mixed in 200 mL of EtOH and 50 mL of H2O, stirred at 60°C for 14 hours, and evaporated. The residue was diluted with water and acidified to pH=3-4 with 6 M HCl. The resulting solid 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-methylpyridine-2-yl)-1,2,4-oxadiazole-5-yl]butanoate (P39) [ka]

[0909] Preparation 37. Ethyl 5-({[(1Z)-amino(3-methyl-5-nitropyridine-2-yl)methylene]amino}oxy)-5-oxopentanoate (P37) To a 20 mL solution of 5-ethoxy-5-oxopentanoic acid (0.50 g, 3.1 mmol) in 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 (aqueous solution), 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-nitropyridine-2-yl)-1,2,4-oxadiazole-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 using silica gel. Yield of compound P38 from the two steps (preparations 37 and 38): 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-nitropyridine-2-yl)-1,2,4-oxadiazole-5-yl]butanoate (P39) To a solution of compound P38 (0.37 g, 1.15 mmol) in 20 mL of acetic acid, Fe powder (0.65 g, 11.5 mmol) was added. The suspension was stirred at 70°C for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with Depositphotos (100 mL), and filtered through Celite. The filtrate was evaporated. The residue was diluted with saturated NaHCO3 (aqueous solution) and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography. 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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}butanonic acid (P41) [ka]

[0912] Preparation 40. Ethyl 4-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}butanoate (P40). To a solution of compound P36 (0.24 g, 1.0 mmol) in 20 mL of toluene, Et3N (0.6 mL, 4.0 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Then, 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 silica gel column chromatography to obtain 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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}butanonic 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 H2O was stirred at 60°C for 14 hours and evaporated. The residue was diluted with water and acidified to pH=3-4 with 6 M HCl. The resulting solid 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-methylpyridine-2-yl)-1,2,4-oxadiazole-5-yl]propanoate (P44) [ka]

[0914] Preparation 42. Ethyl 4-({[(1Z)-amino(3-methyl-5-nitropyridine-2-yl)methylene]amino}oxy)-4-oxobutanoate (P42). To a 20 mL solution of 4-ethoxy-4-oxo-butanoic acid (0.50 g, 3.4 mmol) in DCM, Et3N (1.4 mL, 10.2 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Then, 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% K2CO3 (aqueous solution), dried over Na2SO4, 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-nitropyridine-2-yl)-1,2,4-oxadiazole-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 using silica gel. The yield of compound P43 in 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-methylpyridine-2-yl)-1,2,4-oxadiazole-5-yl]propanoate (P44). To a 20 mL solution of compound P43 (0.56 g, 1.8 mmol) in acetic acid, Fe powder (1.0 g, 18.0 mmol) was added. The suspension was stirred at 70°C for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with SiO2 (100 mL), and filtered through Celite. The filtrate was evaporated. The residue was diluted with saturated NaHCO3 (aqueous solution) and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography. 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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}propanoic acid (P46) [ka]

[0917] Preparation 45. Ethyl 3-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}propanoate (P45). To a 20 mL solution of compound P36 (0.39 g, 1.7 mmol) in toluene, Et3N (1.0 mL, 6.8 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Then, 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 using 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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}propanoic acid (P46). Compound P45 (0.41 g, 0.8 mmol) and NaOH (0.05 g, 1.2 mmol) were mixed in 10 mL of EtOH and 2 mL of H2O, stirred at 60°C for 14 hours, and evaporated. The residue was diluted with water and acidified to pH 3-4 with 6 M HCl. The resulting solid 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-methylpyridine-2-yl)-1,2,4-oxadiazole-5-yl]pentanoate (P49) [ka]

[0919] Preparation 47. Ethyl 6-({[(1Z)-amino(3-methyl-5-nitropyridine-2-yl)methylene]amino}oxy)-6-oxohexanoate (P47) To a 20 mL solution of 6-ethoxy-6-oxohexanoic acid (0.60 g, 3.4 mmol) in DCM, Et3N (1.5 mL, 10.2 mmol) was added. 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% K2CO3 (aqueous solution), dried over Na2SO4, 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-nitropyridine-2-yl)-1,2,4-oxadiazole-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 using silica gel. The yield of compound P48 in 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-methylpyridine-2-yl)-1,2,4-oxadiazole-5-yl]pentanoate (P49). To a 20 mL solution of compound P48 (0.58 g, 1.7 mmol) in acetic acid, Fe powder (1.0 g, 17 mmol) was added. The suspension was stirred at 70°C for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with RINKAN (100 mL), and filtered through Celite. The filtrate was evaporated. The residue was diluted with saturated NaHCO3 (aqueous solution) and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography. 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-carbonitride N-(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)-N'-{5-methyl-6-[5-(5-oxopentyl)-1,2,4-oxadiazole-3-yl]pyridine-3-yl}urea (P53) [ka]

