Proteolytic targeting chimerism of mucosa-associated lymphatic tissue lymphoma translocation protein 1

Abstract

The present invention relates to a compound of formula (I), which is characterized as PROTAC for MALT1. The PROTACs described herein can be used to treat diseases or conditions 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 conditions associated with MALT1, and methods of synthesizing these compounds. I) # imgabs0 #

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application Serial No. 63 / 314,205 entitled “PROTAC of MALT1”, filed February 25, 2022, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0003] This invention relates to the use of Proteolytic Targeted Chimera (PROTAC) technology for the treatment of diseases or conditions associated with mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and more particularly to compounds that degrade MALT1 and methods thereof. Background Technology

[0004] Proteolytic targeted chimera (PROTAC) technology is an effective tool for the degradation of endogenous proteins developed in recent years. It can ubiquitinate target proteins through the ubiquitin-proteasome system (UPS), thereby acting on tumor growth. Several literature studies on PROTAC technology have demonstrated its feasibility in degrading target proteins. Furthermore, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging results in clinical trials for the treatment of prostate and breast cancer, stimulating greater enthusiasm for PROTAC research (Min Si Qi et al., Front. Pharmacol., May 7, 2021, https: / / doi.org / 10.3389 / fphar.2021.692574).

[0005] Chemotherapy plays an irreplaceable role in cancer treatment as a conventional treatment method. The main drawbacks of conventional anticancer drugs are that most of them have poor selectivity and are prone to 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). Therefore, targeted therapy for cancer has attracted considerable attention. Based on this, the discovery of new targets and small molecule inhibitors (SMIs) has become a powerful treatment strategy. Specifically, the development of small molecule kinase inhibitors has become one of the most widely pursued areas in drug discovery and has achieved great success in cancer treatment (Wu et al., Trends Pharmacol. Sci. 2015, 36, 422-439. doi:10.1016 / j.tips.2015.04.005). However, following its success, this treatment strategy also faces the same drug resistance problem as chemotherapy (Xu et al., Front. Cell Dev Biol 2020, 8, 621428. doi:10.3389 / fcell.2020.621428). Therefore, drug resistance is a major limitation of cancer therapy and urgently needs to be addressed.

[0006] In recent years, novel strategies targeting disease-related proteins for degradation have garnered significant attention. Proteolytic targeting chimeras (PROTACs), also known as bivalent chemical protein degraders, are heterobifunctional molecules that degrade specific endogenous proteins via the E3 ubiquitin ligase pathway (Potjewyd et al., Cel Chem. Biol. 2020, 27, 47-56. doi:10.1016 / j.chembiol.2019.11.006). They structurally link a protein of interest (POI) binding ligand and an E3 ubiquitin ligase (E3) ligand through appropriate linkers (Vollmer et al., J. Med. Chem. 2020, 63, 157-162. doi:10.1021 / acs.jmedchem.9b00810). The potential advantages of PROTAC technology can compensate for the shortcomings of conventional drug therapies, which has prompted its rapid development (Sun and Rao, Biochemistry 2020, 59, 240-249. doi:10.1021 / acs.biochem.9b00848).

[0007] Bifunctional PROTAC molecules consist of a ligand (primarily a small molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of the E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC recruits E3 for POI ubiquitination, and E3 is then subjected to proteasome-mediated degradation. PROTACs complement nucleic acid-based gene knockdown / knockout techniques for targeting 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, some of which are in clinical trials for cancer treatment.

[0008] The PROTAC molecule consists of ligands of POI (mainly small molecule inhibitors) and ligands of E3 ubiquitin ligase (E3), which are covalently linked together by linkers consisting mainly of 5-15 carbon atoms or other atoms. Mechanistically, upon binding to POI, PROTAC recruits E3 for neighbor-induced ubiquitination of POI, after which E3 is degraded by the endogenous 26S proteasome. Recent X-ray structures of the POI-PROTAC-E3 ternary complex have provided strong evidence supporting this mechanism (Gadd M.S. et al., Nat Chem Biol. 2017, 13(5):514).

[0009] PROTAC technology offers several potential advantages (Xin Li et al., J Hematol Oncol 2020, 13, 50. https: / / doi.org / 10.1186 / s13045-020-00885-3). First, despite their relatively large molecular weight, PROTACs are more like drugs, unlike RNA / DNA-based protein reducing agents. By selecting drug-like ligands for POIs and E3 and then optimizing them with medicinal chemistry, PROTACs can possess favorable ADME (absorption, distribution, metabolism, and elimination) properties, which are essential for becoming clinically useful drugs. Second, PROTACs can eliminate POIs at a substoichiometric level because they can be reused after a round of protein degradation. Therefore, it is possible that the DC50 of a PROTAC can be significantly lower than its binding affinity to POI (or its inhibitory IC50). For example, PROTACs as low as 10 pM can effectively induce BRD4 degradation (Qin C et al., J Med Chem. 2018, 61(15), 6685-704). This feature offers a potentially significant advantage over pharmacological protein inhibition. Third, because PROTACs can only transiently bind to POIs, they offer the opportunity to overcome mutation-directed resistance. For example, the ibrutinib-containing PROTAC MT-802 induces the degradation of the C481S mutant BTK (which is resistant to ibrutinib) as effectively as the wild-type protein and effectively inhibits the proliferation of ibrutinib-resistant leukemia cells (Buhimschi AD et al., Biochemistry 2018, 57(26), 3564-75). Fourth, PROTACs only require a ligand to bind to the POI, which may not necessarily affect the function of the POI. Therefore, PROTACs can target any protein, including those considered undruggable. Furthermore, the degradation induced by PROTACs is also based on lysine residues on the POI surface, which represents another requirement for selectivity. This could lead to higher selectivity and has been successfully used, starting with pan-inhibitors of protein families, to develop selective PROTACs that target isoforms of protein families such as CDK9 (Robb CM et al., ChemCommun. 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(Supplementary Material 1), 2073-4) and HDAC6 (An Z. et al., Protein & Cell 2019, 10(8), 606-9).

[0010] Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a protein encoded by the MALT1 gene in humans. It is a human paracaspase. Gene ablation and biochemical studies of the paracaspase gene in mice have shown that paracaspase is a key protein in the activation of T and B lymphocytes. It plays an important role in the activation of the transcription factor NF-κB, the production of interleukin-2 (IL-2), and the proliferation of T and B lymphocytes. Furthermore, paracaspase has been shown to play a role in innate immune responses mediated by the yeast glycan receptor Dectin-1 in macrophages and dendritic cells, as well as in responses to stimulation by certain G protein-coupled receptors. When BCL10 / MALT1 is recruited to activated CARD-CC family proteins (CARD9, CARD-10, CARD-11, or CARD-14) in the so-called CBM (CARD-CC / BCL10 / MALT1) signaling complex, downstream NF-κB signaling and protease activity of MALT1 are activated. In T lymphocytes, caspase-like enzymes have shown proteolytic activity through their caspase-like domains. By targeting the proteolytic activity of caspase-like enzymes, it is possible to develop new drugs for the treatment of certain lymphomas or autoimmune diseases.

[0011] In summary, to date, PROTACs targeting approximately 50 proteins have been successfully developed, with two compounds currently in clinical trials for the treatment of therapy-resistant prostate and breast cancer. Clinical results have not yet been disclosed. Given the relatively small number of these POIs and clinical candidates, it remains to be seen whether these PROTACs can become clinically useful anticancer drugs. However, PROTAC technology is far from being well researched and developed. It has great potential in cancer therapy. There are >600 E3 ubiquitin ligases in humans, many of which can be used to design PROTACs (Ottis P. et al., ACS ChemBiol. 2017, 12(10), 2570-8). Success in this area, along with a greater understanding of the function and tissue-specific expression of these E3s, could greatly broaden the feasibility, practicality, and selectivity of PROTAC technology. Summary of the Invention

[0012] The first aspect of the present invention relates to a compound of chemical formula (A):

[0013]

[0014] and its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers,

[0015] in:

[0016] Each X is independently selected from N and CH;

[0017] Y is selected from -NR5C(O)NR5- and -NR5C(O)-;

[0018] Ring A is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups;

[0019] Ring B is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups;

[0020] The ring C is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups;

[0021] M is selected from -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-;

[0022] L1 and L2 are independently selected from bonds, C1-C1 bonds, and C2-C2 bonds, respectively. 12 Alkyl, C2-C 12 alkendiyl, C2-C 12 Alkyne diyl, C3-C8 cycloalkyl diyl, C3-C8 cycloalkyl diyl-(CH2) p -、C1-C 12 Alkoxyalkenyl, -((CH2) 1-6 O) o -(CH2) p -、-((CH2) 1-6 O) o -(CH2) p -NH-、-((CH2) 1-6 O) o -(CH2) p -NH-C(O)- and -((CH2)- 1-6 O) o -(CH2) p -C(O)-NH-; or

[0023] M and L2 together form a bond; or

[0024] L1-M-L2 is a bond;

[0025] L3 and L4 are independently selected from bonds, C1-C1 bonds, and C2-C3 bonds, respectively. 12 Alkyl, C2-C 12 alkendiyl, C2-C 12 alkynyl diol, C1-C 12 Alkoxyalkenyl, -((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-;

[0026] 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R1 groups. 11 replace;

[0027] Each of R2, R3, and R9 is independently selected from hydrogen, halogen, -OH, -CN, -NO2, and -NR. 12 R 13 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 Replace; or

[0028] Both R3 values ​​are equal to 0;

[0029] Each R4, R6, R7 and R 10 Independently selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 12 R 13C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace;

[0030] Each R5 is independently selected from hydrogen and C1-C6 alkyl groups;

[0031] R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R groups. 11 replace;

[0032] Each R 11 Independently selected from halogens, -OH, -CN, -NO2, -NR 12 R 13 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic and heteroaryl;

[0033] Each R L Independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

[0034] R 12 and R 13 Each of the following is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclic, and heteroaryl; and

[0035] g is an integer selected from 0, 1, and 2;

[0036] m and n are integers independently selected from 0, 1, 2 and 3, respectively;

[0037] o is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0038] Each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0039] t is an integer selected from 0 and 1;

[0040] u is an integer selected from 0, 1, and 2;

[0041] w is an integer selected from 0, 1, and 2;

[0042] The condition is that if t is 0, then L4 is a key;

[0043] The condition is that at least one of L3 and L4 is not a key.

[0044] in,

[0045] Cycloalkyl groups are saturated or partially saturated C3-C. 10 Single ring, C5-C 18 Double ring (fused, bridged, or screw) or C6-C 18 Three-ring (fused, bridged, or spiral) ring system;

[0046] Aryl groups are cyclic aromatic hydrocarbon systems comprising one to three aromatic rings;

[0047] The heterocyclic group is a saturated or partially saturated 3-10 member monocyclic, 7-12 member bicyclic (fused, bridged or spirocyclic) or 11-14 member tricyclic (fused, bridged or spirocyclic) ring system containing 1-7 heteroatoms selected from O, N, S, P, Se or B.

[0048] Heteroaryl is a monovalent monocyclic or polycyclic aromatic ring system containing 5 to 24 ring atoms, wherein 1 to 7 ring atoms are heteroatoms selected from N, O, S, P or B, and the remaining ring atoms are C.

[0049] Another aspect of the invention relates to compounds of chemical formula (I):

[0050]

[0051] and its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers,

[0052] in:

[0053] Each X is independently selected from N and CH;

[0054] Y is selected from -NR5C(O)NR5- and -NR5C(O)-;

[0055] Ring A is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups;

[0056] Ring B is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups;

[0057] M is selected from -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 LSO2-, -O-, -OC(O)-, -OC(O)NR L -、-OC(O)O-、-S(O)2NR L -、-S- and -S(O)2-;

[0058] L1 and L2 are independently selected from bonds, C1-C1 bonds, and C2-C2 bonds, respectively. 12 Alkyl, C2-C 12 alkendiyl, C2-C 12 Alkyne diyl, C3-C8 cycloalkyl diyl, C3-C8 cycloalkyl diyl-(CH2) p -、C1-C 12 Alkoxyalkenyl and -((CH2) 1-6 O) o -(CH2) p -、-((CH2) 1-6 O) o -(CH2) p -NH-、-((CH2) 1-6 O) o -(CH2) p -NH-C(O)- and -((CH2)- 1-6 O) o -(CH2) p -C(O)-NH-; or

[0059] M and L2 together form a bond; or

[0060] L1-M-L2 is a bond;

[0061] L3 and L4 are independently selected from bonds, C1-C1 bonds, and C2-C3 bonds, respectively. 12 Alkyl alkenyl, C2-C 12 alkenyl alkenyl, C2-C 12 alkynyl alkenyl, C1-C 12 Alkoxyalkenyl, -((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-;

[0062] 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R1 groups. 11 replace;

[0063] Each of R2, R3, and R9 is independently selected from hydrogen, halogen, -OH, -CN, -NO2, and -NR. 12 R 13 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 Replace; or

[0064] Two R3s form = O;

[0065] Each R4, R6, R7 and R 10 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace;

[0066] Each R5 is independently selected from hydrogen and C1-C6 alkyl groups;

[0067] R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R groups. 11 replace;

[0068] Each R 11 Independently selected from halogens, -OH, -CN, -NO2, -NR 12 R 13 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic and heteroaryl;

[0069] Each R L Independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

[0070] R 12 and R 13 Each of the following is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclic, and heteroaryl; and

[0071] m and n are integers independently selected from 0, 1, 2 and 3, respectively;

[0072] o is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0073] Each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0074] t is an integer selected from 0 and 1;

[0075] u is an integer selected from 0, 1, and 2;

[0076] w is an integer selected from 0, 1, and 2;

[0077] The condition is that if t is 0, then L4 is a key;

[0078] The condition is that at least one of L3 and L4 is not a key.

[0079] in,

[0080] Cycloalkyl groups are saturated or partially saturated C3-C. 10 Single ring, C5-C 18 Double ring (fused, bridged, or screw) or C6-C 18 Three-ring (fused, bridged, or spiral) ring system;

[0081] Aryl groups are cyclic aromatic hydrocarbon groups having one to three aromatic rings;

[0082] Heterocyclic groups are saturated or partially unsaturated 3-10 member monocyclic, 7-12 member bicyclic (fused, bridged or spirocyclic) or 11-14 member tricyclic (fused, bridged or spirocyclic) ring systems, having 1-7 heteroatoms selected from O, N, S, P, Se or B;

[0083] Heteroaryl groups are monovalent monocyclic or polycyclic aryl groups with 5 to 24 ring atoms, containing 1 to 7 heteroatoms selected from N, O, S, P or B, with the remaining ring atoms being C.

[0084] Another aspect of the invention relates to compounds of chemical formula (II):

[0085]

[0086]

[0087] and its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers,

[0088] in:

[0089] Each X is independently selected from N and CH;

[0090] Y is selected from -NR5C(O)NR5- and -NR5C(O)-;

[0091] Ring A is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups;

[0092] Ring B is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups;

[0093] M is selected from -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-;

[0094] L1 and L2 are independently selected from bonds, C1-C1 bonds, and C2-C2 bonds, respectively. 12 Alkyl, C2-C 12 alkendiyl, C2-C 12 Alkyne diyl, C3-C8 cycloalkyl diyl, C3-C8 cycloalkyl diyl-(CH2) p -、C1-C 12 Alkoxyalkenyl, -((CH2) 1-6 O) o -(CH2) p -、-((CH2) 1-6 O) o -(CH2) p -NH-、-((CH2) 1-6 O) o -(CH2) p -NH-C(O)- and -((CH2)- 1-6 O) o -(CH2) p-C(O)-NH-; or

[0095] M and L2 together form a bond; or

[0096] L1-M-L2 is a bond;

[0097] L3 and L4 are independently selected from bonds, C1-C1 bonds, and C2-C3 bonds, respectively. 12 Alkyl alkenyl, C2-C 12 alkendiyl, C2-C 12 alkynyl diol, C1-C 12 Alkoxyalkenyl, -((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-;

[0098] 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R1 groups. 11 replace;

[0099] Each of R2 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace;

[0100] R4, R6, R7 and R 10 Each of these elements 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace;

[0101] Each R5 is independently selected from hydrogen and C1-C6 alkyl groups;

[0102] R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R groups. 11 replace;

[0103] Each R 11 Independently selected from halogens, -OH, -CN, -NO2, -NR 12 R 13 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic and heteroaryl;

[0104] Each R L Independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

[0105] R 12 and R 13 Each of the following is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclic, and heteroaryl; and

[0106] m and n are integers independently selected from 0, 1, 2 and 3, respectively;

[0107] o is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0108] Each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0109] t is an integer selected from 0 and 1;

[0110] u is an integer selected from 0, 1, and 2;

[0111] w is an integer selected from 0, 1, and 2;

[0112] The condition is that if t is 0, then L4 is a key;

[0113] The condition is that at least one of L3 and L4 is not a key.

[0114] in,

[0115] Cycloalkyl groups are saturated or partially saturated C3-C. 10 Single ring, C5-C 18 Double ring (fused, bridged, or screw) or C6-C 18 Three-ring (fused, bridged, or spiral) ring system;

[0116] Aryl groups are cyclic aromatic hydrocarbon systems comprising one to three aromatic rings;

[0117] The heterocyclic group is a saturated or partially saturated 3-10 member monocyclic, 7-12 member bicyclic (fused, bridged, or spirocyclic), or 11-14 member tricyclic (fused, bridged, or spirocyclic) ring system containing 1-7 heteroatoms selected from O, N, S, P, Se, or B.

[0118] Heteroaryl is a monovalent monocyclic or polycyclic aromatic ring system containing 5 to 24 ring atoms, of which 1 to 7 ring atoms are heteroatoms selected from N, O, S, P or B, and the remaining ring atoms are C.

[0119] Another aspect of the invention relates to pharmaceutical compositions comprising a compound of formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, a diluent, or a surfactant.

[0120] Another aspect of the invention relates to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, a diluent, or a surfactant.

[0121] Another aspect of the invention relates to pharmaceutical compositions comprising a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, a diluent, or a surfactant.

[0122] Another aspect of the invention relates to a method for treating a disease or condition associated with MALT1. The method comprises administering to a patient requiring treatment for a disease or condition associated with MALT1 an effective amount of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0123] Another aspect of the invention relates to a method for treating a disease or condition associated with MALT1. The method comprises administering to a patient requiring treatment for a disease or condition associated with MALT1 an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0124] Another aspect of the invention relates to a method for treating a disease or condition associated with MALT1. The method comprises administering to a patient requiring treatment for a disease or condition associated with MALT1 an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0125] Another aspect of the invention relates to a method for the degradation of MALT1. The method comprises administering to a patient in need an effective amount of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0126] Another aspect of the invention relates to a method for the degradation of MALT1. The method comprises administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0127] Another aspect of the invention relates to a method for the degradation of MALT1. The method comprises administering to a patient in need an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0128] Another aspect of the present invention relates to a compound of chemical formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof for the production of an agent for the degradation of MALT1.

[0129] Another aspect of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof for the production of an agent for the degradation of MALT1.

[0130] Another aspect of the present invention relates to compounds of chemical formula (II) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers or pharmaceutical compositions thereof for the production of agents for the degradation of MALT1.

[0131] Another aspect of the invention relates to the use of a compound of chemical formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the treatment of diseases associated with MALT1.

[0132] Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the treatment of diseases associated with MALT1.

[0133] Another aspect of the 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.

[0134] Another aspect of the present invention relates to a compound of chemical formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof for use in the production of a medicament for the treatment or prevention of the diseases or conditions disclosed herein.

[0135] Another aspect of the present invention relates to a compound of chemical formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof for use in the production of a medicament for the treatment or prevention of the diseases or conditions disclosed herein.

[0136] Another aspect of the present invention relates to compounds of formula (II) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers or pharmaceutical compositions thereof, for use in the production of medicaments for the treatment or prevention of the diseases or conditions disclosed herein.

[0137] Another aspect of the invention relates to a method for treating or preventing a disease or condition disclosed herein in a subject in need of treatment. 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.

[0138] Another aspect of the invention relates to a method for treating or preventing a disease or condition disclosed herein in a subject in need of treatment. The method comprises administering to a patient in need of treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0139] Another aspect of the invention relates to a method for treating or preventing a disease or condition disclosed herein in a subject in need of treatment. The method comprises administering to a patient in need of treatment an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0140] Another aspect of the invention relates to the use of a compound of chemical formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the treatment of the diseases or conditions disclosed herein.

[0141] Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the treatment of the diseases or conditions disclosed herein.

[0142] Another aspect of the 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 the diseases or conditions disclosed herein.

[0143] The present invention also provides a method for treating diseases or conditions associated with MALT1, comprising administering to a patient suffering from at least one of said diseases or conditions a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0144] The present invention also provides a method for treating diseases or conditions associated with MALT1, comprising administering to a patient suffering from at least one of said diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0145] The present invention also provides a method for treating diseases or conditions associated with MALT1, comprising administering to a patient suffering from at least one of said diseases or conditions a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0146] The present invention provides a PROTAC of MALT1 as a therapeutic agent in the treatment of diseases or conditions.

[0147] The present invention also provides compounds and compositions that have improved potency and safety profiles relative to known MALT1 PROTAC.

[0148] The present invention also provides a method for treating diseases or conditions associated with MALT1, comprising administering to a patient suffering from at least one of said diseases or conditions a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0149] The present invention also provides a method for treating diseases or conditions associated with MALT1, comprising administering to a patient suffering from at least one of said diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0150] The present invention also provides a method for treating diseases or conditions associated with MALT1, comprising administering to a patient suffering from at least one of said diseases or conditions a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0151] The present invention provides a PROTAC of MALT1 as a therapeutic agent in the treatment of diseases or conditions.

[0152] The present invention also provides a method for treating diseases, conditions or illnesses selected from: immunodeficiency type 12; mucosa-associated lymphoid lymphoma (MALTOMA); combined immunodeficiency; combined T-cell and B-cell immunodeficiency; or lymphoma, comprising administering to a patient suffering from at least one of said diseases or conditions a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0153] The present invention also provides a method for treating diseases, conditions or illnesses selected from: immunodeficiency type 12; mucosa-associated lymphoid lymphoma (MALTOMA); combined immunodeficiency; combined T-cell and B-cell immunodeficiency; or lymphoma, comprising administering to a patient suffering from at least one of said diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0154] The present invention also provides a method for treating diseases, conditions or illnesses selected from: immunodeficiency type 12; mucosa-associated lymphoid lymphoma (MALTOMA); combined immunodeficiency; combined T-cell and B-cell immunodeficiency; or lymphoma, comprising administering to a patient suffering from at least one of said diseases or conditions a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0155] In some aspects, this disclosure provides compounds that are obtainable or acquireable by methods for preparing the compounds described herein (e.g., methods comprising one or more steps described in the section entitled "Routine Procedure").

[0156] In some aspects, this disclosure provides intermediates as described herein suitable for use in methods for preparing compounds as described herein (e.g., the intermediates are selected from those described in the Synthesis Methods section of this disclosure).

[0157] In some respects, this disclosure provides methods for preparing the compounds of this disclosure.

[0158] In some aspects, this disclosure provides methods for preparing the compounds of this disclosure, which include one or more steps described herein.

[0159] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Unless the context clearly requires, the singular form also includes the plural form in the specification. Although similar or equivalent methods and materials to those described herein may be used in practice or testing of this disclosure, suitable methods and materials are described below. All patent publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety for all purposes. In case of conflict, this specification, including its definitions, shall prevail. Furthermore, the materials, methods, and examples described are illustrative only and are not intended to be limiting. In case of conflict between the chemical structures and names of compounds disclosed herein, the chemical structure shall prevail.

[0160] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. Attached Figure Description

[0161] Figure 1 A bar chart is provided showing the PROTAC activity of compounds 10, 12, and 13 of this disclosure against MALT1, compared to reference compounds 1 and 2, under the experimental conditions provided in Example C; and

[0162] Figure 2 A bar chart is provided showing the PROTAC activity of compounds 14, 16 and 17 of this disclosure against MALT1, compared with reference compound 3, under the experimental conditions provided in Example C. Detailed Implementation

[0163] This disclosure provides a method for treating, preventing, or improving a disease or condition related to MALT1 by administering a therapeutically effective amount of a compound as disclosed herein to a subject in need.

[0164] Detailed information about this disclosure is set forth in the following description. While similar or equivalent methods and materials to those described herein may be used in the practice or testing of this disclosure, illustrative methods and materials are described here. Other features, objectives, and advantages of this disclosure will be apparent from the description and the claims. Unless the context clearly requires, the singular form also includes the plural form in the specification and appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents and patent disclosures referenced in this specification are incorporated herein by reference in their entirety.

[0165] definition

[0166] The articles “a” and “an” are used in this disclosure to indicate one or more (i.e., at least one) grammatical objects of the articles. For example, “an element” means one element or more.

[0167] Unless otherwise stated, the term “and / or” is used in this disclosure to mean either “and” or “or”.

[0168] The term "optionally substituted" should be understood to mean that a given chemical moiety (e.g., alkyl) may (but does not need to) bond with 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 be bonded 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 has the potential to contain other functional groups, but is not required to have any other functional groups. Suitable substituents used in the optional substitution of the said group include, without limitation, halogens, oxygen, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, -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, -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 substituent itself may be optionally substituted. As used herein, "optionally substituted" refers to substituted or unsubstituted material, as defined below.

[0169] As used herein, the term "substituted" means that a particular group or portion has one or more suitable substituents, which may be attached to the particular group or portion at one or more positions. For example, an aryl group substituted with a cycloalkyl group may mean that the cycloalkyl group is attached to an atom of the aryl group by a bond or by fusion with the aryl group to share two or more common atoms.

[0170] As used herein, the term “unsubstituted” means that a particular group does not have substituents.

[0171] Unless otherwise explicitly defined, the term "aryl" refers to a cyclic aromatic hydrocarbon having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may optionally be substituted with one or more substituents at any connection point, for example, substituted with one to five 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)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, -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 substituent itself may be optionally substituted. Furthermore, when containing two fused rings, the aryl group as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include (but are not limited to) phenyl, biphenyl, naphthyl, anthraceneyl, phenalenyl, phenanthyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoxenyl, etc.

[0172] Unless otherwise explicitly defined, “heteroaryl” means a monovalent monocyclic or polycyclic aryl group having 5 to 24 ring atoms, containing one or more cyclic heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. Polycyclic aryl groups include two or more fused rings and may further include two or more spirofused rings, such as bicyclic, tricyclic, tetracyclic, etc. Unless otherwise explicitly defined, “fused” means two rings sharing two ring atoms. Unless otherwise explicitly defined, “spirofused” means two rings sharing one ring atom. Heteroaryl as defined herein also means a bicyclic heteroaryl group, wherein the heteroatom is selected from N, O, S, P, or B. Heteroaryl as defined herein also means a tricyclic heteroaryl group containing one or more cyclic heteroatoms selected from N, O, S, P, or B. Heteroaryl as defined herein also means a tetracyclic heteroaryl group containing one or more cyclic heteroatoms selected from N, O, S, P, or B. The aryl group may optionally be independently substituted by one or more substituents described herein.Examples include (but are not limited to) furanyl, thiophene, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazoleyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indoleyl, thiophene-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furan[2,3-c]pyridyl, imidazo[1,2-a]pyridyl, indazoleyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thiophene[3,2-c]pyridyl, thiophene Pheno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indolyl, dihydroindolyl, indololinone, dihydrobenzothiophene, dihydrobenzofuranyl, benzofuran, benzodihydropyranyl, thio-chromiumyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinazolyl, 1,6-naphthidyl, benzo[de]isoquinazolyl, pyrido[4,3-b][1,6]naphthidyl, thieno[2,3-b]pyrazinyl, quinazolyl, tetrazo[1,5-a]pyridyl, [1,2,4]triazol[4,3-a]pyridyl, isozanoindyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4- [b]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidinyl, dibenzo[b,d]thiophene, pyridin-2-one, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzoisoxazolyl, furano[2,3-b]pyridyl, benzothiophene, 1,5-naphthidyl, furano[3,2-b]pyridine, [1,2,4]triazol[1,5] -a]pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazol[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, thiazo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrroleyl, 3H-indolyl and their derivatives. Furthermore, when containing two or more fused rings, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings.In heteroaryl ring systems containing two or more fused rings, saturated or partially unsaturated rings may be further fused with saturated or partially unsaturated rings as described herein. Furthermore, when containing three or more fused rings, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated spirofused rings. Any saturated or partially unsaturated ring described herein may optionally be substituted with one or more oxygen atoms. Exemplary ring systems of these heteroaryl groups include, for example, dihydroindolyl, indololinone, dihydrobenzothiophene, dihydrobenzofuran, benzodihydropyranyl, thio-chromiumyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinazolyl, 2,3-dihydrobenzofuranyl, benzofuranone, dihydroindolyl, hydroxyindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolazinyl, 8H-pyrido[3,2-b]pyrrolazinyl, 1,5,6,7-tetrahydrocyclopentane[b]pyrazolo[4,3-e ]pyridyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizine, pyrazolo[1,5-a]pyrimidin-7(4H)-keto, 3,4-dihydropyrazolo[1,2-a]indole-1(2H)-keto, benzo[c][1,2]oxaborphane-1(3H)-keto, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-keto or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9'-keto.

[0173] Halogens, or "halogenated" halogens, refer to fluorine, chlorine, bromine, or iodine.

[0174] Alkyl groups are 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.

[0175] "Alkoxy" refers to a straight-chain or branched saturated hydrocarbon containing 1-12 carbon atoms, i.e., -O (alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.

[0176] "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 the chain. The double bond in an alkenyl group can be non-conjugated or conjugated with another unsaturated group. Examples of alkenyl groups include vinyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. Alkenyl groups can be unsubstituted or substituted. As defined herein, alkenyl groups can be straight-chain or branched.

[0177] "Alynyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An alkynyl group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, pentyynyl, or hexynyl. Alynyl groups can be unsubstituted or substituted.

[0178] The term "alkylene" or "alkylene" refers to a divalent alkyl group. Any of the above-mentioned monovalent alkyl groups can become alkylene groups by abstracting a second hydrogen atom from the alkyl group. As defined herein, alkylene groups can also be C1-C6 alkylene groups. Alkylene groups can also be C1-C4 alkylene groups. Typical alkylene groups include (but are not limited to) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0179] The term "alkoxyalkenyl" refers to a divalent alkoxy group. Any of the above-mentioned monovalent alkoxy groups can become alkoxyalkenyl groups 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.

[0180] “Cycloalkyl” means a monocyclic or polycyclic saturated or partially unsaturated carbon ring containing 3 to 18 carbon atoms. A polycyclic cycloalkyl group can be a fused bicyclic cycloalkyl group, a bridged bicyclic cycloalkyl group, or a spirofused bicyclic cycloalkyl group. A polycyclic cycloalkyl group contains at least one non-aromatic ring. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norbornenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclic[1.1.1]pentyl, bicyclic[2.2.2]octyl, or bicyclic[2.2.2]octenyl.

[0181] "Heterocyclic group," "heterocycle," or "heterocyclic alkyl" is a monocyclic or polycyclic compound containing 3-24 atoms, comprising a carbon atom and one or more heteroatoms selected from N, O, S, P, or B, wherein the ring is not aromatic. The ring structure of a heterocyclic alkyl group can be substituted by one or more substituents. The substituents themselves may be optionally substituted. Examples of heterocyclic rings include (but are not limited to) oxobutyranyl, aziroxybutyranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolinyl, thiazolinyl, thiazolinyl, pyranyl, thiaranyl, tetrahydropyranyl, dioxopranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazine, aziroxy, oxazolinyl, diaziroxy, hyoscyamine, oxazolidinone, and homohyoscyamine.

[0182] The term "aromatic" refers to a planar ring with 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a system of connected p orbitals with delocalized electrons, and this system may include lone pairs.

[0183] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens as defined herein. Examples of haloalkyl groups include (but are not limited to) trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0184] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens as defined herein. Examples of halogenated alkyl groups include (but are not limited to) trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0185] As used herein, the term "cyano" refers to a substituent that connects a carbon atom to a nitrogen atom via a triple bond, i.e., C≡N.

[0186] "Spirocycloalkyl" or "spirocycloyl" refers to a carbon bicyclic system in which two rings are linked by a single atom. The rings may differ in size and properties, or be identical in size and properties. Examples include spiropentane, spirohexane, spiroheptane, spiroctane, spirononane, or spirodecane. One or both rings of the spirocyclic ring may be fused to another ring of carbon, heterocyclic, aromatic, or heteroaromatic rings. One or more carbon atoms in the spirocyclic ring may be substituted with heteroatoms (e.g., O, N, S, or P). (C3-C) 12 Spirocycloalkyl groups are spirocyclic rings containing 3 to 12 carbon atoms. One or more carbon atoms may be replaced by heteroatoms.

[0187] The terms “spiroheteroalkyl”, “spiroheterocyclic” or “spiroheterocyclic group” should be understood to mean a spirocycle in which at least one ring is a heterocycle (e.g., at least one ring is furanyl, morpholinyl or piperidinyl).

[0188] The term "solvent" refers to a complex of variable stoichiometry formed by a solute and a solvent. These solvents used for the purposes of this disclosure should not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is a solvent molecule are generally referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0189] 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 lie in their configuration (geometric isomers) or ability to rotate the plane of polarization (stereoisomers). In the case of stereoisomers, compounds represented by chemical formula (I) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0190] This disclosure also considers isotopically labeled compounds of formula I (e.g., using...). 2 H and 14 Those marked with C). Deuteration (i.e. 2 H or D) and carbon-14 (i.e., H or D) and carbon-14 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium, can provide certain therapeutic advantages stemming from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and is therefore preferred in some cases. Isotopically labeled compounds of Formula I can generally be prepared by substituting non-isotopically labeled reagents with appropriately isotopically labeled reagents, following procedures similar to those disclosed in the schemes and / or examples below.

[0191] This disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier. Representative “pharmaceutically acceptable salts” include, for example, water-soluble and water-insoluble salts such as acetates, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium, calcium ethylenediaminetetraacetate, dextrorotatory camphor sulfonate, carbonates, chlorides, citrates, clavulanates, dihydrochlorides, ethylenediaminetetraacetate, ethanedisulfonate, propionate lauryl sulfate, ethanesulfonate, fumarate, gluconate, gluconate, glutamate, glycolyl-p-aminobenzoarsine, hexafluorophosphate, hexylresorcinol, halogen, hydrobromide, etc. Hydrochloride, hydroxynaphthylcarboxylate, iodide, isothiosulfate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalene sulfonate, nitrate, N-methylglucosamine ammonium salt, 3-hydroxy-2-naphthylcarboxylate, oleate, oxalate, palmitate, dihydroxynaphthylcarboxylate, pantothenate, phosphate / bisphosphate, picrate, polygalacturonic acid ester, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, tannin, tartrate, theochloroate, toluenesulfonate, triethyliodide, and valerate.

[0192] "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0193] When used in combination with a compound, an “effective amount” is an amount that is effective for treating or preventing a disease in a subject as described in this article.

[0194] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents and refers to a material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in the delivery or transport of a drug from one organ or part of the body to another organ or part of the body of a subject.

[0195] In the context of a subject, the term "treatment" refers to the improvement of at least one symptom of the subject's condition. Treatment includes curing, improving, or at least partially alleviating the condition.

[0196] Unless otherwise stated, the term “symptom” is used in this disclosure to mean the term disease, condition or illness and is used interchangeably with disease, condition or illness.

[0197] As used in this disclosure, the term "administer" refers to the direct administration of the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound to a subject, or the administration of a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt or composition of the compound to a subject, which may form an equivalent amount of the active compound in the subject's body.

[0198] As used in this disclosure, the term "prodrug" refers to a compound that can be converted into the disclosed compound in vivo through metabolism (e.g., by hydrolysis).

[0199] The term "salt" refers to a pharmaceutically acceptable salt.

[0200] The term "pharmaceutically acceptable salt" also refers to a salt of the composition of this disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.

[0201] As used herein, “PROTAC of MALT1” refers to a compound of formula I and / or a composition containing a compound of formula I that degrades MALT1.

[0202] The amount of compounds in the compositions described herein required to achieve a therapeutic effect may be empirically determined according to routine procedures for a particular purpose. Generally, for therapeutic purposes, a pharmacologically effective dose is provided for the administration of a therapeutic agent (e.g., a compound or composition of Formula I described herein (and / or other agents)). "Pharmacologically effective dose," "pharmacologically effective amount," "therapeuticly effective amount," or "effective amount" means an amount sufficient to produce the desired physiological effect or to achieve the desired result, particularly for the treatment of a condition or disease. As used herein, an effective amount will include an amount sufficient to, for example, delay the development of symptoms of a condition or disease, alter the course of symptoms of a condition or disease (e.g., slow the development of symptoms of a disease), alleviate or eliminate one or more symptoms or manifestations of a condition or disease, and reverse the symptoms of a condition or disease. For example, administration of a therapeutic agent to a subject with cancer provides therapeutic benefit not only when the underlying condition is eradicated or improved, but also when the subject reports a reduction in the severity or duration of disease-related symptoms (e.g., reduced tumor burden, reduced circulating tumor cells, prolonged progression-free survival). Therapeutic benefits also include stopping or slowing the development of the underlying disease or condition, regardless of whether improvement is achieved.

[0203] The compounds disclosed herein

[0204] In one aspect, this disclosure provides compounds of chemical formula (A) and their salts, stereoisomers, solvates, prodrugs, isotope derivatives, and tautomers:

[0205]

[0206] Among them, 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 are as described in this article.

[0207] It should be understood that, for compounds of chemical formula (A), when applicable, 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 selected from the groups described herein, and where applicable, this text applies to R1, R2, C, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, and R... 10 Any group of any of X, g, m, n, t, u, and w can be used in conjunction with the present document for R1, R2, C, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 Any combination of one or more of the remaining parts of X, g, m, n, t, u, and w.

[0208] In some embodiments, this disclosure provides compounds of formula (I), and their salts, stereoisomers, solvates, prodrugs, isotope derivatives, and tautomers:

[0209]

[0210] Among them, 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 in this article.

[0211] It should be understood that, for compounds of chemical formula (I), when applicable, 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 selected from the groups described herein, and where applicable, this text applies to R1, R2, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, and R... 10 Any group of any of X, m, n, t, u, and w can be used in conjunction with the present document for R1, R2, R3, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10Any combination of one or more of the remaining parts of X, m, n, t, u, and w.

[0212] In some embodiments, this disclosure provides compounds of formula (II), and their salts, stereoisomers, solvates, prodrugs, isotope derivatives, and tautomers:

[0213]

[0214] Among them, 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 in this article.

[0215] It should be understood that, for compounds of chemical formula (I), when applicable, 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 selected from the groups described herein, and where applicable, this text applies to R1, R2, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, and R... 10 Any group of any of X, m, n, t, u, and w can be used in conjunction with the present document for R1, R2, R4, Y, L1, M, L2, A, R6, L3, B, R7, L4, R8, R9, R 10 Any combination of one or more of the remaining parts of X, m, n, t, u, and w.