[0922] Preparation 50. Ethyl 5-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}pentanoate (P50). To a 20 mL solution of compound P36 (0.36 g, 1.6 mmol) in toluene, Et3N (0.9 mL, 6.4 mmol) was added. 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 using 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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}pentanoic acid (P51). Compound P50 (0.52 g, 1.0 mmol) and NaOH (0.06 g, 1.5 mmol) were mixed in 10 mL of EtOH and 2 mL of H2O, stirred at 60°C for 14 hours, and evaporated. The residue was diluted with water and acidified to pH=3-4 with 6 M HCl. The resulting solid was filtered 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]pyrimidine-6-yl)-N'-{6-[5-(5-hydroxypentyl)-1,2,4-oxadiazole-3-yl]-5-methylpyridine-3-yl}urea (P52). To a 10 mL solution of compound P51 (0.45 g, 0.9 mmol) in THF, Et3N (0.16 mL, 1.17 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Then, 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 10 mL solution of sodium borohydride (0.17 g, 4.5 mmol) in water 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 extract was dried over Na2SO4 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]pyrimidine-6-yl)-N'-{5-methyl-6-[5-(5-oxopentyl)-1,2,4-oxadiazole-3-yl]pyridine-3-yl}urea (P53). A solution of dimethyl sulfoxide (0.14 mL, 1.88 mmol) in DCM (0.1 mL) was added at -70°C to a stirred solution of trifluoroacetic anhydride (0.2 mL, 1.37 mmol) in DCM (10 mL). A solution of compound P52 (0.28 g, 0.57 mmol) in DCM (1.0 mL) was added dropwise to the above-prepared solution over 15 minutes, and the mixture was stirred for a further 3.5 hours. Triethylamine (0.5 mL, 3.42 mmol) was added dropwise over 15 minutes with stirring, and the entire mixture was warmed to room temperature. The mixture was diluted with DCM, washed with saturated NaHCO3 (aqueous solution), 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]pyrimidine-6-yl)-N'-{5-methyl-6-[5-(3-oxopropyl)-1,2,4-oxadiazole-3-yl]pyridine-3-yl}urea (P55) [ka]

[0926] Preparation 54. N-(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)-N'-{6-[5-(3-hydroxypropyl)-1,2,4-oxadiazole-3-yl]-5-methylpyridine-3-yl}urea (P54). Et3N (0.16 mL, 1.04 mmol) was added to 10 mL of a solution of compound P46 (0.4 g, 0.8 mmol) in THF. The mixture was stirred at room temperature for 10 minutes. Then, 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 extract was dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography to obtain 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]pyrimidine-6-yl)-N'-{5-methyl-6-[5-(3-oxopropyl)-1,2,4-oxadiazole-3-yl]pyridine-3-yl}urea (P55). A solution of DMSO (0.03 mL, 0.43 mmol) in DCM (0.1 mL) was added at -70°C to a stirred solution of trifluoroacetic anhydride (0.045 mL, 0.31 mmol) in DCM (10 mL). A solution of compound P54 (0.06 g, 0.13 mmol) in DCM (1.0 mL) was added dropwise to the above-prepared solution over 15 minutes, and the mixture was stirred for a further 3.5 hours. Triethylamine (0.11 mL, 0.78 mmol) was added dropwise over 15 minutes with stirring, and the entire mixture was warmed to room temperature. The mixture was diluted with DCM, washed with saturated NaHCO3 (aqueous solution), 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]pyrimidine-6-yl)-N'-{5-methyl-6-[5-(3-oxopropyl)-1,2,4-oxadiazole-3-yl]pyridine-3-yl}urea (P56) [ka]