[0216] Among some compounds with the structure of chemical formula (A),

[0217] Each X is independently selected from N and CH;

[0218] Y is selected from -NR5C(O)NR5- and -NR5C(O)-;

[0219] Ring A is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups;

[0220] Ring B is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups;

[0221] The ring C is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups;

[0222] M is selected from -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-;

[0223] L1 and L2 are independently selected from bonds, C1-C1 bonds, and C2-C2 bonds, respectively. 12 Alkyl, C2-C 12 alkendiyl, C2-C 12 Alkyne diyl, C3-C8 cycloalkyl diyl, C3-C8 cycloalkyl diyl-(CH2) p -、C1-C 12 Alkoxyalkenyl, -((CH2) 1-6 O) o -(CH2) p -、-((CH2) 1-6 O) o -(CH2) p -NH-、-((CH2) 1-6 O) o -(CH2) p -NH-C(O)- and -((CH2)- 1-6 O) o -(CH2) p -C(O)-NH-; or

[0224] M and L2 together form a bond; or

[0225] L1-M-L2 is a bond;

[0226] L3 and L4 are independently selected from bonds, C1-C1 bonds, and C2-C3 bonds, respectively. 12 Alkyl, C2-C 12 alkendiyl, C2-C 12 alkynyl diol, C1-C 12 Alkoxyalkenyl, -((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)2NRL -、-S- and -S(O)2-;

[0227] 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R1 groups. 11 replace;

[0228] Each of R2, R3, and R9 is independently selected from hydrogen, halogen, -OH, -CN, -NO2, and -NR. 12 R 13 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups are optionally separated by one or more R 11 Replace; or

[0229] Both R3 values ​​are equal to 0;

[0230] Each R4, R6, R7 and R 10 Independently selected from halogens, -OH, -CN, -NO2, -NR 12 R 13 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace;

[0231] Each R5 is independently selected from hydrogen and C1-C6 alkyl groups;

[0232] R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R groups. 11 replace;

[0233] Each R 11 Independently selected from halogens, -OH, -CN, -NO2, -NR 12 R 13C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic and heteroaryl;

[0234] Each R L Independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

[0235] R 12 and R 13 Each of the following is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclic, and heteroaryl; and

[0236] g is an integer selected from 0, 1, and 2;

[0237] m and n are integers independently selected from 0, 1, 2 and 3, respectively;

[0238] o is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0239] Each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0240] t is an integer selected from 0 and 1;

[0241] u is an integer selected from 0, 1, and 2;

[0242] w is an integer selected from 0, 1, and 2;

[0243] The condition is that if t is 0, then L4 is a key;

[0244] The condition is that at least one of L3 and L4 is not a bond.

[0245] In some embodiments, ring A is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups.

[0246] 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 heterocyclic group. In some embodiments, ring A is a heteroaryl group.

[0247] In some implementations, each X is independently selected from N or CH.

[0248] In some implementations, at least one of the two X's is nitrogen.

[0249] In some implementations, one X is N and the other X is CH.

[0250] In some implementations, both X are N. In some implementations, both X are CH.

[0251] In some embodiments, ring A is a cycloalkyl group.

[0252] In some implementations, ring A is C 3- C 12 Cycloalkyl.

[0253] In some embodiments, ring A is a C3-C8 monocyclic cycloalkyl group.

[0254] In some implementations, ring A is

[0255] In some implementations, ring A is

[0256] In some implementations, ring A is

[0257] In some implementations, ring A is

[0258] In some implementations, ring A is fused C. 3- C 12 Bicyclic cycloalkyl. In some embodiments, ring A is a bridged C. 3- C 12 Bicyclic cycloalkyl. In some embodiments, ring A is a spirofused C 3- C 12 Bicyclic cycloalkyl.

[0259] In some implementations, ring A is an aryl group.

[0260] In some implementations, ring A is C6-C. 10 Aryl.

[0261] In some implementations, ring A is

[0262] In some implementations, ring A is

[0263] In some implementations, ring A is

[0264] In some implementations, ring A is

[0265] In some implementations, ring A is a heterocyclic group.

[0266] In some implementations, ring A is a 3-10 member heterocyclic group.

[0267] In some implementations, ring A is a 3-membered heterocyclic group.

[0268] In some embodiments, ring A is a 3-membered heterocyclic group containing one heteroatom selected from O and N.

[0269] In some implementations, ring A is a 4-membered heterocyclic group.

[0270] In some embodiments, ring A is a 4-membered heterocyclic group containing one or two heteroatoms, each heteroatom being independently selected from N, O, and S.

[0271] In some implementations, ring A is a 5-membered heterocyclic group.

[0272] In some embodiments, ring A is a 5-membered heterocyclic group containing one or two heteroatoms, each heteroatom being independently selected from N, O, and S.

[0273] In some implementations, ring A is a 6-membered heterocyclic group.

[0274] In some embodiments, ring A is a 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms, each heteroatom being independently selected from N, O, and S.

[0275] In some implementations, ring A is a 7-membered heterocyclic group.

[0276] In some embodiments, ring A is a 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms, each heteroatom being independently selected from N, O, and S.

[0277] In some implementations, ring A is

[0278] In some implementations, ring A is

[0279] In some implementations, ring A is

[0280] In some implementations, ring A is

[0281] In some implementations, ring A is

[0282] In some implementations, ring A is

[0283] In some implementations, ring A is

[0284] In some implementations, ring A is

[0285] In some implementations, ring A is

[0286] In some implementations, ring A is

[0287] In some implementations, ring A is a heteroaryl group.

[0288] In some implementations, ring A is a 5-membered heteroaryl group.

[0289] In some embodiments, ring A is a 5-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms, each heteroatom being independently selected from N, O and S.

[0290] In some implementations, ring A is a 6-membered heteroaryl group.

[0291] In some embodiments, ring A is a 6-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms, each heteroatom being independently selected from N, O and S.

[0292] In some implementations, ring A is selected from...

[0293] In some implementations, ring A is

[0294] In some implementations, ring A is

[0295] In some implementations, ring A is

[0296] In some implementations, ring A is

[0297] In some implementations, ring A is

[0298] In some implementations, ring A is

[0299] In some implementations, ring A is

[0300] In some implementations, ring A is

[0301] In some implementations, ring A is

[0302] In some implementations, ring A is

[0303] In some embodiments, ring B is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups.

[0304] 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 heterocyclic group. In some embodiments, ring B is a heteroaryl group.

[0305] In some implementations, t is 0. In some implementations, t is 1.

[0306] In some implementations, t is 0.

[0307] In some implementations, t is 1.

[0308] In some implementations, ring B is optionally bounded by one or more R... 11 Substituted cycloalkyl groups.

[0309] In some embodiments, ring B is a cycloalkyl group.

[0310] In some implementations, ring B is C 3- C 12 Cycloalkyl.

[0311] In some embodiments, ring B is a C3-C8 monocyclic cycloalkyl group.

[0312] In some implementations, ring B is

[0313] In some implementations, ring B is

[0314] In some implementations, ring B is

[0315] In some implementations, ring B is

[0316] In some implementations, ring B is fused with C. 3- C 12 Bicyclic cycloalkyl. In some embodiments, ring B is a bridged C. 3- C 12 Bicyclic cycloalkyl. In some embodiments, ring B is spirofused C. 3- C 12 Bicyclic cycloalkyl.

[0317] In some implementations, ring B is an aryl group.

[0318] In some implementations, ring B is C6-C. 10 Aryl.

[0319] In some implementations, ring B is

[0320] In some implementations, ring B is

[0321] In some implementations, ring B is a heterocyclic group.

[0322] In some implementations, ring B is a 3-membered heterocyclic group.

[0323] In some embodiments, ring B is a 3-membered heterocyclic group containing one heteroatom selected from O and N.

[0324] In some implementations, ring B is a 4-membered heterocyclic group.

[0325] In some embodiments, ring B is a 4-membered heterocyclic group containing one or two heteroatoms, each heteroatom being independently selected from N, O, and S.

[0326] In some implementations, ring B is a 5-membered heterocyclic group.

[0327] In some embodiments, ring B is a 5-membered heterocyclic group containing one or two heteroatoms, each heteroatom being independently selected from N, O, and S.

[0328] In some implementations, ring B is a 6-membered heterocyclic group.

[0329] In some embodiments, ring B is a 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms, each heteroatom being independently selected from N, O, and S.

[0330] In some implementations, ring B is a 7-membered heterocyclic group.

[0331] In some embodiments, ring B is a 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms, each heteroatom being independently selected from N, O, and S.

[0332] In some implementations, ring B is

[0333] In some implementations, ring B is

[0334] In some implementations, ring B is optionally bounded by one or more R... 11 Substituted heteroaryl groups.

[0335] In some implementations, ring B is a heteroaryl group.

[0336] In some implementations, ring B is a 5-membered heteroaryl group.

[0337] In some embodiments, ring B is a 5-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms, each heteroatom being independently selected from N, O and S.

[0338] In some implementations, ring B is a 6-membered heteroaryl group.

[0339] In some embodiments, ring B is a 6-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms, each heteroatom being independently selected from N, O and S.

[0340] In some implementations, ring B is

[0341] In some implementations, ring B is

[0342] In some implementations, ring B is

[0343] In some implementations, ring B is

[0344] In some implementations, ring B is

[0345] In some implementations, ring B is

[0346] In some implementations, ring B is

[0347] In some implementations, ring B is

[0348] In some implementations, ring B is

[0349] In some implementations, ring B is

[0350] In some implementations, ring B is

[0351] In some embodiments, the cyclic C is selected from cycloalkyl, aryl, heterocyclic, and heteroaryl groups.

[0352] In some implementations, the cyclic C is an aryl group.

[0353] In some implementations, ring C is

[0354] In some implementations, ring C is

[0355] In some implementations, ring C is a heterocyclic group.

[0356] In some implementations, ring C is a bicyclic heterocyclic group.

[0357] In some embodiments, the ring C is a bicyclic heterocyclic group, one of which is a C6 aromatic hydrocarbon.

[0358] In some implementations, the cyclic C is a heteroaryl group.

[0359] In some implementations, ring C is a bicyclic heteroaryl group.

[0360] In some implementations, ring C is

[0361] In some implementations, ring C is

[0362] In some implementations, ring C is

[0363] In some implementations, ring C is

[0364] In some implementations, ring C is

[0365] In some implementations, ring C is

[0366] In some implementations, ring C is

[0367] In some implementations, Y is selected from -NR5C(O)NR5- and -NR5C(O)-.

[0368] In some implementations, Y is

[0369] In some implementations, Y is -NR5C(O)NR5-.

[0370] In some implementations, Y is In some implementations, Y is -NHC(O)NH-.

[0371] In some implementations, Y is

[0372] In some implementations, Y is -NHC(O)NH-.

[0373] In some implementations, Y is -NR5C(O)-.

[0374] In some implementations, -NR5C(O)- connects ring C to L1, as shown here (ring C)-NR5C(O)-(L1).

[0375] In some implementations, -NR5C(O)- connects ring C to L1, as shown here (L1)-NR5C(O)-(ring C).

[0376] In some implementations, Y is -NHC(O)-.

[0377] In some implementations, -NHC(O)- connects ring C to L1, as shown here (ring C)-NHC(O)-(L1).

[0378] In some implementations, -NHC(O)- connects ring C to L1, as shown here (L1)-NHC(O)-(ring C).

[0379] In some embodiments, M is -CH2-. In some embodiments, M is -C(O)-. In some embodiments, M is -C(O)NR. L - In some implementations, M is -C(O)O-. In some implementations, M is -NR. L - In some implementations, M is -NR L C(O)-. In some implementations, M is -NR. L C(O)NR L - In some implementations, M is -NR L C(O)O-. In some implementations, M is -NR. L SO2-. In some implementations, M is -O-. In some implementations, M is -OC(O)-. In some implementations, M is -OC(O)NR. L In some implementations, M is -OC(O)O-. In some implementations, M is -S(O)2NR. L - In some implementations, M is -S-. In some implementations, M is -S(O)2-.

[0380] In some implementations, M is -CH2-.

[0381] In some implementations, M is -C(O)-.

[0382] In some implementations, M is -O-.

[0383] In some implementations, M is -NR L C(O)-.

[0384] In some implementations, o is 0. In some implementations, o is 1. In some implementations, o is 2. In some implementations, o is 3. In some implementations, o is 4. In some implementations, o is 5. In some implementations, o is 6. In some implementations, o is 7. In some implementations, o is 8. In some implementations, o is 9. In some implementations, o is 10.

[0385] In some implementations, o is 0.

[0386] In some implementations, o is 1.

[0387] In some implementations, o is 2.

[0388] In some implementations, o is 3.

[0389] In some implementations, each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0390] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, p is 4. In some implementations, p is 5. In some implementations, p is 6. In some implementations, p is 7. In some implementations, p is 8. In some implementations, p is 9. In some implementations, p is 10.

[0391] In some implementations, p is 0.

[0392] In some implementations, p is 1.

[0393] In some implementations, p is 2.

[0394] In some implementations, p is 3.

[0395] In some implementations, L1 is a key. In some implementations, L1 is C1-C. 12 Alkyl. In some embodiments, L1 is C2-C. 12 Alkenediyl. In some embodiments, L1 is C2-C 12 Alkyne diol. In some embodiments, L1 is a C3-C8 cycloalkane diol. In some embodiments, L1 is a C3-C8 cycloalkane diol-(CH2). p - In some implementations, L1 is C1-C 12 Alkoxyalkenyl. In some embodiments, L1 is -((CH2) 1-6 O) o -(CH2) p - In some implementations, L1 is -((CH2) 1-6 O) o -(CH2) p -NH-. In some implementations, L1 is -((CH2) 1-6 O) o -(CH2) p-NH-C(O)-. In some embodiments, L1 is -((CH2)-. 1-6 O) o -(CH2) p -C(O)-NH-.

[0396] In some implementations, L1 is a key.

[0397] In some implementations, L1 is C1-C 12 Alkylene group.

[0398] In some implementations, L1 is -CH2-.

[0399] In some implementations, L1 is -CH2CH2-.

[0400] In some implementations, L1 is -CH2CH2CH2-.

[0401] In some implementations, L1 is -CH2CH2CH2CH2-.

[0402] In some implementations, L1 is -CH2CH2CH2CH2CH2-.

[0403] In some implementations, L1 is -((CH2) 1-6 O) o -(CH2) p -

[0404] In some implementations, L1 is -CH2CH2-O-CH2CH2-.

[0405] In some implementations, L1 is -((CH2) 1-6 O) o -(CH2) p -

[0406] In some implementations, L1 is -((CH2) 1-6 O) o -(CH2) p -NH-.

[0407] In some implementations, L1 is -((CH2) 1-6 O) o -(CH2) p -NH-C(O)-.

[0408] In some implementations, L1 is -((CH2) 1-6 O) o -(CH2) p -C(O)-NH-.

[0409] In some implementations, L1 is a C3-C8 cycloalkyldiyl group.

[0410] In some implementations, L1 is

[0411] In some implementations, L1 is

[0412] In some implementations, L1 is

[0413] In some implementations, L1 is

[0414] In some implementations, L1 is

[0415] In some implementations, L1 is

[0416] In some implementations, L1 is

[0417] In some implementations, L1 is

[0418] In some implementations, L2 is a bond. In some implementations, L2 is C1-C. 12 Alkyl. In some embodiments, L2 is C2-C. 12 Alkenediyl. In some embodiments, L2 is C2-C 12 Alkyne diol. In some embodiments, L2 is a C3-C8 cycloalkane diol. In some embodiments, L2 is a C3-C8 cycloalkane diol-(CH2). p - In some implementations, L2 is C1-C 12 Alkoxyalkenyl. In some embodiments, L2 is -((CH2) 1-6 O) o -(CH2) p - In some implementations, L2 is -((CH2) 1-6 O) o -(CH2) p -NH-. In some implementations, L2 is -((CH2) 1-6 O) o -(CH2) p -NH-C(O)-. In some embodiments, L2 is -((CH2)-. 1-6 O) o -(CH2) p -C(O)-NH-.

[0419] In some implementations, L2 is the key.

[0420] In some implementations, L2 is C1-C 12 Alkylene group.

[0421] In some implementations, L2 is -CH2-.

[0422] In some implementations, L2 is -CH2CH2-.

[0423] In some implementations, L2 is -CH2CH2CH2-.

[0424] In some implementations, L2 is -CH2CH2CH2CH2-.

[0425] In some implementations, L2 is -CH2CH2CH2CH2CH2-.

[0426] In some implementations, L2 is -CH2-C(CH3)2-CH2-.

[0427] In some implementations, L2 is -((CH2) 1-6 O) o -(CH2) p -

[0428] In some implementations, L2 is -CH2-O-CH2CH2CH2-.

[0429] In some implementations, L2 is -CH2CH2CH2CH2-O-CH2-.

[0430] In some implementations, L2 is -((CH2) 1-6 O) o -(CH2) p -

[0431] In some implementations, L2 is -((CH2) 1-6 O) o -(CH2) p -NH-.

[0432] In some implementations, L2 is -((CH2) 1-6 O) o -(CH2) p -NH-C(O)-.

[0433] In some implementations, L2 is -((CH2) 1-6 O) o -(CH2) p -C(O)-NH-.

[0434] In some embodiments, L2 is C3-C8 cycloalkyldiyl-(CH2). p -

[0435] In some implementations, L2 is C3-C8 cycloalkyldiyl-CH2-.

[0436] In some implementations, L2 is

[0437] In some implementations, L2 is a C3-C8 cycloalkyldiyl group.

[0438] In some implementations, L2 is

[0439] In some implementations, L2 is

[0440] In some implementations, L2 is

[0441] In some implementations, L2 is

[0442] In some implementations, L2 is

[0443] In some implementations, L2 is

[0444] In some implementations, L2 is

[0445] In some implementations, L2 is

[0446] In some implementations, M-L2 is a bond.

[0447] In some implementations, L1-M-L2 are bonds.

[0448] In some implementations, L3 is a bond. In some implementations, L3 is C1-C. 12 Alkyl. In some embodiments, L3 is C2-C. 12 Alkenediyl. In some embodiments, L3 is C2-C 12 Alkyne diol. In some embodiments, L3 is C1-C. 12 Alkoxyalkenyl. In some embodiments, L3 is -((CH2) 1-6 O) o -(CH2) p In some implementations, L3 is -C(O)-. In some implementations, L3 is -C(O)NR. LIn some implementations, L3 is -C(O)O-. In some implementations, L3 is -NR. L - In some implementations, L3 is -NR L C(O)-. In some implementations, L3 is -NR. L C(O)NR L - In some implementations, L3 is -NR L C(O)O-. In some implementations, L3 is -NR. L SO2-. In some implementations, L3 is -O-. In some implementations, L3 is -OC(O)-. In some implementations, L3 is -OC(O)NR. L In some implementations, L3 is -OC(O)O-. In some implementations, L3 is -S(O)2NR. L - In some implementations, L3 is -S-. In some implementations, L3 is -S(O)2-.

[0449] In some implementations, L3 is a key.

[0450] In some implementations, L4 is a key. In some implementations, L4 is C1-C. 12 Alkyl. In some embodiments, L4 is C2-C. 12 Alkenediyl. In some embodiments, L4 is C2-C. 12 Alkyne diol. In some embodiments, L4 is C1-C. 12 Alkoxyalkenyl group. In some embodiments, L4 is -((CH2) 1-6 O) o -(CH2) p In some implementations, L4 is -C(O)-. In some implementations, L4 is -C(O)NR. L In some implementations, L4 is -C(O)O-. In some implementations, L4 is -NR. L - In some implementations, L4 is -NR L C(O)-. In some implementations, L4 is -NR. L C(O)NR L - In some implementations, L4 is -NR L C(O)O-. In some implementations, L4 is -NR. L SO2-. In some implementations, L4 is -O-. In some implementations, L4 is -OC(O)-. In some implementations, L4 is -OC(O)NR. LIn some implementations, L4 is -OC(O)O-. In some implementations, L4 is -S(O)2NR. L - In some implementations, L4 is -S-. In some implementations, L4 is -S(O)2-.

[0451] In some implementations, L4 is -NR L C(O)NR L -

[0452] In some implementations, L4 is -NHC(O)NH-.

[0453] In some implementations, L4 is -NR L C(O)-.

[0454] In some implementations, L4 is -NHC(O)-.

[0455] In some implementations, L4 is -C(O)NH-.

[0456] 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally replaced by one or more R1 groups. 11 replace.

[0457] In some embodiments, R1 is hydrogen. 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 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 heterocyclic group.

[0458] In some implementations, R1 is hydrogen.

[0459] In some embodiments, R1 is a C1-C6 alkyl group.

[0460] In some implementations, R1 is a methyl group.

[0461] In some embodiments, R1 is a -CH2-OC(O)C1-C6 alkyl group.

[0462] In some implementations, R1 is

[0463] In some embodiments, R1 is -CH2-OP(O)(OC1-C6 alkyl)2.

[0464] In some implementations, R1 is

[0465] In some embodiments, each R2 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace.

[0466] In some implementations, each R2 is H.

[0467] In some implementations, at least one R2 is a halogen.

[0468] In some embodiments, at least one R2 is a methyl group.

[0469] In some embodiments, at least one R2 is a methoxy group.

[0470] In some implementations, at least one R2 is -CN.

[0471] In some implementations, each R3 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace.

[0472] In some implementations, each R3 is H.

[0473] In some implementations, at least one R3 is a halogen.

[0474] In some implementations, one R3 is a halogen and the other is H.

[0475] In some embodiments, at least one R3 is a methyl group.

[0476] In some implementations, each R3 is a methyl group.

[0477] In some implementations, one R3 is a methyl group and the other is an H group.

[0478] In some implementations, the two R3s form = O.

[0479] In some implementations, each R4 is independently selected from halogens, -OH, -CN, -NO2, and -NR. 12 R 13 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace.

[0480] In some implementations, w is an integer selected from 0, 1, and 2.

[0481] In some implementations, w is 0. In some implementations, w is 1. In some implementations, w is 2.

[0482] In some implementations, w is 0.

[0483] In some implementations, R4 is a halogen.

[0484] In some implementations, R4 is F.

[0485] In some implementations, w is 1 and R4 is a halogen.

[0486] 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.

[0487] In some implementations, w is 1 and R4 is F.

[0488] In some implementations, w is 1 and R4 is -CN.

[0489] In some implementations, w is 1 and R4 is -OH.

[0490] In some implementations, w is 1 and R4 is a methyl group.

[0491] In some embodiments, w is 1 and R4 is a methoxy group.

[0492] In some embodiments, each R5 is independently selected from hydrogen and C1-C6 alkyl groups.

[0493] In some implementations, each R5 is H.

[0494] In some embodiments, each R6 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace.

[0495] In some implementations, m is an integer selected from 0, 1, 2, and 3.

[0496] In some implementations, m is 0.

[0497] In some implementations, m is 1 and R6 is a halogen.

[0498] 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.

[0499] In some implementations, m is 1 and R6 is -OH.

[0500] In some implementations, m is 1 and R6 is -CN.

[0501] In some embodiments, m is 1 and R6 is a C1-C6 alkyl group.

[0502] In some implementations, m is 1 and R6 is -NR 12 R 13 .

[0503] In some implementations, m is 2.

[0504] In some implementations, m is 3.

[0505] In some implementations, each R7 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, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace.

[0506] In some implementations, n is an integer selected from 0, 1, 2, and 3.

[0507] In some implementations, n is 0.

[0508] In some implementations, n is 1 and R7 is a halogen.

[0509] In some implementations, n is 1 and R7 is Cl.

[0510] In some embodiments, n is 1 and R7 is a C1-C6 alkyl group.

[0511] In some implementations, n is 1 and R7 is CH3.

[0512] In some implementations, n is 2.

[0513] In some implementations, n is 3.

[0514] In some embodiments, R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R groups. 11 replace.

[0515] In some implementations, R8 is H.

[0516] In some embodiments, R8 is a C1-C6 alkyl group.

[0517] In some implementations, R8 is optionally replaced by one or more R 11 Substituted C1-C6 alkyl groups.

[0518] In some implementations, R8 is a methyl group.

[0519] In some implementations, R8 is ethyl.

[0520] In some implementations, R8 is propyl.

[0521] In some implementations, R8 is n-propyl.

[0522] In some implementations, R8 is isopropyl.

[0523] In some implementations, R8 is butyl.

[0524] In some implementations, R8 is tert-butyl.

[0525] In some implementations, R8 is

[0526] In some implementations, R8 is

[0527] In some implementations, R8 is a cycloalkyl group.

[0528] In some implementations, R8 is C 3- C 12 Cycloalkyl.

[0529] In some embodiments, R8 is a C3-C8 monocyclic cycloalkyl group.

[0530] 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.

[0531] In some implementations, R8 is

[0532] In some implementations, R8 is

[0533] In some implementations, R8 is

[0534] In some implementations, R8 is

[0535] In some implementations, R8 is fused C5-C 12 Bicyclic cycloalkyl. In some embodiments, R8 is a bridged C5-C. 12 Bicyclic cycloalkyl. In some embodiments, ring R8 is a spirofused C5-C... 12 Bicyclic cycloalkyl.

[0536] In some implementations, R8 is an aryl group.

[0537] In some implementations, R8 is C6-C 10 Aryl.

[0538] In some implementations, R8 is a phenyl group.

[0539] In some implementations, R8 is

[0540] In some implementations, R8 is a heterocyclic group.

[0541] In some implementations, R8 is a 3-10 member heterocyclic group.

[0542] In some embodiments, R8 is a 3-membered heterocyclic group. In some embodiments, R8 is a 4-membered heterocyclic group. In some embodiments, R8 is a 5-membered heterocyclic group. In some embodiments, R8 is a 6-membered heterocyclic group. In some embodiments, R8 is a 7-membered heterocyclic group.

[0543] In some implementations, R8 is a 3-membered heterocyclic group.

[0544] In some implementations, R8 is a 3-membered heterocyclic group containing one heteroatom selected from O and N.

[0545] In some implementations, R8 is a 4-membered heterocyclic group.

[0546] In some embodiments, R8 is a 4-membered heterocyclic group containing one or two heteroatoms, each heteroatom being independently selected from N, O, and S.

[0547] In some implementations, R8 is a 5-membered heterocyclic group.

[0548] In some embodiments, R8 is a 5-membered heterocyclic group containing one or two heteroatoms, each heteroatom being independently selected from N, O, and S.

[0549] In some implementations, R8 is a 6-membered heterocyclic group.

[0550] In some embodiments, R8 is a 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms, each heteroatom being independently selected from N, O, and S.

[0551] In some implementations, R8 is a 7-membered heterocyclic group.

[0552] In some embodiments, R8 is a 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms, each heteroatom being independently selected from N, O, and S.

[0553] In some implementations, R8 is

[0554] In some implementations, R8 is

[0555] In some implementations, R8 is

[0556] In some implementations, R8 is a heteroaryl group.

[0557] In some embodiments, R8 is a 5-membered heteroaryl group. In some embodiments, R8 is a 6-membered heteroaryl group.

[0558] In some implementations, R8 is

[0559] In some embodiments, R9 is selected from hydrogen, halogen, -OH, -CN, -NO2, and -NR. 12 R 13 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace.

[0560] In some implementations, R9 is hydrogen.

[0561] In some embodiments, R9 is a cycloalkyl group.

[0562] In some embodiments, R9 is a C3-C8 cycloalkyl group.

[0563] In some implementations, R9 is

[0564] In some implementations, R 10 Selected from halogens, -OH, -CN, -NO2, -NR 12 R 13 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally separated by one or more R groups. 11 replace.

[0565] In some implementations, u is 0. In some implementations, u is 1.

[0566] In some implementations, u is 1.

[0567] In some implementations, R 10 It is halogen.

[0568] In some implementations, R 10 It is F.

[0569] In some implementations, R 10 It is Cl.

[0570] In some implementations, R 10 It is Br.

[0571] In some implementations, R 10 It is a C1-C6 alkyl group.

[0572] In some implementations, R 10 It is -CH3.

[0573] In some implementations, each R 11 Independently selected from halogens, -OH, -CN, -NO2, -NR 12 R 13 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclic and heteroaryl.

[0574] In some implementations, R 11 It is halogen.

[0575] In some implementations, R 11 It is F. In some implementations, R 11 It is Cl. In some implementations, R 11 It is Br.

[0576] In some implementations, R 11 It is -OH.

[0577] In some implementations, R 11 Yes - CN.

[0578] In some implementations, R 11 It is a C1-C6 alkyl group.

[0579] In some implementations, R 11 It is -CF3.

[0580] In some implementations, each R L It is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl.

[0581] In some implementations, R L It is hydrogen.

[0582] In some implementations, R L It is a C1-C6 alkyl group.

[0583] In some implementations, R 12 and R 13 They are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclic and heteroaryl.

[0584] In some implementations, R 12 and R 13 They are hydrogen.

[0585] In some implementations, R 12 It is methyl and R13 It is H.

[0586] In some implementations, R 12 It is H and R 13 It is a methyl group.

[0587] In some implementations, R 12 and R 13 They are methyl groups.

[0588] In some implementations, R 12 and R 13 They are ethyl groups.

[0589] In some implementations, R 12 It is H and R 13 It is -OH.

[0590] In some embodiments, the compound has the chemical formula (II):

[0591]

[0592] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0593] In some embodiments, the compound has the chemical formula (I-II):

[0594]

[0595] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0596] In some embodiments, the compound has chemical formulas (I-III):

[0597]

[0598] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0599] In some embodiments, the compound has the chemical formula (IIH):

[0600]

[0601] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0602] In some embodiments, the compound has the chemical formula (I-II-H):

[0603]

[0604] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0605] In some embodiments, the compound has the chemical formula (IIO):

[0606]

[0607] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0608] In some embodiments, the compound has the chemical formula (I-II-O):

[0609]

[0610] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0611] In some embodiments, the compound has the chemical formula (I-I'):

[0612]

[0613] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0614] In some embodiments, the compound has the chemical formula (I-II'):

[0615]

[0616] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0617] In some embodiments, the compound has the chemical formula (IIA):

[0618]

[0619] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0620] In some embodiments, the compound has the chemical formula (IIA-1):

[0621]

[0622] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0623] In some embodiments, the compound has the chemical formula (IIA-1-a):

[0624]

[0625] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0626] In some embodiments, the compound has the chemical formula (IIA-1-a-1):

[0627]

[0628] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0629] In some embodiments, the compound has the chemical formula (IIA-1-a-1-I):

[0630]

[0631] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0632] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA):

[0633]

[0634] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0635] In some embodiments, the compound has the chemical formula:

[0636]

[0637] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, wherein n is selected from 0 and 1; wherein each R3 is H or two R3s form = O; and all other variables are as defined herein.

[0638] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-I):

[0639]

[0640] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, wherein n is selected from 0 and 1; wherein each R3 is H or two R3s form = O; and all other variables are as defined herein.

[0641] In some embodiments, the compound has the chemical formula (I-1):

[0642]

[0643] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0644] In some embodiments, the compound has the chemical formula (I-2):

[0645]

[0646] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0647] In some embodiments, the compound has the chemical formula (I-3):

[0648]

[0649] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0650] In some embodiments, the compound has the chemical formula (I-4):

[0651]

[0652] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0653] In some embodiments, the compound has the chemical formula (I-5):

[0654]

[0655] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0656] In some embodiments, the compound has the chemical formula (I-6):

[0657]

[0658] Or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein n is an integer selected from 0 and 1; wherein both R3s are H or both R3s form = O, and wherein the remaining variables are as defined herein.

[0659] In some embodiments, the compound has the chemical formula (I-7):

[0660]

[0661] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0662] In some embodiments, the compound has the chemical formula (I-8):

[0663]

[0664] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0665] In some embodiments, the compound has the chemical formula (I-9):

[0666]

[0667] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0668] In some embodiments, the compound has the chemical formula (I-10):

[0669]

[0670] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0671] In some embodiments, the compound has the chemical formula (I-11):

[0672]

[0673] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0674] In some embodiments, the compound has the chemical formula (I-12):

[0675]

[0676] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0677] In some embodiments, the compound has the chemical formula (I-13):

[0678]

[0679]

[0680] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0681] In some embodiments, the compound has the chemical formula (I-14):

[0682]

[0683] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0684] In some embodiments, the compound has the chemical formula (I-15):

[0685]

[0686] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0687] In some embodiments, the compound has the chemical formula (I-16):

[0688]

[0689] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer, where n is an integer selected from 0 and 1; where both R3s are H or both R3s form = O, and where the remaining variables are as defined herein.

[0690] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IA):

[0691]

[0692] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, wherein n is selected from 0 and 1; wherein each R3 is H or two R3s form = O; and all other variables are as defined herein.

[0693] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IA-1):

[0694]

[0695] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each R3 is H or two R3s form = O; n is selected from 0 and 1; and all other variables are as defined herein.

[0696] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IA-1-a):

[0697]

[0698] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each R3 is H or two R3s form =O; each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0699] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IA-1-aH):

[0700]

[0701] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0702] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IA-1-aO):

[0703]

[0704] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein w, u, and n are independently selected from 0 and 1, respectively; and all other variables are as defined herein.

[0705] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IA-2):

[0706]

[0707] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each R3 is H or two R3s form = O; n is selected from 0 and 1; and all other variables are as defined herein.

[0708] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IA-2-H):

[0709]

[0710] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0711] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IA-2-O):

[0712]

[0713] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0714] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IA-3):

[0715]

[0716] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each R3 is H or two R3s form = O; n is selected from 0 and 1; and all other variables are as defined herein.

[0717] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IA-3-H):

[0718]

[0719] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0720] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IA-3-O):

[0721]

[0722] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0723] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IB):

[0724]

[0725] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0726] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IB-1):

[0727]

[0728] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each R3 is H or two R3s form = O; n is selected from 0 and 1; and all other variables are as defined herein.

[0729] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IB-1-a):

[0730]

[0731] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; each R3 is H or both R3s are =O; and all other variables are as defined herein.

[0732] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IB-1-aH):

[0733]

[0734] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0735] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IB-1-aO):

[0736]

[0737] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0738] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IB-2):

[0739]

[0740] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each R3 is H or both R3 are =O; n is selected from 0 and 1; and all other variables are as defined herein.

[0741] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IB-2-H):

[0742]

[0743] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0744] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IB-2-O):

[0745]

[0746] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0747] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IB-3):

[0748]

[0749] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each R3 is H or both R3 are =O; n is selected from 0 and 1; and all other variables are as defined herein.

[0750] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IB-3-H):

[0751]

[0752] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0753] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IB-3-O):

[0754]

[0755] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0756] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC):

[0757]

[0758] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0759] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-1):

[0760]

[0761] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each R3 is H or both R3 are =O; each n is independently selected from 0 and 1; and all other variables are as defined herein.

[0762] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-1-a):

[0763]

[0764] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; each R3 is H or both R3s are =O; and all other variables are as defined herein.

[0765] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-1-aH):

[0766]

[0767] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0768] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-1-aO):

[0769]

[0770] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0771] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-1-b):

[0772]

[0773] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; each R3 is H or both R3s are =O; and all other variables are as defined herein.

[0774] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-1-bH):

[0775]

[0776] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0777] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-1-bO):

[0778]

[0779] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0780] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-1-c):

[0781]

[0782]

[0783] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; each R3 is H or both R3s are =O; and all other variables are as defined herein.

[0784] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-1-cH):

[0785]

[0786] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0787] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-1-cO):

[0788]

[0789] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0790] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-2):

[0791]

[0792] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein n is selected from 0 and 1; each R3 is H or both R3 are =O; and all other variables are as defined herein.

[0793] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-2-a):

[0794]

[0795] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each x is independently selected from 0 and 1; each R3 is H or both R3s are =O; all other variables are as defined herein.

[0796] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-2-aH):

[0797]

[0798] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each x is independently selected from 0 and 1; and all other variables are as defined herein.

[0799] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-2-aO):

[0800]

[0801] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each x is independently selected from 0 and 1; and all other variables are as defined herein.

[0802] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-3):

[0803]

[0804] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein n is selected from 0 and 1; each R3 is H or both R3 are =O; and all other variables are as defined herein.

[0805] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-3-a):

[0806]

[0807] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each x is independently selected from 0 and 1; each R3 is H or both R3s are =O; and all other variables are as defined herein.

[0808] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-3-aH):

[0809]

[0810] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each x is independently selected from 0 and 1; and all other variables are as defined herein.

[0811] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-IC-3-aO):

[0812]

[0813] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each x is independently selected from 0 and 1; and all other variables are as defined herein.

[0814] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-ID):

[0815]

[0816] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0817] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-ID-1):

[0818]

[0819] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each R3 is H or both R3 are =O; each n is independently selected from 0 and 1; and all other variables are as defined herein.

[0820] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-ID-1-a):

[0821]

[0822]

[0823] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; each R3 is H or both R3s are =O; and all other variables are as defined herein.

[0824] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-ID-1-aH):

[0825]

[0826] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0827] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-ID-1-aO):

[0828]

[0829] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0830] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-ID-1-b):

[0831]

[0832] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; each R3 is H or both R3s are =O; and all other variables are as defined herein.

[0833] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-ID-1-bH):

[0834]

[0835] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each of w, u, and n is independently selected from 0 and 1; and all other variables are as defined herein.

[0836] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-ID-1-bO):

[0837]

[0838] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each x is independently selected from 0 and 1; and all other variables are as defined herein.

[0839] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-ID-1-c):

[0840]

[0841] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each x is independently selected from 0 and 1; each R3 is H or both R3s are =O; and all other variables are as defined herein.

[0842] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-ID-1-cH):

[0843]

[0844] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each x is independently selected from 0 and 1; and all other variables are as defined herein.

[0845] In some embodiments, the compound has the chemical formula (IIA-1-a-1-IA-1-ID-1-cO):

[0846]

[0847] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each x is independently selected from 0 and 1; and all other variables are as defined herein.

[0848] In some embodiments, the compound has the chemical formula (IIA-2):

[0849]

[0850] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0851] In some embodiments, the compound has the chemical formula (IIA-2-a):

[0852]

[0853] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0854] In some embodiments, the compound has the chemical formula (IIA-2-a-1):

[0855]

[0856] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0857] In some embodiments, the compound has the chemical formula (IIA-2-a-1-I):

[0858]

[0859] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0860] In some embodiments, the compound has the chemical formula (IIA-2-a-1-IA):

[0861]

[0862] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0863] In some embodiments, the compound has the chemical formula (IIB):

[0864]

[0865] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0866] In some embodiments, the compound has the chemical formula (IIB-1):

[0867]

[0868] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0869] In some embodiments, the compound has the chemical formula (IIB-1-a):

[0870]

[0871] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0872] In some embodiments, the compound has the chemical formula (IIB-1-a-1):

[0873]

[0874] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0875] In some embodiments, the compound has the chemical formula (IIB-1-a-1-I):

[0876]

[0877] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0878] In some embodiments, the compound has the chemical formula (IIB-1-a-1-IA):

[0879]

[0880] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0881] In some embodiments, the compound has the chemical formula (IIB-2):

[0882]

[0883] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0884] In some embodiments, the compound has the chemical formula (IIB-2-a):

[0885]

[0886] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0887] In some embodiments, the compound has the chemical formula (IIB-2-a-1):

[0888]

[0889] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0890] In some embodiments, the compound has the chemical formula (IIB-2-a-1-I):

[0891]

[0892] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0893] In some embodiments, the compound has the chemical formula (IIB-2-a-1-IA):

[0894]

[0895] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0896] In some embodiments, the compound has the chemical formula (IIB-2-a-1-IA-1):

[0897]

[0898] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0899] In some embodiments, the compound has the chemical formula (IIB-2-a-1-IA-1-I):

[0900]

[0901] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0902] In some embodiments, the compound has the chemical formula (IIB-2-a-1-IA-1-IC):

[0903]

[0904] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where n is selected from 0 and 1; and all other variables are as defined herein.

[0905] In some embodiments, the compound has the chemical formula (IIB-2-a-1-IA-1-IC-3):

[0906]

[0907] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein n is selected from 0 and 1; each R3 is H or both R3 are =O; and all other variables are as defined herein.

[0908] In some embodiments, the compound has the chemical formula (IIB-2-a-1-IA-1-IC-3-a):

[0909]

[0910] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each R3 is H or both R3s are =O; and all other variables are as defined herein.