[0928] Preparation 56. N-(3-chloro-7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)-N'-{5-methyl-6-[5-(3-oxopropyl)-1,2,4-oxadiazole-3-yl]pyridine-3-yl}urea (P56). A solution of DMSO (0.06 mL, 0.80 mmol) in DCM (0.1 mL) was added at -70°C to a stirred solution of oxalyl chloride (0.05 mL, 0.53 mmol) in DCM (10 mL). A solution of compound P54 (0.1 g, 0.24 mmol) in DCM (1.0 mL) was added dropwise to the above-prepared solution over 15 minutes, and the mixture was stirred for a further 3.5 hours. Triethylamine (0.20 mL, 1.44 mmol) was added dropwise over 15 minutes with stirring, and the entire mixture was warmed to room temperature. The mixture was diluted with CH2Cl2, washed with saturated NaHCO3 (aqueous solution), dried over Na2SO4, 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]pyrimidine-6-yl)-N'-{5-methyl-6-[5-(4-oxobutyl)-1,2,4-oxadiazole-3-yl]pyridine-3-yl}urea (P58) [ka]

[0929] Preparation 57. N-(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)-N'-{6-[5-(4-hydroxybutyl)-1,2,4-oxadiazole-3-yl]-5-methylpyridine-3-yl}urea (P57). To a 10 mL solution of compound P41 (0.27 g, 0.55 mmol) in THF, Et3N (0.1 mL, 0.72 mmol) was added. 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 10 mL solution of sodium borohydride (0.1 g, 2.75 mmol) in water 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 extract was dried over Na2SO4 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]pyrimidine-6-yl)-N'-{5-methyl-6-[5-(4-oxobutyl)-1,2,4-oxadiazole-3-yl]pyridine-3-yl}urea (P58). A solution of DMSO (0.05 mL, 0.66 mmol) in DCM (0.1 mL) was added at -70°C to a stirred solution of oxalyl chloride (0.045 mL, 0.48 mmol) in DCM (10 mL). A solution of compound P57 (0.1 g, 0.2 mmol) in DCM (1.0 mL) was added dropwise to the above-prepared solution over 15 minutes, and the mixture was stirred for a further 3.5 hours. Triethylamine (0.2 mL, 1.20 mmol) was added dropwise over 15 minutes with stirring, and the entire mixture was warmed to room temperature. The mixture was diluted with DCM, washed with saturated NaHCO3 (aqueous solution), 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]pyrimidine-6-yl)-N'-{5-methyl-6-[5-(4-oxobutyl)-1,2,4-oxadiazole-3-yl]pyridine-3-yl}urea (P59) [ka]

[0931] Preparation 59. N-(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)-N'-{5-methyl-6-[5-(4-oxobutyl)-1,2,4-oxadiazole-3-yl]pyridine-3-yl}urea (P59) A solution of DMSO (0.025 mL, 0.33 mmol) in DCM (0.1 mL) was added at -70°C to a stirred solution of trifluoroacetic anhydride (0.036 mL, 0.24 mmol) in DCM (10 mL). A solution of compound P57 (0.05 g, 0.1 mmol) in DCM (1.0 mL) was added dropwise to the above-prepared solution over 15 minutes, and the mixture was stirred for a further 3.5 hours. Triethylamine (0.09 mL, 0.60 mmol) was added dropwise over 15 minutes with stirring, and the entire mixture was warmed to room temperature. The mixture was diluted with DCM, washed with saturated NaHCO3 (aqueous solution), 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-nitropyridine-2-yl)-1,2,4-oxadiazole-5-yl]hexanoate (P8) - Second Option [ka]

[0932] Preparation 60. Ethyl 7-{[(E)-(hydroxyimino)(3-methyl-5-nitropyridine-2-yl)methyl]amino}-7-oxoheptanoate (P60) To a 40 mL solution of 7-ethoxy-7-oxoheptanoic acid (0.78 g, 4.2 mmol) in 1,4-dioxane, N-ethyl-N-isopropylpropan-2-amine (0.645 g, 4.98 mmol) was added. The solution was stirred for 5 minutes, then N'-hydroxy-3-methyl-5-nitropyridine-2-carboximidoamide 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-trioxatriphosfinan 2,4,6-trioxide (1.98 g, 6.3 mmol, 50 wt% solution in ethylethanol) was poured into the reaction flask, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete as shown by TLC, the reaction mixture was concentrated under vacuum, 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-nitropyridine-2-yl)-1,2,4-oxadiazole-5-yl]hexanoate (P8) Ethyl 7-{[(E)-(hydroxyimino)(3-methyl-5-nitropyridine-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 the completion of the reaction as shown by TLC, the reaction mixture was concentrated under vacuum. The residue was purified with silica gel eluted with ethyl 6-[3-(3-methyl-5-nitropyridine-2-yl)-1,2,4-oxadiazole-5-yl]hexanoate P8 (0.55 g). The yield was 38% for the two 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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}hexanoic acid (P62) [ka]