[0911] In some embodiments, the compound has the chemical formula (IIB-2-a-1-IA-1-IC-3-aH):

[0912]

[0913] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0914] In some embodiments, the compound has the chemical formula (IIB-2-a-1-IA-1-IC-3-aO):

[0915]

[0916] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0917] In some embodiments, the compound has the chemical formula (I-II-A):

[0918]

[0919] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0920] In some embodiments, the compound has the chemical formula (I-II-A-1):

[0921]

[0922] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0923] In some embodiments, the compound has the chemical formula (I-II-A-1-a):

[0924]

[0925] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0926] In some embodiments, the compound has the chemical formula (I-II-A-1-a-1):

[0927]

[0928] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0929] In some embodiments, the compound has the chemical formula (I-II-A-1-a-1-I):

[0930]

[0931] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0932] In some embodiments, the compound has the chemical formula (I-II-A-1-a-1-IA):

[0933]

[0934] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0935] In some embodiments, the compound has the chemical formula (I-II-A-1-a-1-IA-1):

[0936]

[0937] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, where n is 0 or 1, and all other variables are as defined herein.

[0938] In some embodiments, the compound has the chemical formula (I-II-A-1-a-1-IA-1-I):

[0939]

[0940] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, where n is 0 or 1, and all other variables are as defined herein.

[0941] In some embodiments, the compound has the chemical formula (I-II-A-1-a-1-IA-1-IC):

[0942]

[0943] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, where n is 0 or 1, and all other variables are as defined herein.

[0944] In some embodiments, the compound has the chemical formula (I-II-A-1-a-1-IA-1-IC-1):

[0945]

[0946] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, where n is 0 or 1; each R3 is H or both R3s are =O; and all other variables are as defined herein.

[0947] In some embodiments, the compound has the chemical formula (I-II-A-1-a-1-IA-1-IC-1-a):

[0948]

[0949] Or it may be a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer, wherein each R3 is H or both R3s are =O; and all other variables are as defined herein.

[0950] In some embodiments, the compound has the chemical formula (I-II-A-1-a-1-IA-1-IC-1-aH):

[0951]

[0952] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0953] In some embodiments, the compound has the chemical formula (I-II-A-1-a-1-IA-1-IC-1-aO):

[0954]

[0955] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0956] In some embodiments, the compound has the chemical formula (I-II-A-2):

[0957]

[0958] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0959] In some embodiments, the compound has the chemical formula (I-II-A-2-a):

[0960]

[0961] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0962] In some embodiments, the compound has the chemical formula (I-II-A-2-a-1):

[0963]

[0964] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0965] In some embodiments, the compound has the chemical formula (I-II-A-2-a-1-I):

[0966]

[0967] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0968] In some embodiments, the compound has the chemical formula (I-II-A-2-a-1-IA):

[0969]

[0970] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0971] In some embodiments, the compound has the chemical formula (I-II-B):

[0972]

[0973] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0974] In some embodiments, the compound has the chemical formula (I-II-B-1):

[0975]

[0976] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0977] In some embodiments, the compound has the chemical formula (I-II-B-1-a):

[0978]

[0979] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0980] In some embodiments, the compound has the chemical formula (I-II-B-1-a-1):

[0981]

[0982] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0983] In some embodiments, the compound has the chemical formula (I-II-B-1-a-1-I):

[0984]

[0985] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0986] In some embodiments, the compound has the chemical formula (I-II-B-1-a-1-IA):

[0987]

[0988]

[0989] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0990] In some embodiments, the compound has the chemical formula (I-II-B-2):

[0991]

[0992] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0993] In some embodiments, the compound has the chemical formula (I-II-B-2-a):

[0994]

[0995] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0996] In some embodiments, the compound has the chemical formula (I-II-B-2-a-1):

[0997]

[0998] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[0999] In some embodiments, the compound has the chemical formula (I-II-B-2-a-1-I):

[1000]

[1001] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1002] In some embodiments, the compound has the chemical formula (I-II-B-2-a-1-IA):

[1003]

[1004] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1005] In some embodiments, the compound has the chemical formula (II-A):

[1006]

[1007] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1008] In some embodiments, the compound has the chemical formula (II-AI):

[1009]

[1010] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1011] In some embodiments, the compound has the chemical formula (II-Ala):

[1012]

[1013] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1014] In some embodiments, the compound has the chemical formula (II-AIa-1):

[1015]

[1016]

[1017] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1018] In some embodiments, the compound has the chemical formula (II-AIa-1-I):

[1019]

[1020] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1021] In some embodiments, the compound has the chemical formula (II-AIa-1-IA):

[1022]

[1023] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1024] In some embodiments, the compound has the chemical formula (II-AIa-1-IA-1):

[1025]

[1026] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1027] In some embodiments, the compound has the chemical formula (II-B):

[1028]

[1029] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1030] In some embodiments, the compound has the chemical formula (II-BI):

[1031]

[1032]

[1033] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1034] In some embodiments, the compound has the chemical formula (II-BIa):

[1035]

[1036] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1037] In some embodiments, the compound has the chemical formula (II-BIa-1):

[1038]

[1039] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1040] In some embodiments, the compound has the chemical formula (II-BIa-1-I):

[1041]

[1042] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1043] In some embodiments, the compound has the chemical formula (II-BIa-1-IA):

[1044]

[1045] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1046] In some embodiments, the compound has the chemical formula (II-BIa-1-IA-1):

[1047]

[1048] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1049] In some embodiments, the compound has the chemical formula (AI):

[1050]

[1051] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1052] In some embodiments, the compound has the chemical formula (AI-1):

[1053]

[1054] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1055] In some embodiments, the compound has the chemical formula (AI-1-a):

[1056]

[1057] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1058] In some embodiments, the compound has the chemical formula (Al-1-aI):

[1059]

[1060]

[1061] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1062] In some embodiments, the compound has the chemical formula (AI-1-aIA):

[1063]

[1064] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1065] In some embodiments, the compound has the chemical formula (AI-1-aIA-1):

[1066]

[1067] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1068] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a):

[1069]

[1070]

[1071] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1072] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-1):

[1073]

[1074] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1075] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-1-a):

[1076]

[1077] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1078] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-1-a-1):

[1079]

[1080] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 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.

[1081] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-1-a-1-a):

[1082]

[1083] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1084] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-1-a-1-a-1):

[1085]

[1086] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1087] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-1-a-1-a-2):

[1088]

[1089] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1090] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-1-a-1-a-3):

[1091]

[1092] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1093] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-1-a-1-b):

[1094]

[1095]

[1096] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1097] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-1-a-1-b-1):

[1098]

[1099] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1100] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-1-a-1-b-2):

[1101]

[1102] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1103] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-1-a-1-b-3):

[1104]

[1105] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1106] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-2):

[1107]

[1108] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1109] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-2-a):

[1110]

[1111] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1112] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-2-a-1):

[1113]

[1114] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 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.

[1115] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-2-a-1-a):

[1116]

[1117] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1118] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-2-a-1-a-1):

[1119]

[1120] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1121] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-2-a-1-a-2):

[1122]

[1123] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1124] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-2-a-1-a-3):

[1125]

[1126] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1127] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-2-a-1-b):

[1128]

[1129] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1130] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-2-a-1-b-1):

[1131]

[1132] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1133] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-2-a-1-b-2):

[1134]

[1135] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1136] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-2-a-1-b-3):

[1137]

[1138] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1139] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-a-3):

[1140]

[1141] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1142] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b):

[1143]

[1144] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1145] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-1):

[1146]

[1147] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1148] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-1-a):

[1149]

[1150] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1151] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-1-a*):

[1152]

[1153] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1154] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-1-a**):

[1155]

[1156] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1157] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-1-a***):

[1158]

[1159] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1160] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-1-a****):

[1161]

[1162] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1163] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2):

[1164]

[1165] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1166] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2-a):

[1167]

[1168] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1169] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2-a-1):

[1170]

[1171] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1172] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2-a-1*):

[1173]

[1174] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1175] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2-a-1**):

[1176]

[1177] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1178] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2-a-1***):

[1179]

[1180] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1181] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2-a-1****):

[1182]

[1183] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1184] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2-a-2):

[1185]

[1186] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1187] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2-a-2*):

[1188]

[1189] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1190] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2-a-2**):

[1191]

[1192] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1193] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2-a-2***):

[1194]

[1195] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1196] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-b-2-a-2****):

[1197]

[1198] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1199] In some embodiments, the compound has the chemical formula (AI-1-aIA-1-c):

[1200]

[1201] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1202] In some embodiments, the compound has the chemical formula (AI-1-aIA-2):

[1203]

[1204] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1205] In some embodiments, the compound has the chemical formula (AI-1-aIA-2-a):

[1206]

[1207] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1208] In some embodiments, the compound has the chemical formula (AI-1-aIA-3):

[1209]

[1210] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1211] In some embodiments, the compound has the chemical formula (AI-1-aIA-3-a):

[1212]

[1213] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1214] In some embodiments, the compound has the chemical formula (AI-1-aIA-3-b):

[1215]

[1216] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1217] In some embodiments, the compound has the chemical formula (AI-1-aIA-4):

[1218]

[1219]

[1220] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where m' is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[1221] In some embodiments, the compound has the chemical formula (AI-1-aIA-4-a):

[1222]

[1223] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where m' is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[1224] In some embodiments, the compound has the chemical formula (AI-1-aIA-4-a-1):

[1225]

[1226] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where m' is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[1227] In some embodiments, the compound has the chemical formula (AI-1-aIA-4-a-1-A):

[1228]

[1229]

[1230] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where m' is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[1231] In some embodiments, the compound has the chemical formula (AI-1-aIA-5):

[1232]

[1233] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where m' is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[1234] In some embodiments, the compound has the chemical formula (AI-1-aIA-5-a):

[1235]

[1236] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where m' is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[1237] In some embodiments, the compound has the chemical formula (AI-1-aIA-5-a-1):

[1238]

[1239] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where m' is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[1240] In some embodiments, the compound has the chemical formula (AI-1-aIA-5-a-1-A):

[1241]

[1242] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where m' is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[1243] In some embodiments, the compound has the chemical formula (AI-1-aIA-6):

[1244]

[1245] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where m' is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[1246] In some embodiments, the compound has the chemical formula (AI-1-aIA-6-a):

[1247]

[1248] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1249] In some embodiments, the compound has the chemical formula (AI-1-aIA-6-a-1):

[1250]

[1251] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1252] In some embodiments, the compound has the chemical formula (AI-1-aIA-6-a-2):

[1253]

[1254] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1255] In some embodiments, the compound has the chemical formula (AI-1-aIA-7):

[1256]

[1257] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[1258] In some embodiments, the compound has the chemical formula (AI-1-aIA-7-a):

[1259]

[1260] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1261] In some embodiments, the compound has the chemical formula (AI-1-aIA-7-a-1):

[1262]

[1263] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1264] In some embodiments, the compound has the chemical formula (AI-1-aIA-7-a-1-a):

[1265]

[1266] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1267] In some embodiments, the compound has the chemical formula (Al-1-a-II):

[1268]

[1269] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1270] In some embodiments, the compound has the chemical formula (AI-1-b):

[1271]

[1272] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1273] In some embodiments, the compound has the chemical formula (Al-1-bI):

[1274]

[1275] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1276] In some embodiments, the compound has the chemical formula (AI-1-bIA):

[1277]

[1278] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1279] In some embodiments, the compound has the chemical formula (AI-1-bIA-1):

[1280]

[1281] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1282] In some embodiments, the compound has the chemical formula (AI-1-bIA-1-a):

[1283]

[1284] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1285] In some embodiments, the compound has the chemical formula (AI-1-bIA-1-a-1):

[1286]

[1287] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1288] In some embodiments, the compound has the chemical formula (AI-1-c):

[1289]

[1290] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1291] In some embodiments, the compound has the chemical formula (Al-1-cI):

[1292]

[1293] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1294] In some embodiments, the compound has the chemical formula (AI-1-cIA):

[1295]

[1296] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1297] In some embodiments, the compound has the chemical formula (AI-1-cIA-1):

[1298]

[1299] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1300] In some embodiments, the compound has the chemical formula (AI-1-cIA-1-a):

[1301]

[1302] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1303] In some embodiments, the compound has the chemical formula (AI-1-cIA-1-a-1):

[1304]

[1305] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1306] In some embodiments, the compound has the chemical formula (AI-1-cIA-1-a-1-a):

[1307]

[1308] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1309] In some embodiments, the compound has the chemical formula (AI-1-cIA-2):

[1310]

[1311] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1312] In some embodiments, the compound has the chemical formula (AI-1-cIA-2-a):

[1313]

[1314] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1315] In some embodiments, the compound has the chemical formula (AI-1-cIA-2-a-1):

[1316]

[1317] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where r is an integer selected from the following: 1, 2, 3, 4, 5 and 6; and all other variables are as defined herein.

[1318] In some embodiments, the compound has the chemical formula (AI-2):

[1319]

[1320] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1321] In some embodiments, the compound has the chemical formula (A-II):

[1322]

[1323] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1324] In some embodiments, the compound has the chemical formula (A-II-1):

[1325]

[1326] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1327] In some embodiments, the compound has the chemical formula (A-II-1-a):

[1328]

[1329] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1330] In some embodiments, the compound has the chemical formula (A-II-1-aI):

[1331]

[1332] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1333] In some embodiments, the compound has the chemical formula (A-II-1-aIA):

[1334]

[1335] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1336] In some embodiments, the compound has the chemical formula (A-II-1-aIA-1):

[1337]

[1338] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1339] In some embodiments, the compound has the chemical formula (A-II-1-aIA-1-a):

[1340]

[1341] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1342] In some embodiments, the compound has the chemical formula (A-II-1-aIA-1-a-1):

[1343]

[1344] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1345] In some embodiments, the compound has the chemical formula (A-II-2):

[1346]

[1347] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1348] In some embodiments, the compound has the chemical formula (A-II-2-a):

[1349]

[1350] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1351] In some embodiments, the compound has the chemical formula (A-II-2-aI):

[1352]

[1353] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1354] In some embodiments, the compound has the chemical formula (A-II-2-aIA):

[1355]

[1356] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1357] In some embodiments, the compound has the chemical formula (A-II-2-aIA):

[1358]

[1359] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1360] In some embodiments, the compound has the chemical formula (A-II-2-aIA-1):

[1361]

[1362] Or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer, where all variables are as defined herein.

[1363] Suitable pharmaceutically acceptable salts of the compounds disclosed herein are, for example, sufficiently basic acid addition salts of the compounds disclosed, such as acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citrate methanesulfonate, or maleic acid. Alternatively, suitable pharmaceutically acceptable salts of sufficiently acidic compounds disclosed herein are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine.

[1364] It will be understood that compounds of any of the chemical formulas disclosed herein and any pharmaceutically acceptable salts thereof include stereoisomers of said compounds, mixtures of stereoisomers, and polymorphs of all isomer forms.

[1365] In some embodiments, the compound is selected from the compounds listed in Table 1 and their pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotope derivatives, or tautomers.

[1366] In some embodiments, the compound is selected from the compounds listed in Table 1, their prodrugs, and pharmaceutically acceptable salts.

[1367] In some embodiments, the compound is selected from the compounds listed in Table 1 and their pharmaceutically acceptable salts.

[1368] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 1 and their pharmaceutically acceptable salts.

[1369] In some embodiments, the compound is selected from the compounds described in Table 1.

[1370] Table 1. Examples of compounds with chemical formula A

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379]

[1380]

[1381]

[1382]

[1383]

[1384]

[1385]

[1386]

[1387]

[1388]

[1389]

[1390]

[1391]

[1392]

[1393]

[1394]

[1395]

[1396]

[1397]

[1398]

[1399]

[1400]

[1401]

[1402]

[1403]

[1404]

[1405]

[1406]

[1407]

[1408]

[1409]

[1410]

[1411]

[1412]

[1413]

[1414]

[1415]

[1416]

[1417]

[1418]

[1419]

[1420]

[1421]

[1422]

[1423]

[1424]

[1425]

[1426]

[1427]

[1428]

[1429]

[1430]

[1431]

[1432]

[1433]

[1434]

[1435]

[1436]

[1437]

[1438]

[1439]

[1440]

[1441]

[1442]

[1443]

[1444]

[1445]

[1446] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds described in Table 1.

[1447] In some embodiments, the compound is a lithium, sodium, potassium, calcium, or magnesium salt of any of the compounds described in Table 1.

[1448] In some embodiments, the compound is a sodium or potassium salt of any of the compounds described in Table 1.

[1449] In some embodiments, the compound is any of the acids described in Table 2 and a salt of any of the compounds described in Table 1.

[1450] Table 2. Pharmaceutically acceptable acids that form salts with compounds of chemical formula (A).

[1451]

[1452] In some embodiments, the compound is a salt of acetic acid and any of the compounds described in Table 1.

[1453] In some embodiments, the compound is a salt of ferrous acid and any of the compounds described in Table 1.

[1454] In some embodiments, the compound is a salt of ascorbic acid (L) and any of the compounds described in Table 1.

[1455] In some embodiments, the compound is a salt of hydrobromic acid and any of the compounds listed in Table 1.

[1456] In some embodiments, the compound is a salt of hydrochloric acid and any of the compounds described in Table 1.

[1457] In some embodiments, the compound is a salt of citric acid and any of the compounds described in Table 1.

[1458] In some embodiments, the compound is a salt of glutamic acid and any of the compounds described in Table 1.

[1459] In some embodiments, the compound is a salt of oxalic acid and any of the compounds described in Table 1.

[1460] In some embodiments, the compound is a salt of formic acid and any of the compounds described in Table 1.

[1461] In some embodiments, the compound is a salt of sulfuric acid and any of the compounds described in Table 1.

[1462] In some respects, this disclosure provides a compound that is an isotopic derivative (e.g., an isotopically labeled compound) of any of the compounds of the chemical formula disclosed herein.

[1463] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 1, as well as its prodrug and pharmaceutically acceptable salt.

[1464] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 1 and a pharmaceutically acceptable salt thereof.

[1465] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds described in Table 1 and a pharmaceutically acceptable salt thereof.

[1466] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 1.

[1467] It should be understood that the isotope derivatives can be prepared using any of a variety of techniques recognized in the art. For example, the isotope derivatives can typically be prepared by implementing the schemes described herein and / or the procedures disclosed in the examples, by using isotopically labeled reagents instead of non-isotopically labeled reagents.

[1468] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[1469] In some embodiments, the isotope derivative is a deuterium-labeled compound of any of the chemical formulas disclosed herein.

[1470] As used herein, the term "isotope derivative" refers to a derivative of a compound in which one or more atoms are enriched with or labeled with an isotope. For example, an isotope derivative of a compound of formula (A) is enriched with or labeled with one or more isotopes compared to the corresponding compound of formula (A). In some embodiments, the isotope derivative enrichment is selected from... 2 H, 13 C 14 C 15 N、 18 O、 29 Si、 31 P and 34 One or more atoms of S or labeled therewith. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., enriched in terms of one or more of its atoms). 2 H).

[1471] In some embodiments, the compound is a deuterated compound of any of the compounds described in Table 1, as well as its prodrug and pharmaceutically acceptable salt.

[1472] In some embodiments, the compound is a deuterated compound of any of the compounds described in Table 1 and a pharmaceutically acceptable salt thereof.

[1473] In some embodiments, the compound is a deuterated compound of any of the prodrugs of the compounds described in Table 1 and a pharmaceutically acceptable salt thereof.

[1474] In some embodiments, the compound is a deuterium-labeled compound of any of the compounds described in Table 1.

[1475] It should be understood that deuterium-labeled compounds contain deuterium atoms, the deuterium abundance of which is significantly greater than the natural abundance of deuterium (which is 0.015%).

[1476] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor per deuterium atom of at least 3500 (52.5% deuterium doped at each deuterium atom), at least 4000 (60% deuterium doped), at least 4500 (67.5% deuterium doped), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium doped), at least 6000 (90% deuterium doped), at least 6333.3 (95% deuterium doped), at least 6466.7 (97% deuterium doped), at least 6600 (99% deuterium doped), or at least 6633.3 (99.5% deuterium doped). As used herein, the term "deuterium enrichment factor" represents the ratio between the deuterium abundance and the natural abundance of deuterium.

[1477] It should be understood that deuterium-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by replacing non-deuterium-labeled reagents with deuterium-labeled reagents by implementing the schemes described herein and / or the procedures disclosed in the examples.

[1478] Compounds of this disclosure containing the aforementioned deuterium atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of this disclosure. Furthermore, deuterium (i.e., 2 H) substitution can provide certain therapeutic advantages, which result from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[1479] In some embodiments, the compound is 18 F-labeled compounds.

[1480] In some embodiments, the compound is 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compounds or any combination thereof.

[1481] In some embodiments, the compound is 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compounds or any combination thereof.

[1482] It should be understood 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135I, 3 S, 34 S, 35 S and / or 36 S-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, the deuterium-labeled compounds can generally be prepared by implementing the schemes described herein and / or the procedures disclosed in the examples, by using... 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S and / or 36 The preparation was carried out using S-labeled reagents instead of non-isotope-labeled reagents.

[1483] Contains one or more of the above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S and 36 The S atom of the compounds described in this disclosure, or their pharmaceutically acceptable salts or solvates, are within the scope of this 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 S) substitution can provide certain therapeutic advantages, which result from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[1484] For the avoidance of doubt, it should be understood that in this specification, when a group is defined as “described herein”, the group encompasses the first appearance and the broadest definition, as well as each and all specific definitions of that group.

[1485] Typically, various functional groups and substituents are chosen to form compounds of chemical formula (I), such that the molecular weight of the compound does not exceed 1100 Daltons. More typically, the molecular weight of the compound will be less than 1000, for example, less than 900 or less than 800.

[1486] As used herein, the term "isomer" refers to compounds that have the same molecular formula but differ in the bonding order of their atoms or in the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other and do not overlap are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of enantiomers with opposite chirality is called a "racemic mixture."

[1487] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[1488] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center may exist as a single diastereomer or as a mixture of diastereomers (referred to as a "diastereomer mixture"). When a chiral center is present, the stereoisomer is characterized by the absolute configuration (R or S) of the chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center are arranged according to the Cahn, Ingold, and Prelog order. (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).

[1489] As used herein, the term "geometric isomer" refers to a diastereomer whose existence is due to steric rotation around a double bond or cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, which indicate that, according to the Cahn-Ingold-Prelog rule, the groups are located on the same or opposite sides of the double bond in the molecule.

[1490] It should be understood that the compounds of this disclosure may be described as different chiral or geometric isomers. It should also be understood that when a compound has chiral or geometric isomers, all isomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any isomer. It should be understood that not all isomers may have the same level of activity.

[1491] It should be understood that the structures and other compounds discussed in this disclosure include all their isomers. It should also be understood that not all isomers can have the same level of activity.

[1492] As used herein, the term "isomeric isomer" refers to a class of stereoisomers in which the atoms of two isomers are arranged differently in space. The presence of isomers is due to restricted rotation caused by the rotational steric hindrance of the larger group around the central bond. These isomers usually exist as mixtures; however, due to recent advancements in chromatographic techniques, it is now possible to selectively separate mixtures of two isomers.

[1493] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and readily convert from one isomer to another. This conversion results in a shift in the form of hydrogen atoms accompanying a switching of adjacent conjugated double bonds. Tautomers exist in solution as a mixture of tautomers. In solutions in which tautomerization can occur, a chemical equilibrium of tautomers will be reached. The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. The concept of interchangeable tautomers through tautomerization is called tautomerism. Of the many possible types of tautomerism, two are typically observed. In keto-enol tautomerism, simultaneous changes of electrons and hydrogen atoms occur. Ring-chain tautomerism arises because the aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule, thus providing a cyclic (cyclic) form as shown by glucose.

[1494] It should be understood that the compounds of this disclosure may be described as different tautomers. It should also be understood that when a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomer form. It will be understood that some tautomers may have higher levels of activity than others.

[1495] Compounds with the same molecular formula but different atomic bonding properties, sequences, or spatial arrangements are called "isomers." Isomers with different spatial arrangements of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and those stereoisomers that are mirror images of each other and do not overlap are called "enantiomers." When a compound has an asymmetric center, for example, that center is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-order rules of Cahn and Prelog, or by rotating the molecular plane of polarization and specifying them as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as single enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[1496] The compounds described in this disclosure may have one or more asymmetric centers; therefore, these compounds may be prepared as single (R)- or (S)- stereoisomers or as mixtures thereof. Unless otherwise stated, the description or naming of particular compounds in this specification and claims is intended to include their individual enantiomers and mixtures (racemic or otherwise). Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution in racemic form. Some of the compounds described in this disclosure may have geometric isomer centers (E- and Z-isomers). It should be understood that this disclosure covers all optical, diastereomers and geometric isomers and mixtures thereof with inflammasome inhibitory activity.

[1497] This disclosure also covers compounds containing one or more isotope substitutions as defined herein.

[1498] It should be understood that, where applicable, any compound of any chemical formula described herein includes the compound itself, its salts, and its solvates. For example, salts can be formed between an anion and a positively charged group (e.g., an amino group) on the substituted compound disclosed herein. Suitable anions include chlorides, bromides, iodides, sulfates, hydrogen sulfates, aminosulfonates, nitrates, phosphates, citrates, methanesulfonates, trifluoroacetates, glutamates, glucurons, glutarates, malates, maleates, succinates, fumarates, tartrates, toluenesulfonates, salicylates, lactates, naphthalenesulfonates, and acetates (e.g., trifluoroacetates).

[1499] 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 and a negatively charged group (e.g., a carboxyl group) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine ions. The substituted compounds disclosed herein also include those salts containing a quaternary nitrogen atom.

[1500] It should be understood that the compounds disclosed herein, for example, salts of said compounds, may exist as hydrates or non-hydrates (anhydrous) or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[1501] As used herein, the term "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to retain a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming solvates. If the solvent is water, the formed solvate is a hydrate; if the solvent is an alcohol, the formed solvate is an alcohol. Hydrates are formed by the combination of one or more water molecules with one molecule of the substance, wherein water retains its molecular state as H₂O.

[1502] As used herein, the term "analogue" refers to a compound that is structurally similar to another compound but differs slightly in composition (e.g., an atom is substituted by an atom of a different element, or, in the presence of a specific functional group, one functional group is substituted by another). Thus, an analogue is a compound that is functionally similar to or equivalent to a reference compound but differs in structure or origin.

[1503] As used herein, the term “derivative” refers to a compound having a common core structure and being substituted by multiple groups as described herein.

[1504] As used herein, the term "bioisostere" refers to a compound resulting from the exchange of one atom or group of atoms with a substantially similar other atom or group of atoms. The aim of bioisostere substitution is to produce a new compound with biological properties similar to the parent compound. Bioisostere substitution can be based on physicochemical or topological principles. Examples of carboxylic acid bioisosteres include (but are not limited to) acylsulfonamides, tetrazolium, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[1505] It should also be understood that certain compounds of any of the chemical formulas disclosed herein may exist in solvated and non-solvated forms, such as, for example, in a hydrated form. Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this disclosure covers all such solvated forms having inflammasome-inhibiting activity.

[1506] It should also be understood that certain compounds of any of the chemical formulas disclosed herein can exhibit polymorphism, and this disclosure covers all such forms or mixtures thereof that have inflammasome-inhibiting activity. It is generally known that conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy can be used to analyze the water content of these crystalline materials.

[1507] Compounds of any of the chemical formulas disclosed herein may exist in several different tautomeric forms, and compounds referred to in formula (I) or (II) include all of these forms. For the avoidance of ambiguity, when a compound may exist in one of several tautomeric forms, and only one form is specifically described or shown, all other forms are still covered by formula (I) or (II). Examples of tautomeric forms include ketones, enols, and enol salts, such as (for example) in the following tautomeric pairs: ketone / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acid-nitro.

[1508]

[1509] Compounds containing any of the chemical formulas disclosed herein that are amine functional can also form N-oxides. Compounds of formula (I) or (II) containing amine functionality mentioned herein also include N-oxides. When a compound contains several amine functionalities, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent (such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid)), see, for example, Advanced Organic Chemistry, by Jerry March, 4th ed., Wiley Interscience, p. More specifically, N-oxides can be prepared by the LWDeady procedure (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[1510] Compounds of any of the chemical formulas disclosed herein can be administered as prodrugs, which decompose in humans or animals to release the compounds described herein. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds described herein. Prodrugs can be formed when the compounds described herein contain suitable groups or substituents that can attach modifying groups. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any of the chemical formulas disclosed herein.

[1511] Therefore, this disclosure includes compounds of any of the chemical formulas disclosed herein as defined above, when available through organic synthesis and when available in humans or animals through the cleavage of their prodrugs. Thus, this disclosure includes compounds of any of the chemical formulas disclosed herein produced by organic synthesis, as well as those produced in humans or animals through the metabolism of precursor compounds, i.e., compounds of any of the chemical formulas disclosed herein can be synthetically produced or metabolically produced compounds.

[1512] A suitable pharmaceutically acceptable prodrug of any of the chemical formulas disclosed herein is a prodrug that is deemed suitable for administration to humans or animals based on reasonable medical judgment, without undesirable pharmacological activity and without excessive toxicity. For example, various forms of prodrugs have been described in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, 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., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Vol. 14; and h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[1513] Suitable pharmaceutically acceptable prodrugs of compounds having a hydroxyl group in any of the chemical formulas disclosed herein are, for example, in vivo cleavable esters or ethers thereof. In vivo cleavable esters or ethers of compounds containing a hydroxyl group in any of the chemical formulas disclosed herein are, for example, pharmaceutically acceptable esters or ethers cleaved in humans or animals to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include inorganic esters, such as phosphate esters (including cyclic phosphoramide esters). Other suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include C1-C1 esters. 10 Alkyl groups, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C 10Alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of cyclic 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 the hydroxyl group include α-acyloxyalkyl groups, such as acetoxymethyl and neopentyloxymethyl.

[1514] Suitable pharmaceutically acceptable prodrugs of compounds having a carboxyl group in any of the chemical formulas disclosed herein are, for example, their in vivo cleavable amides, such as amides formed with amines like ammonia, C 1-4 Alkylamines such as methylamine, (C1-C4 alkyl)2amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amino acids such as glycine or its esters.

[1515] Suitable pharmaceutically acceptable prodrugs of compounds having an amino group, any of the chemical formulas disclosed herein, are, for example, their in vivo cleavable amide derivatives. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, those with C1-C... 10 Amides formed from alkyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of cyclic 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.

[1516] The in vivo effects of any compound of the chemical formulas disclosed herein can be exerted in part through one or more metabolites formed in a human or animal following administration of any compound of the chemical formulas disclosed herein. As mentioned above, the in vivo effects of any compound of the chemical formulas disclosed herein can also be exerted through the metabolism of a prodrug. Method for synthesizing compounds of chemical formula (A)

[1517] The compounds described in this invention can be prepared by a variety of methods, including standard chemistry. Suitable synthetic routes are shown in the following embodiments.

[1518] Compounds of formula (I) can be prepared by methods known in the field of organic synthesis, partly as described in the following synthetic schemes. In the schemes described below, it is well known that protecting groups with sensitive or reactive groups are used, where necessary, according to general principles or chemistry. Protecting groups are used according to standard methods of organic synthesis (TW Greene and PGM Uts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999). These groups are removed at appropriate stages of the compound synthesis using methods readily apparent to those skilled in the art. The method chosen by those skilled in the art, as well as the reaction conditions and sequence, will determine the presence of a stereocenter in the compound of formula (I). Therefore, the present invention includes two possible stereoisomers (unless otherwise stated in the synthesis) and includes not only racemic compounds but also single enantiomers and / or diastereomers. When a single enantiomer or diastereomer is desired, it can be obtained by stereooriented synthesis or by resolving the final product or any suitable intermediate. Resolving the final product, intermediate, or starting material can be achieved by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds", edited by E.L. Leel, S.H. Wilen and L.N. Mander (Wiley-Interscience, 1994).

[1519] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic methods.

[1520] The compounds described in this invention can be prepared using a variety of methods well known to those skilled in the art of organic synthesis. For example, the compounds of this invention can be synthesized using the methods described below in conjunction with synthetic methods known in the field of synthetic organic chemistry or variations thereof understood by those skilled in the art. Suitable methods include (but are not limited to) those described below. The compounds of this invention can be synthesized according to the steps listed in conventional procedure A or B, which includes different sequences of assembling intermediates or compounds. Starting materials are commercially available or prepared by procedures reported in the literature or known as shown below.

[1521] Standard procedure

[1522] Generally, compounds of formula (I) can be prepared using reaction sequences known to those skilled in the art of organic synthesis. The following conventional schemes illustrate several routes for compounds of formula (I):

[1523]

[1524] All reagents may be commercially available compounds themselves or synthetic products derived from commercially available reagents. For each compound in preparation, a one-step or multi-step synthetic procedure may be used, including (but not limited to) the procedures described in the Preparation section herein.

[1525] Specific, non-limiting examples of the reaction sequence that produces compounds of formula (I) can be provided through the preparation of compound 4:

[1526]

[1527] Specific, non-limiting examples of the reaction sequence that produces compounds of formula (I) can be provided through the preparation of compound 15:

[1528]

[1529] Specific, non-limiting examples of the reaction sequence that produces compounds of formula (I) can be provided through the preparation of compound 16:

[1530]

[1531] Specific, non-limiting examples of the reaction sequence that produces compounds of formula (I) can be provided through the preparation of compound 6:

[1532]

[1533] Specific, non-limiting examples of the reaction sequence that produces compounds of formula (I) can be provided through the preparation of compound 19:

[1534]

[1535] Those skilled in the art will readily understand that the compound of chemical formula (I) obtained according to the above procedure can be further transformed and modified to obtain compounds of other chemical formula (I).

[1536] Bioassay

[1537] Once generated, compounds designed, selected, and / or optimized by the methods described above 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 can be characterized by conventional assays (including, but not limited to, those described below) to determine whether they possess predicted activity, binding activity, and / or binding specificity.

[1538] Furthermore, high-throughput screening can be used to accelerate analyses using these assays. Therefore, it is possible to rapidly screen the activity of molecules described herein using techniques known in the art. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques, including (but not limited to) those described below.

[1539] A variety of in vitro or in vivo bioassays may be suitable for detecting the effects of the compounds disclosed herein. These in vitro or in vivo bioassays may include (but are not limited to) enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[1540] Pharmaceutical Composition

[1541] In some aspects, this disclosure provides pharmaceutical compositions comprising compounds of this disclosure as active ingredients. In some embodiments, this disclosure provides pharmaceutical compositions comprising at least one compound of each of the chemical formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, this disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

[1542] As used herein, the term "composition" is intended to cover products containing the specified amount of the specified ingredient, and any products directly or indirectly produced from a combination of the specified amounts of the specified ingredient.

[1543] The compounds described herein can be formulated into forms for oral administration, such as tablets, capsules (each comprising a sustained-release or time-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds described herein can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all in forms well known to those skilled in the art of pharmaceutical manufacturing.

[1544] The formulations disclosed herein may be in the form of an aqueous solution comprising an aqueous medium. The aqueous medium component may comprise water and at least one pharmaceutically acceptable excipient. Suitable excipients include those selected from solubility enhancers, chelating agents, preservatives, tensile agents, viscosity / suspension agents, buffers, and pH adjusters, and mixtures thereof.

[1545] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins, such as those selected from hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, preacetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylamino)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfonyl ether, branched-chain β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, random methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[1546] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from ethylenediaminetetraacetic acid (EDTA) and its metal salts, disodium EDTA, trisodium EDTA, and tetrasodium EDTA and mixtures thereof.

[1547] Any suitable preservative may be used. Examples of preservatives include those selected from the following: quaternary ammonium salts, such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzyl chloride, cetylpyridine chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, and butylparaben and sorbic acid and mixtures thereof.

[1548] In some embodiments, examples of preservatives include those selected from: quaternary ammonium salts, such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzyl chloride, cetylpyridine chloride, benzyl bromide, phenylmercuric nitrate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, butylparaben, and sorbic acid and mixtures thereof.

[1549] The aqueous medium may also include a tensioning agent to adjust the osmotic pressure. The tensioning agent may be selected from glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the tensioning agent is selected from glycols (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[1550] Aqueous media may also contain viscosity / suspension agents. Suitable viscosity / suspension agents include those selected from: cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropyl methylcellulose, and crosslinked acrylic polymers (carbopol), such as polymers crosslinked with acrylic acid and polyolefin ethers or divinyl glycol (Carbopol - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P) and mixtures thereof.

[1551] To adjust the formulation to an acceptable pH (typically a pH range 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 a pH adjuster. The pH adjuster is typically an inorganic acid or metal hydroxide base selected from potassium hydroxide, sodium hydroxide, and hydrochloric acid and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to a target acceptable pH range. Therefore, it may not be necessary to use both acid- and base-based formulations; adding either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[1552] Aqueous media may also contain buffers to stabilize pH. When used, buffers are selected from phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate), and ε-aminocaproic acid and mixtures thereof.

[1553] The formulation may also contain a wetting agent. Suitable wetting agents include those selected from the following: polyoxypropylene-polyoxyethylene block copolymers (poloxapol), polyethoxylated ethers of castor oil, polyoxyethylene-modified sorbitol esters (polysorbate), polymers of ethoxylated octylphenol (Tyloxapol), polyethylene glycol 40 stearate, ethylene glycol esters of fatty acids, glycerol esters of fatty acids, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[1554] Oral compositions typically contain an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, excipients may be incorporated into the active compound and administered in tablet, lozenge, or capsule form. For use as a mouthwash, oral compositions may also be prepared using a fluid carrier, wherein the compound in the fluid carrier is applied orally and rinsed and coughed up or swallowed. 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 components or compounds with similar properties: binders, such as microcrystalline cellulose, astragalus gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, Primogel, or corn starch; lubricants, such as magnesium stearate or sterotes; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[1555] According to other aspects of this disclosure, pharmaceutical compositions are provided comprising a compound as defined above, a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[1556] In some embodiments, the pharmaceutical compositions described herein may further comprise one or more other pharmaceutically active agents.

[1557] The compositions described herein may be in forms suitable for oral administration (e.g., as tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), forms suitable for topical administration (e.g., as creams, ointments, gels or aqueous or oily solutions or suspensions), forms suitable for inhalation administration (e.g., as fine powders or liquid aerosols), forms suitable for inhalation administration (e.g., as fine powders), or forms suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular doses, or as suppositories for rectal doses).

[1558] The compositions described herein can be obtained through conventional procedures using conventional pharmaceutical excipients well known in the art. Therefore, compositions designed for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[1559] The therapeutically effective amount of the compounds disclosed herein used in a therapy is sufficient to treat or prevent the MLL-related conditions mentioned herein, slow their progression, and / or reduce symptoms associated with said conditions.

[1560] The therapeutically effective amount of the compounds disclosed herein used in a therapy is sufficient to treat the MLL-related conditions mentioned herein, slow their progression, and / or reduce symptoms associated with said conditions.

[1561] The dosage of a compound of chemical formula (I) for therapeutic or preventative purposes will naturally vary according to the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration, in accordance with well-known medical principles.

[1562] How to use

[1563] In some aspects, this disclosure provides a method for the degradation of MALT1 (e.g., in vitro or in vivo), which includes contacting cells with a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[1564] In some aspects, this disclosure provides methods for treating or preventing diseases or conditions disclosed herein in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[1565] In some aspects, this disclosure provides methods for treating a subject in need of a disease or condition disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[1566] In some embodiments, the disease or condition is related to MALT1. In some embodiments, the disease or condition is one in which MALT1 is involved.