[0934] Preparation 61. Ethyl 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}hexanoate (P61). Triethylamine (0.166 g, 1.64 mmol) was added to a 40 mL suspension of 7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.095 g, 0.41 mmol) in toluene. The mixture was stirred for 5 minutes. Then, DPPA (1.136 g, 0.49 mmol) was added and the mixture was stirred at room temperature for 60 minutes. After that, ethyl 6-[3-(5-amino-3-methylpyridine-2-yl)-1,2,4-oxadiazole-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 LC-MS. The mixture was quenched with water, and the separated toluene was dried over Na2SO4 and evaporated. The residue was purified with silica gel eluted in hexane / ethyl acetate in a 1:1 ratio to obtain ethyl 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}hexanoic acid (P62). A solution of NaOH (0.026 g, 0.46 mmol) was added to a 10 ml solution of ethyl 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}hexanoate P61 (0.127 g, 0.23 mmol) in 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 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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-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 at 0°C 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). 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 obtain 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 heated and stirred at 80°C for 18 hours. After the reaction was complete (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 using 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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-1-yl}butoxy)acetic acid (P66) [ka]

[0938] Preparation 65. tert-butyl(4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-1-yl}butoxy)acetate (P65). N-(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)-N'-(6-ethynyl-5-methylpyridine-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 volumes 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 the completion of the reaction as shown by LC-MS, the product was extracted with ethyl acetate and concentrated. The residue was purified with silica gel eluted with ethyl / MeOH at a ratio of 40:1 to obtain tert-butyl(4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-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]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-1-yl}butoxy)acetic acid (P66). tert-butyl(4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-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 hours. TLC control was used. The product was concentrated under vacuum and evaporated with HCl-saturated dioxane. (4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1H-1,2,3-triazole-1-yl}butoxy)hydrochloride acetate 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 20 mL solution of tert-butyl 2-(4-hydroxybutoxy)acetate (1.0 g, 4.9 mmol) in DCM, Et3N (1.7 mL, 12.3 mmol) was added. Then, benzoyl chloride (0.7 mL, 5.9 mmol) was added at 0-5°C. The mixture was stirred at room temperature for 14 hours. The mixture was diluted with DCM, washed with saturated NaHCO3 (aqueous solution), dried over Na2SO4, 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). TFA (2.6 mL, 33.0 mmol) was added to 15 mL of a solution of compound P67 (1.0 g, 3.3 mmol) in DCM. 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-methylpyridine-2-yl)-1,2,4-oxadiazole-5-yl]methoxy}butylbenzoate (P70) [ka]

[0942] Preparation 69.4-{[3-(3-methyl-5-nitropyridine-2-yl)-1,2,4-oxadiazole-5-yl]methoxy}butylbenzoate (P69) To a 20 mL solution of compound P68 (0.84 g, 3.3 mmol) in dioxane, CDI (0.6 g, 3.7 mmol) was added. 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 under reflux for 72 hours. The mixture was evaporated. The residue was diluted with water and extracted with ethyl acetate. The combined organic extract was dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography. 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-methylpyridine-2-yl)-1,2,4-oxadiazole-5-yl]methoxy}butylbenzoate (P70). To a 10 mL solution of compound P69 (0.25 g, 0.6 mmol) in acetic acid, Fe powder (0.3 g, 6.0 mmol) was added. The suspension was stirred at 70°C for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with Depositphotos (100 mL), and filtered through Celite. The filtrate was evaporated. The residue was diluted with saturated NaHCO3 (aqueous solution) and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography. Yield of compound P70: 0.14 g, 60%. LCMS ESI (m / z): 383.5 ([M+1] + ). Synthesis of N-(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)-N'-(5-methyl-6-{5-[(4-oxobutoxy)methyl]-1,2,4-oxadiazole-3-yl}pyridine-3-yl)urea (P73) [ka]