[1567] The compound described in this invention is a PROTAC of MALT1.

[1568] The compounds described in this invention are also useful in treating diseases associated with MALT1. For example, diseases and conditions treatable by the methods described in this invention include immunodeficiency type 12; mucosa-associated lymphoid lymphoma (MALTOMA); combined immunodeficiency; combined T-cell and B-cell immunodeficiency; or lymphoma.

[1569] In some implementations, the disease or condition is lymphoma.

[1570] In some embodiments, the disease or condition is mucosa-associated lymphoid lymphoma (MALTOMA).

[1571] In some implementations, the disease or condition is immunodeficiency type 12.

[1572] In some implementations, the disease or condition is combined immunodeficiency.

[1573] In some embodiments, the disease or condition is a combination of T-cell and B-cell immunodeficiency.

[1574] In some aspects, this disclosure provides methods for treating or preventing lymphoma in a subject in need, the methods comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[1575] In some aspects, this disclosure provides a method for treating or preventing immunodeficiency type 12 in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[1576] In some aspects, this disclosure provides a method for treating or preventing mucosa-associated lymphoid lymphoma (MALTOMA) in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[1577] In some aspects, this disclosure provides methods for treating or preventing combined immunodeficiency in a subject in need, the methods comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[1578] In some aspects, this disclosure provides methods for treating or preventing combined T-cell and B-cell immunodeficiency in subjects in need, the methods comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[1579] In some aspects, this disclosure provides a method for treating lymphoma in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[1580] In some aspects, this disclosure provides a method for treating immunodeficiency type 12 in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[1581] In some aspects, this disclosure provides a method for treating mucosa-associated lymphoid lymphoma (MALTOMA) in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[1582] In some aspects, this disclosure provides a method for treating combined immunodeficiency in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[1583] In some aspects, this disclosure provides a method for treating combined T-cell and B-cell immunodeficiency in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[1584] In some respects, this disclosure provides compounds of this disclosure or pharmaceutically acceptable salts thereof for (e.g., in vitro or in vivo) degradation of MALT1.

[1585] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment or prevention of diseases or conditions disclosed herein.

[1586] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment of the diseases or conditions disclosed herein.

[1587] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment or prevention of lymphoma in subjects in need of such treatment.

[1588] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment or prevention of immunodeficiency type 12 in subjects in need of such treatment.

[1589] In some respects, this disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for the treatment or prevention of mucosa-associated lymphoid lymphoma (MALTOMA) in subjects in need of such treatment.

[1590] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment or prevention of combined immunodeficiency in subjects in need of such treatment.

[1591] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment or prevention of combined T-cell and B-cell immunodeficiency in subjects in need of such treatment.

[1592] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment of lymphoma in subjects in need of treatment.

[1593] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment of immunodeficiency type 12 in subjects in need of such treatment.

[1594] In some respects, this disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for the treatment of mucosa-associated lymphoid lymphoma (MALTOMA) in subjects in need of treatment.

[1595] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for treating combined immunodeficiency in subjects in need of such treatment.

[1596] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for treating combined T-cell and B-cell immunodeficiency in subjects in need of such treatment.

[1597] In some aspects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of pharmaceutical agents for (e.g., in vitro or in vivo) the degradation of MALT1.

[1598] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of medicaments for the treatment or prevention of the diseases or conditions disclosed herein.

[1599] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of medicaments for treating the diseases or conditions disclosed herein.

[1600] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of a medicament for the treatment or prevention of lymphoma in a subject in need.

[1601] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of a medicament for the treatment or prevention of mucosa-associated lymphoid lymphoma (MALTOMA) in subjects in need thereof.

[1602] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of a medicament for the treatment or prevention of immunodeficiency type 12 in a subject in need of such treatment.

[1603] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of medicaments for the treatment or prevention of combined immunodeficiency in subjects in need thereof.

[1604] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of medicaments for the treatment or prevention of combined T-cell and B-cell immunodeficiency in subjects in need thereof.

[1605] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of a medicament for treating lymphoma in subjects in need of such treatment.

[1606] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of a medicament for the treatment of mucosa-associated lymphoid lymphoma (MALTOMA) in subjects in need of treatment.

[1607] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of a medicament for treating immunodeficiency type 12 in subjects in need thereof.

[1608] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of a medicament for treating combined immunodeficiency in subjects in need of it.

[1609] In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the production of a medicament for treating combined T-cell and B-cell immunodeficiency in subjects in need thereof.

[1610] This disclosure provides compounds that act as a (e.g., in vitro or in vivo) PROTAC for MALT1. Therefore, this disclosure provides methods for degrading MALT1 in vitro or in vivo, said methods comprising contacting cells with a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[1611] In some embodiments, the PROTAC of MALT1 is a compound disclosed herein.

[1612] The effectiveness of the compounds described herein can be determined using industry-accepted assays / disease models, based on standard practices that elucidate the same conditions as described in the art or existing in current common sense.

[1613] This disclosure also provides a method for treating a disease or condition involving MALT1 in a subject who requires such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[1614] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[1615] Application route

[1616] The compounds disclosed herein or pharmaceutical compositions comprising such compounds may be administered to a subject via any appropriate route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[1617] Routes of administration include (but are not limited to) oral (e.g., by ingestion); oral cavity; sublingual; transdermal (including (e.g.) by patches, plasters, etc.); transmucosal (including (e.g.) by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or inhalation therapy, which uses (e.g.) aerosols, for example, through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by vaginal suppositories); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; and implants in depots or reservoirs, such as subcutaneous or intramuscular implants.

[1618] The abbreviations used in the following embodiments and elsewhere in this document are:

[1619] AcOH (acetic acid)

[1620] aq. water

[1621] Boc2O ditert-butyl dicarbonate

[1622] br. Broad peak

[1623] CDI 1,1'-carbonyldiimidazole

[1624] d Bimodal

[1625] DCM dichloromethane

[1626] DIPEA N,N-Diisopropylethylamine

[1627] DMAA 1,3-dimethylpentylamine

[1628] DMF N,N-dimethylformamide

[1629] DMSO (dimethyl sulfoxide)

[1630] DPPA (diphenyl azidophosphate)

[1631] DTT dithiothreitol

[1632] ESI Electrospray Ionization

[1633] FBS Fetal Bovine Serum

[1634] h hours

[1635] HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3)

[1637] -Oxide hexafluorophosphate

[1638] HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethane-1-sulfonic acid

[1639] HPLC (High-Performance Liquid Chromatography)

[1640] LCMS (Liquid Chromatography-Mass Spectrometry)

[1641] m multiplet

[1642] M Moore

[1643] MHz

[1644] min minutes

[1645] MsCl methanesulfonyl chloride

[1646] NBS N-bromosuccinimide

[1647] NMR (Nuclear Magnetic Resonance)

[1648] q Quadruple Peak

[1649] rt room temperature

[1650] s Single peak

[1651] STAB sodium triacetoxyborohydride

[1652] t Temperature, triplet

[1653] TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate ammonium

[1654] TEA Triethylamine

[1655] TFA (trifluoroacetic acid)

[1656] THF Tetrahydrofuran

[1657] TLC (Thin Layer Chromatography)

[1658] Example

[1659] Conventional synthetic procedures and examples for compound preparation

[1660] Constructing the composition of blocks

[1661] Synthesis of 7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (P4)

[1662]

[1663] Preparation of 1-ethyl 3-cyclopentyl-3-oxypropionate (P1)

[1664] 1) Carbonyl diimidazole (10.91 g, 67.25 mmol) was added in portions to a mixture of tetrahydrofuran-2-carboxylic acid (7.1 g, 61.14 mmol) and anhydrous EtOAc (100 mL). The mixture was stirred at 50 °C for 3 h.

[1665] 2) MgCl2 (23.3 g, 122.28 mmol) was added fractionally to a mixture of potassium 3-ethoxy-3-oxopropionate (20.81 g, 122.28 mmol) and anhydrous EtOAc (300 mL). The mixture was stirred at 50 °C for 3 h. The solution from step (1) was added dropwise to the suspension from step (2), and the mixture was refluxed and stirred overnight. The mixture was cooled in an ice bath and acidified to pH 3 with 4 M HCl (140 mL). The mixture was heated to ambient temperature and separated into layers. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine and dried (Na2SO4). Concentration and purification by chromatography on silica gel yielded compound P1 (8.5 g, 75%). 1 H NMR (400MHz, CDCl3), δ: 4.40 (dd, J=8.3, 6.5Hz, 1H), 4.21 (q, J=7.1Hz, 2H), 3.93 (dd, J=9.6, 3.9Hz, 2H), 3.5 9(s,2H),2.21(ddd,J=15.4,12.6,7.1Hz,1H),2.13-2.00(m,1H),1.98-1.85(m,2H),1.26(t,J=7.1Hz,3H).

[1666] Preparation of 2-ethyl(2Z)-3-(dimethylamino)-2-(tetrahydrofuran-2-ylcarbonyl)acrylate (P2)

[1667] A solution of compound P1 (10.6 g, 56.9 mmol) and N,N-dimethylformamide dimethylacetal (75 mL, 569.0 mmol) was refluxed and stirred overnight. The mixture was evaporated to dryness, and the residue was purified by column chromatography on silica gel. The yield of compound P2 was 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).

[1668] Preparation of 3-ethyl 7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ester (P3)

[1669] 1H-pyrazole-5-amine (4.0 g, 47.2 mmol) was added to a solution of compound P2 (9.5 g, 39.3 mmol) in 200 mL of EtOH. The mixture was refluxed and stirred overnight. The mixture was evaporated, and the residue was purified by column chromatography on silica gel. 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).

[1670] Preparation of 4,7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (P4)

[1671] A mixture of compound P3 (9.0 g, 34.4 mmol) and NaOH (2.1 g, 51.6 mmol) in 200 mL of EtOH and 50 mL of H2O was stirred at 60 °C for 15 h and then evaporated. The residue was diluted with water and acidified with 6 M HCl to pH 3–4. The resulting solid was filtered off and dried. The yield of compound P4 was 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).

[1672] Synthesis of ethyl 6-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P9)

[1673]

[1674] Preparation of 5,3-methyl-5-nitropyridine-2-onitrile (P5)

[1675] A mixture of 2-chloro-3-methyl-5-nitro-pyridine (5.0 g, 29.0 mmol), zinc cyanide (2.7 g, 23.2 mmol), tris(dibenzylacetone)dipalladium(0) (1.3 g, 1.45 mmol), and (9,9-dimethyl-9H-oxanthracene-4,5-diyl)bis(diphenylphosphine) in 1-methyl-2-pyrrolidone (30 mL) was heated to 130–135 °C for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL), and filtered through diatomaceous earth. 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 column chromatography on silica gel. Yield of compound P5 (4.0 g, 85%). 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),8.83(s,1H),2.64(s,3H).

[1676] Preparation of 6,N'-hydroxy-3-methyl-5-nitropyridine-2-formamidin (P9)

[1677] Na₂CO₃ (6.5 g, 61.3 mmol) was added to a solution of hydroxylamine hydrochloride (8.6 g, 122.5 mmol) in 150 mL of H₂O. The mixture was stirred at ambient temperature for 0.5 h. Compound P5 (4.0 g, 24.5 mmol) was dissolved in EtOH and added to the mixture, and the reaction mixture was stirred at ambient temperature for 14 h. The EtOH was evaporated. The resulting solid was filtered off and dried. The yield of compound P6 was 83% (4.0 g). 1H NMR (400MHz, DMSO-d6) δ10.30 (d, J = 1.7Hz, 1H), 9.20 (s, 1H), 8.52 (s, 1H), 5.95 (s, 2H), 2.61 (s, 3H).

[1678] Preparation of 7-ethyl 7-({[(1Z)-amino(3-methyl-5-nitropyridin-2-yl)methylene]amino}oxy)-7-oxoheptane ester (P7)

[1679] TEA (1.1 mL, 8.1 mmol) was added to a solution of 7-ethoxy-7-oxoheptanoic acid (0.50 g, 2.7 mmol) in 20 mL of DCM. The mixture was stirred at rt for 10 min. Subsequently, 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 h. 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.

[1680] Preparation of 8-ethyl 6-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P8)

[1681] The solution of compound P7 in 50 mL of dioxane was refluxed and stirred for 96 h. The mixture was evaporated and purified by column chromatography on silica gel. The yield of compound P8 in steps 7 and 8 was 0.56 g (61%). LCMS ESI (m / z): 349.5 ([M+1]) + ),303.5.

[1682] Preparation of 9-ethyl 6-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P9)

[1683] Fe powder (0.9 g, 16 mmol) was added to a solution of compound P8 (0.56 g, 1.6 mmol) in 20 mL of acetic acid. The suspension was stirred at 70 °C for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL), and filtered through diatomaceous earth. 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 column chromatography on silica gel. Yield of compound P9 (0.44 g, 86%). LCMS ESI (m / z): 319.4 ([M+1)+ ),149.4.

[1684] Synthesis of 6-(3-{3-methyl-5-[({[7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl]amino}carbonyl)amino]pyridin-2-yl}-1,2,4-oxadiazol-5-yl)hexanoic acid (P11)

[1685]

[1686] Preparation of 10-ethyl 6-(3-{3-methyl-5-[({[7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl]amino}carbonyl)amino]pyridin-2-yl}-1,2,4-oxadiazol-5-yl)hexanoate (P10)

[1687] TEA (0.7 mL, 5.2 mmol) was added to a solution of compound P4 (0.30 g, 1.3 mmol) in 20 mL of toluene. The mixture was stirred at rt for 10 min. Then, DPPA (0.34 mL, 1.56 mmol) was added. The mixture was stirred at rt for 1 h, and then compound P9 (0.40 g, 1.3 mmol) was added. The resulting mixture was stirred at 90 °C for 14 h. The mixture was evaporated and purified by column chromatography on silica gel. The yield of compound P10 was 0.38 g, 54%. LCMS ESI (m / z): 549.7 ([M+1]) + ),345.1.

[1688] Preparation of 11,6-(3-{3-methyl-5-[({[7-(tetrahydrofuran-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl]amino}carbonyl)amino]pyridin-2-yl}-1,2,4-oxadiazol-5-yl)hexanoic acid (P11)

[1689] A mixture of compound P10 (0.38 g, 0.7 mmol) and NaOH (0.05 g, 1.05 mmol) in 10 mL of EtOH and 2 mL of H2O was stirred at 60 °C for 15 h and then evaporated. The residue was diluted with water and acidified with 6 M HCl to pH 3–4. The resulting solid was filtered off and dried. Yield of compound P11 (0.36 g, 99%). LCMS ESI (m / z): 521.7 ([M+1]) + ),317.1.

[1690] 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridine-2-

[1691] Synthesis of [P18]-1,2,4-oxadiazol-5-yl]hexanoic acid

[1692]

[1693] Preparation of 12,3-chloro-5-nitropyridine-2-onitrile (P12)

[1694] Zinc cyanide (1.83 g, 15.55 mmol) was added to a solution of 2,3-dichloro-5-nitropyridine (5.0 g, 25.91 mmol) in 20 mL of N-methyl-2-pyrrolidone. The flask was purged with argon and heated to 135 °C. In a separate flask, tris(dibenzylacetone)dipalladium(0) (1.19 g, 1.30 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (0.75 g, 1.30 mmol) were suspended in 15 mL of N-methyl-2-pyrrolidone and purged with argon, 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 h. When the reaction was complete (monitored by TLC), the reaction mixture was cooled to rt, diluted with ethyl acetate, and filtered through diatomaceous earth (Celite). The solution in ethyl acetate was washed with water, dried over Na₂SO₄ and evaporated. The product was purified by column chromatography on silica gel. The eluent was hexane / ethyl acetate = 40 / 1. Solid product P12 (3.92 g, 82%) was obtained. 1 H NMR (400MHz, DMSO-d6), δ: 9.46 (d, J = 2.2Hz, 2H), 9.17 (d, J = 2.2Hz, 2H).

[1695] Preparation of 13,3-chloro-N'-hydroxy-5-nitropyridine-2-formamidinium (P13)

[1696] A solution of 3-chloro-5-nitropyridin-2-onitrile P12 (3.92 g, 21.4 mmol) in 40 mL of ethanol was added dropwise to a solution of hydroxylamine hydrochloride (5.94 g, 85.4 mmol) and Na2CO3 (4.53 g, 42.7 mmol) in 110 mL of water. The mixture was stirred at 90 °C for 12 h. The reactants were cooled to rt and filtered to provide 3-chloro-N'-hydroxy-5-nitropyridin-2-formamidinium P13 (4.41 g, 90%). The precipitate was used for further reactions without further purification. 1 H NMR (400MHz, DMSO-d6), δ: 10.22 (s, 1H), 9.31 (d, J = 2.2Hz, 1H), 8.77 (d, J = 2.2Hz, 1H), 6.00 (s, 2H).

[1697] Preparation of 14-ethyl 7-{[(E)-(3-chloro-5-nitropyridin-2-yl)(oxime)methyl]amino}-7-oxoheptane ester (P14)

[1698] N-ethyl-N-isopropylpropyl-2-amine (0.30 g, 2.33 mmol) was added to a solution of 7-ethoxy-7-oxoheptanoic acid (0.37 g, 1.94 mmol) in 40 mL of dioxane. The solution was stirred for 5 min, then P13 (0.42 g, 1.94 mmol) was added, and the mixture was stirred for 10 min. 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphonane 2,4,6-trioxide (0.93 g, 2.91 mmol, 50 wt% solution in EtOAc) was poured into a reaction flask, and the reaction mixture was stirred at rt for 12 h. After the reaction was complete as indicated by TLC, the reaction mixture was concentrated under vacuum, dissolved in ethyl acetate, washed with water, and evaporated. The residue (P14) was used for the next step without further purification. LCMS ESI (m / z): 387.4 ([M+1)) + ),217.4.

[1699] Preparation of 15-ethyl 6-[3-(3-chloro-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P15).

[1700] Ethyl 7-{[(E)-(3-chloro-5-nitropyridin-2-yl)(oxime)methyl]amino}-7-oxoheptane ester P14 (1.79 g, 4.61 mmol) was dissolved in 50 mL of 1,4-dioxane. The solution was refluxed for 96 h. After the reaction was complete as indicated by TLC, the reaction mixture was concentrated under vacuum. The residue was purified on silica gel by elution with EtOAc / hexane 1:10, thus providing ethyl 6-[3-(3-chloro-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexane ester P15 (0.62 g). The yields of the two steps (preparations of 14 and 15) were 37%. LCMS ESI (m / z): 369.1 ([M+1) + ),323.5.

[1701] Preparation of 16-ethyl 6-[3-(5-amino-3-chloropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P16).

[1702] Ethyl 6-[3-(3-chloro-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate P15 (0.62 g, 1.69 mmol) was dissolved in 50 mL of a solvent consisting of equal volumes 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 material was completely converted as indicated by TLC. The mixture was cooled to ambient temperature and passed through diatomaceous earth. The filtrate was evaporated, and the residue was dissolved in ethyl acetate, washed with water, and concentrated. The mixture was then dissolved in dichloromethane, washed with an aqueous solution of sodium bicarbonate, dried with sodium sulfate, and concentrated to provide ethyl 6-[3-(5-amino-3-chloropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate P16 (0.46 g, 80%). 1 H NMR (400MHz, DMSO-d6), δ: 7.99 (d, J = 2.3Hz, 1H), 7.09 (d, J = 2.3Hz, 1H), 6.19 (s, 2H), 4.03 (q, J = 7.1Hz, 2H), 2.97 (t, J = 7 .4Hz,2H),2.28(t,J=7.3Hz,2H),1.83-1.69(m,2H),1.67-1.49(m,2H),1.37(m,2H),1.26(m,2H),1.10(t,J=7.1Hz,3H).

[1703] Preparation of 17-ethyl 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate (P17).