[0944] Preparation 71.4-({3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-yl)amino]carbonyl}amino)-3-methylpyridine-2-yl]-1,2,4-oxadiazole-5-yl}methoxy)butylbenzoate (P71). To a 10 mL solution of compound P36 (0.08 g, 0.035 mmol) in toluene, Et3N (0.2 mL, 0.140 mmol) was added. 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 a further 1 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 using 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]pyrimidine-6-yl)-N'-(6-{5-[(4-hydroxybutoxy)methyl]-1,2,4-oxadiazole-3-yl}-5-methylpyridine-3-yl)urea (P72). To a 5 mL solution of compound P71 (0.13 g, 0.21 mmol) in MeOH, K2CO3 (0.12 g, 0.84 mmol) was added. The mixture was stirred at 60°C for 4 hours. The mixture was evaporated. The residue was diluted with water and extracted with ethyl acetate. The combined organic extract was 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]pyrimidine-6-yl)-N'-(5-methyl-6-{5-[(4-oxobutoxy)methyl]-1,2,4-oxadiazole-3-yl}pyridine-3-yl)urea (P73) A solution of dimethyl sulfoxide (0.04 mL, 0.5 mmol) in DCM (0.1 mL) was added at -70°C to a stirred solution of oxalyl chloride (0.032 mL, 0.36 mmol) in DCM (10 mL). A solution of compound P72 (0.078 g, 0.15 mmol) in DCM (1.0 mL) was added dropwise to the above-prepared solution over 15 minutes, and the mixture was stirred for a further 3.5 hours. Triethylamine (0.13 mL, 0.90 mmol) was added dropwise over 15 minutes with stirring, and the entire mixture was warmed to room temperature. The mixture was diluted with DCM, washed with saturated NaHCO3 (aqueous solution), 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)ethylbenzoate (P74). To a 20 mL solution of tert-butyl 3-(2-hydroxyethoxy)propanoate (1.0 g, 5.3 mmol) in DCM, Et3N (1.9 mL, 13.3 mmol) was added. Subsequently, benzoyl chloride (0.7 mL, 5.9 mmol) was added at 0-5°C. The mixture was stirred at room temperature for 14 hours. The mixture was diluted with DCM, washed with saturated NaHCO3 (aqueous solution), dried over Na2SO4, and evaporated. The residue was purified by column chromatography using 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] Prepared 75.3-[2-(benzoyloxy)ethoxy]propanoic acid (P75). TFA (3.2 mL, 41.0 mmol) was added to 15 mL of a solution of compound P74 (1.2 g, 4.1 mmol) in DCM. 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-...

Claims

1. Compounds of formula (I-I-A-1-a-1-I-A): 【Chemistry 1】 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, During the ceremony, Ring A is a five-membered heteroaryl compound containing one, two, three, or four heteroatoms, where each heteroatom is independently selected from N, O, and S. Ring B is a six-membered heteroaryl compound containing one, two, three, or four heteroatoms, where each heteroatom is independently selected from N, O, and S. M is -CH ２ -, -C(O)- are selected, L1 is a bond, L2 is selected from the following bonds: -CH2-, -CH2CH2-, C3-C8 cycloalkanediyl-(CH2)p-, Each R3 and R ９ Is it hydrogen? or two R's ３ is = O, Each R ４ 、R ６ 、R ７ 、and R １０ are independently selected from 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, where the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R １１ s, R ８ H, C １ ~C ６ Selected from alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is one or more R １１ It is sometimes replaced by, Each R １１ These are halogen, -OH, -CN, -NO ２ , -NR １２ R １３、 C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Independently selected from haloalkoxys, cycloalkyls, aryls, heterocyclyls, and heteroaryls, R １２ and R １３ is hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Independently selected from hydroxyalkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, m and n are integers independently selected from 0, 1, 2, and 3, respectively. 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. Compounds of formula (I-I-A-1-a-1-I-A) or their pharmaceutically acceptable salts, stereoisomers, solvates, or tautomers.

2. The aforementioned compounds are those 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), or (I-16): 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 things, or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, where 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 according to claim 1.

3. The following compounds can be selected: or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

4. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to 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 pharmaceutical for degrading MALT1, wherein the compound or the pharmaceutical composition is administered to a subject.

7. 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 pharmaceutical for treating a disease or disorder related to MALT1, wherein the compound or the pharmaceutical composition is administered to a subject.

8. 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 pharmaceutical for treating a disease or disorder selected from lymphoma and immunodeficiency, wherein the compound or the 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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