[1704] Triethylamine (0.548 g, 5.4 mmol) was added to a suspension of 7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.31 g, 1.35 mmol) in 40 mL of toluene. The mixture was stirred for 5 min. Then, DPPA (0.48 g, 1.62 mmol) was added, and the mixture was stirred at rt for 60 min. Subsequently, ethyl 6-[3-(5-amino-3-chloropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate P16 (0.458 g, 1.35 mmol) was added, and the mixture was refluxed for 12 h. The reaction was monitored by LCMS. The mixture was quenched with water, and the separated toluene was dried over Na2SO4 and evaporated. The residue was purified on silica gel by elution with hexane / ethyl acetate at a 1:1 ratio, yielding ethyl 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate P17 (0.55 g, 72%). LCMS ESI (m / z): 567.5 ([M+1) + ).

[1705] Prepare 18,6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid (P18).

[1706] An aqueous solution of NaOH (0.08 g, 1.94 mmol) was added to a solution of ethyl 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate P17 (0.55 g, 0.97 mmol) in 10 mL of ethanol. The mixture was stirred at 50 °C for 12 h. After complete hydrolysis of the ester, the mixture was cooled to ambient temperature. The ethanol was evaporated, and the reaction mixture was acidified to pH 7 with hydrochloric acid, followed by extraction of the product with ethyl acetate. The product solution in ethyl acetate was dried with Na₂SO₄ and evaporated. Solid 6-{3-[3-chloro-5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid P18 (0.378 g, 72%) was obtained. LCMS ESI (m / z): 539.5 ([M+1) + ),431.5.

[1707] Synthesis of 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoic acid (P26)

[1708]

[1709] 19.3-Methyl-5-nitropyridine-2-carboxylic acid (P19) was prepared.

[1710] In a 25 mL microwave-safe vial, 1.75 g (10.7 mmol) of 3-methyl-5-nitropyridine-2-acid P5 was dissolved in a mixture of EtOH (5 mL) and concentrated H2SO4 (15 mL). The vial was sealed and heated in a microwave oven to 120 °C for 60 min. After completion, the reaction mixture was cooled to rt and concentrated to dryness. The resulting residue was dissolved in THF, and 1 N NaOH was slowly added until pH = 9. The resulting mixture was stirred at 50 °C for 1 h. The mixture was then diluted with water and acidified to pH 4–5 with 1 N HCl, followed by extraction with EtOAc. The EtOAc layer was washed with brine (10 mL), dried (Na2SO4), and concentrated to provide a 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).

[1711] Preparation of 20-tert-butyl-2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazine carboxylate (P20).

[1712] N-[(dimethylamino)(3-oxobridge-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methylene]-N-methylmethylammonium hexafluorophosphate (4.89 g, 12.85 mmol) was added to a solution of 3-methyl-5-nitropyridine-2-carboxylic acid P19 (1.56 g, 8.57 mmol) in 30 mL of N,N-dimethylformamide and the solution was mixed for 5 min. Then, tert-butylhydrazine carbamate (1.36 g, 10.28 mmol) and triethylamine (1.73 g, 17.14 mmol) were added at rt. The reaction mixture was stirred at this temperature for 2 h. The mixture was then diluted with water and extracted with EtOAc. The EtOAc layer was washed with brine (10 mL), dried (Na2SO4), and concentrated to provide tert-butyl 2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazine carboxylate (1.78 g, 70%). 1H 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).

[1713] 21,3-methyl-5-nitropyridine-2-carbazine (P21) was prepared.

[1714] tert-Butyl-2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazine carboxylate P20 (1.76 g, 5.94 mmol) was dissolved in 20 mL of 1,4-dioxane. Hydrogen chloride was added as a 3N solution in 20 mL of 1,4-dioxane. The solution was stirred at rt for 12 h. After the reaction was complete as indicated by LCMS, the reaction mixture was concentrated under vacuum, and the residue was dissolved in methanol. Potassium carbonate was added, the mixture was stirred for 5 min, filtered, and concentrated to provide 3-methyl-5-nitropyridin-2-carbazine P21 (460 mg, 40%). LCMS ESI (m / z): 197.2 ([M+1]) + ).

[1715] Preparation of 22-ethyl 7-{2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazinoyl}-7-oxoheptane ester (P22).

[1716] 7-Ethoxy-7-oxoheptanoic acid (0.44 g, 2.35 mmol) and N,N-carbonyldiimidazole (0.456 g, 2.82 mmol) were stirred in 20 mL of 1,4-dioxane at 50 °C for 3 h. Then, 3-methyl-5-nitropyridin-2-carbazine P21 (0.46 g, 2.35 mmol) was added and the mixture was stirred at the same temperature for another 12 h. 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 column chromatography on silica gel (elution buffer - EtOAc / hexane, 5:1) to provide ethyl 7-{2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazinoyl}-7-oxoheptanoate P22 (0.23 g, 27%). LCMS ESI (m / z): 367.5 ([M+1) + ).

[1717] Preparation of 23-ethyl 6-[5-(3-methyl-5-nitropyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate (P23).

[1718] Triphenylphosphine (42.2 mg, 0.16 mmol) was added in portions to a solution of iodine (40.9 mg, 0.16 mmol) in DCM at 0–5 °C. Then, Et3N (32.6 mg, 0.32 mmol) was added, followed by ethyl 7-{2-[(3-methyl-5-nitropyridin-2-yl)carbonyl]hydrazinoyl}-7-oxoheptane ester P22 (118 mg, 0.32 mmol). The reaction mixture was stirred overnight at 0 °C. The mixture was washed with 10% sodium thiosulfate solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel to provide ethyl 6-[5-(3-methyl-5-nitropyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate P23 (51 mg, 45%). LCMS ESI (m / z): 349.5 ([M+1) + ).

[1719] Preparation of 24-ethyl 6-[5-(5-amino-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate (P24)

[1720] Ethyl 6-[5-(3-methyl-5-nitropyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate P23 (0.2 g, 0.57 mmol) was dissolved in 20 mL of a solvent consisting of equal volumes of ethanol and acetic acid. The mixture was heated to 40 °C and Fe powder (0.16 g, 2.85 mmol) was added. Stirring was continued at this temperature until the starting material was completely converted as indicated by TLC. The mixture was cooled to ambient temperature and passed through diatomaceous earth. The filtrate was evaporated, the residue was dissolved in ethyl acetate, washed with water, and concentrated. The mixture was then dissolved in dichloromethane, washed with an aqueous solution of sodium bicarbonate, dried with sodium sulfate, and concentrated to provide ethyl 6-[5-(5-amino-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate P24 (0.15 g, 82%). LCMS ESI (m / z): 319.5 ([M+1) + ).

[1721] Preparation of 25-ethyl 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoate (P25).

[1722] 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 min. Then, DPPA (0.15 g, 0.56 mmol) was added, and the mixture was stirred at rt for 60 min. Subsequently, ethyl 6-[5-(5-amino-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-yl]hexanoate P24 (0.189 g, 0.56 mmol) was added, and the mixture was refluxed for 12 h. The reaction was monitored by LCMS. The mixture was quenched with water, and the separated toluene layer was dried over Na2SO4 and evaporated. The residue was purified on silica gel by elution with hexane / ethyl acetate, 1:1, to provide ethyl 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoate P25 (0.165 g, 62%). LCMS ESI (m / z): 547.6 ([M+1) + ).

[1723] Prepare 26,6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoic acid (P26).

[1724] An aqueous solution of NaOH (8.2 mg, 0.2 mmol) was added to a solution of ethyl 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoate P25 (56 mg, 0.1 mmol) in 10 mL of ethanol. The mixture was stirred at 50 °C for 12 h. After ester hydrolysis was complete, the mixture was cooled to ambient temperature. The ethanol was evaporated and the reaction mixture was acidified to pH 7 with hydrochloric acid, and the product was extracted with ethyl acetate. The product solution in ethyl acetate was dried with Na2SO4 and evaporated. Solid 6-{5-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,3,4-oxadiazol-2-yl}hexanoic acid P26 (47.6 mg, 90%) was obtained. LCMS ESI (m / z): 519.6 ([M+1) + Synthesis of 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoic acid (P32)

[1725]

[1726] Prepare 27,3-methyl-5-nitro-2-[(trimethylsilyl)ethynyl]pyridine (P27).

[1727] 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 h. When the reaction was complete (monitored by TLC), the reaction mixture was cooled to rt, diluted with ethyl acetate, and filtered through diatomaceous earth. The filtrate was washed with saturated aqueous NaHCO3 solution and NaCl, dried over Na2SO4, and concentrated. The product was purified by column chromatography on silica gel. Eluent: hexane / ethyl acetate, 80:1. Solid 3-methyl-5-nitro-2-[(trimethylsilyl)ethynyl]pyridine P27 (1.14 g, 28%) was obtained. 1 HNMR (400MHz, CDCl3) δ9.23(d,J=2.2Hz,1H),8.33(d,J=2.0Hz,1H),2.57(s,3H),0.33(s,9H).

[1728] 28,5-Methyl-6-[(trimethylsilyl)ethynyl]pyridine-3-amine (P28) was prepared.

[1729] 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 material was completely converted as indicated by TLC. The mixture was cooled to ambient temperature and passed through diatomaceous earth. The filtrate was evaporated, and the residue was dissolved in ethyl acetate, washed with water, and concentrated. The mixture was then dissolved in dichloromethane, washed with an aqueous solution of sodium bicarbonate, dried with sodium sulfate, and concentrated to provide 5-methyl-6-[(trimethylsilyl)ethynyl]pyridine-3-amine P28 (0.87 g, 88%). 1 H 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).

[1730] Prepare 29.N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[(trimethylsilyl)ethynyl]pyridin-3-yl}urea (P29).

[1731] Triethylamine (1.44 g, 14.2 mmol) was added to a suspension of 7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.82 g, 3.55 mmol) in 40 mL of toluene. The mixture was stirred for 5 min. Then, DPPA (1.17 g, 4.26 mmol) was added, and the mixture was stirred at rt for 60 min. Subsequently, 5-methyl-6-[(trimethylsilyl)ethynyl]pyridine-3-amine P28 (0.87 g, 4.26 mmol) was added, and the mixture was refluxed for 12 h. The reaction was monitored by LCMS. The mixture was quenched with water, and the separated toluene was dried over Na2SO4 and evaporated. The residue was purified on silica gel by elution with 1:1 hexane / ethyl acetate, thus providing N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[(trimethylsilyl)ethynyl]pyridin-3-yl}urea P29 (0.47 g, 30%). 1 H NMR (400MHz, DMSO-d6), δ: 9.22 (s, 1H), 8.45 (br.s, 3H), 8.22 (d, J = 2.4Hz, 1H), 7.87 (s, 1H), 6.74 (d, J = 2.2Hz ,1H),3.97-3.74(m,1H),2.34(s,3H),2.36-2.32(m,2H),1.99(s,2H),1.85(s,2H),1.70(s,2H),0.25(s,9H).

[1732] Prepare 30.N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(6-ethynyl-5-methylpyridin-3-yl)urea (P30).

[1733] N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[(trimethylsilyl)ethynyl]pyridin-3-yl}urea P29 (0.24 g, 0.56 mmol) was dissolved in 20 mL of a solvent consisting of equal volumes of methanol and dichloromethane. Potassium fluoride (0.097 g, 1.67 mmol) was added to the flask, and the mixture was stirred at rt for 2 h. After the reaction was complete as indicated by TLC, the reactants were diluted with water and extracted with ethyl acetate. N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(6-ethynyl-5-methylpyridin-3-yl)urea P30 (0.186 g, 93%) was concentrated and used in the next stage without purification. LCMS ESI (m / z): 361.5 ([M+H) + ).

[1734] Preparation of 31-ethyl 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoate (P31).

[1735] N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(6-ethynyl-5-methylpyridin-3-yl)urea P30 (0.186 g, 0.52 mmol) and ethyl 7-azidoheptanate (0.103 g, 0.52 mmol) were dissolved in 20 mL of a solvent consisting of equal volumes 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 a flask and the reaction mixture was stirred at rt for 12 h. After the reaction was complete as indicated by LCMS, the product was extracted with ethyl acetate and concentrated. The residue was purified on silica gel by elution with ethyl acetate to provide ethyl 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoate P31 (0.149 g, 51%). 1H NMR(400MHz,DMSO-d6),δ:9.12(s,1H),8.53(s,1H),8.47(s,1H),8.46(s,1H),8 .42(s,1H),8.23(d,J=2.4Hz,1H),4.40(t,J=7.2Hz,2H),4.03(q,J=7.1Hz,2H), 3.87(s,1H),2.60(s,3H),2.33(s,2H),2.26(t,J=7.3Hz,2H),1.99(s,2H),1.86 (s,4H),1.70(s,2H),1.50(d,J=7.8Hz,2H),1.28(s,4H),1.16(t,J=7.1Hz,3H).

[1736] Prepare 32,7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoic acid (P32).

[1737] An aqueous solution of NaOH (0.021 g, 0.53 mmol) was added to a solution of ethyl 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoate P31 (0.149 g, 0.27 mmol) in 10 mL of ethanol. The mixture was stirred at 50 °C for 12 h. After ester hydrolysis was complete, the mixture was cooled to ambient temperature. The ethanol was evaporated and the reaction mixture was acidified to pH 7 with hydrochloric acid, and the product was extracted with ethyl acetate. The product solution in ethyl acetate was dried with Na₂SO₄ and evaporated. Solid 7-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}heptanoic acid P32 (0.138 g, 97%) was obtained. LCMS ESI (m / z): 532.3 ([M+H) + ).

[1738] 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)pyrido[3,2-d]pyrimidine

[1739] Synthesis of (P36)

[1740]

[1741] 33-Ethyl 3-cyclopentyl-3-oxypropionate (P33) was prepared.

[1742] 1) Add carbonyl imidazole (12.5 g, 77.11 mmol) in portions to a mixture of cyclopentacarboxylic acid (8.0 g, 70.10 mmol) and anhydrous EtOAc (100 mL). Stir the mixture at 50 °C for 3 h.

[1743] 2) MgCl2 (26.7 g, 280.4 mmol) was added in portions to a mixture of potassium 3-ethoxy-3-oxopropionate (23.86 g, 140.2 mmol) and anhydrous EtOAc (300 mL). The mixture was stirred at 50 °C for 3 h.

[1744] The solution from step (1) was added dropwise to the suspension from step (2), and the mixture was refluxed and stirred overnight. The mixture was cooled in an ice bath and acidified to pH 3 with 4M HCl (140 mL). The mixture was heated to ambient temperature and separated into layers. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine and dried (Na2SO4). Concentration and purification by chromatography on silica gel yielded 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).

[1745] Preparation of 34-ethyl(2Z)-2-(cyclopentylcarbonyl)-3-(dimethylamino)acrylate (P34).

[1746] A solution of compound P33 (10.1 g, 54.8 mmol) and N,N-dimethylformamide dimethylacetal (73 mL, 548.0 mmol) was refluxed and stirred overnight. The mixture was evaporated to dryness, and the residue was purified by column chromatography on silica gel. The yield of compound P34 was 11.0 g (84%). 1 H NMR (400MHz, DMSO-d6), δ: 1 H 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).

[1747] Prepare 35-ethyl-7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid ester (P35).

[1748] 1H-pyrazole-5-amine (4.6 g, 55.2 mmol) was added to a solution of P34 (11.0 g, 46.0 mmol) in 200 mL of EtOH. The mixture was refluxed and stirred overnight. The mixture was evaporated, and the residue was purified by column chromatography on silica gel. 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).

[1749] 36,7-Cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (P36) was prepared.

[1750] A mixture of compound P35 (9.2 g, 35.5 mmol) and NaOH (2.2 g, 53.2 mmol) in 200 mL of EtOH and 50 mL of H2O was stirred at 60 °C for 14 h and then evaporated. The residue was diluted with water and acidified with 6 M HCl to pH 3–4. The resulting solid was filtered off and dried. The yield of compound P36 was 8.1 g (98%). 1 H 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).

[1751] Synthesis of ethyl 4-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]butyrate (P39)

[1752]

[1753] Preparation of 37-ethyl 5-({[(1Z)-amino(3-methyl-5-nitropyridin-2-yl)methylene]amino}oxy)-5-oxovalerate (P37).

[1754] TEA (1.3 mL, 9.3 mmol) was added to a solution of 5-ethoxy-5-oxovalerate (0.50 g, 3.1 mmol) in 20 mL of DCM. The mixture was stirred at rt for 10 min. 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 h. 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.

[1755] Preparation of 38-ethyl 4-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]butyrate (P38)

[1756] The solution of compound P37 in 50 mL of dioxane was refluxed and stirred for 96 h. The mixture was evaporated and purified by column chromatography on silica gel. The yield of compound P38 in steps 2 (preparations of 37 and 38) was 0.37 g (37%). LCMS ESI (m / z): 321.5 ([M+1]) + ),275.4,179.3.

[1757] Preparation of 39-ethyl 4-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]butyrate (P39)

[1758] Fe powder (0.65 g, 11.5 mmol) was added to a solution of compound P38 (0.37 g, 1.15 mmol) in 20 mL of acetic acid. The suspension was stirred at 70 °C for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL), and filtered through diatomaceous earth. 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 column chromatography on silica gel. Yield of compound P39 (0.30 g, 89%). LCMS ESI (m / z): 291.4 ([M+1) + ),149.6.

[1759] Synthesis of 4-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}butyric acid (P41)

[1760]

[1761] Prepare 40-ethyl 4-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}butyrate (P40).

[1762] Et3N (0.6 mL, 4.0 mmol) was added to a solution of compound P36 (0.24 g, 1.0 mmol) in 20 mL of toluene. The mixture was stirred at rt for 10 min. Then, DPPA (0.27 mL, 1.2 mmol) was added. The mixture was stirred at rt for 1 h, and then compound P39 (0.30 g, 1.0 mmol) was added. The resulting mixture was stirred at 90 °C for 14 h. The mixture was evaporated and purified by column chromatography on silica gel to obtain compound P40 (0.35 g, 65%). LCMS ESI (m / z): 519.5 ([M+1]) + ),431.6.

[1763] Prepare 41,4-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}butyric acid (P41).

[1764] 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 h and then evaporated. The residue was diluted with water and acidified with 6 M HCl to pH 3–4. The resulting solid was filtered off and dried. The yield of compound P41 was 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] + ).

[1765] Synthesis of ethyl 3-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]propionate (P44)

[1766]

[1767] Preparation of 42-ethyl 4-({[(1Z)-amino(3-methyl-5-nitropyridin-2-yl)methylene]amino}oxy)-4-oxobutyrate (P42).

[1768] Et3N (1.4 mL, 10.2 mmol) was added to a solution of 4-ethoxy-4-oxo-butyric acid (0.50 g, 3.4 mmol) in 20 mL of DCM. The mixture was stirred at rt for 10 min. Subsequently, 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 h. 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.

[1769] Preparation of 43-ethyl 3-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]propionate (P43).

[1770] The solution of compound P42 in 50 mL of dioxane was refluxed and stirred for 96 h. The mixture was evaporated and purified by column chromatography on silica gel. The yield of compound P43 in both steps (P42 and P43) was 0.56 g (53%). LCMS ESI (m / z): 307.5 ([M+1) + ),261.4,233.1.

[1771] Preparation of 44-ethyl 3-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]propionate (P44).

[1772] Fe powder (1.0 g, 18.0 mmol) was added to a solution of compound P43 (0.56 g, 1.8 mmol) in 20 mL of acetic acid. The suspension was stirred at 70 °C for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL), and filtered through diatomaceous earth. 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 column chromatography on silica gel. Yield of compound P44 (0.46 g, 91%). LCMS (m / z): 277.4 ([M+1]) + ),149.4.

[1773] Synthesis of 3-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}propionic acid (P46)

[1774]

[1775] Prepare 45-ethyl 3-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}propionate (P45).

[1776] Et3N (1.0 mL, 6.8 mmol) was added to a solution of compound P36 (0.39 g, 1.7 mmol) in 20 mL of toluene. The mixture was stirred at rt for 10 min. Then, DPPA (0.44 mL, 2.0 mmol) was added. The mixture was stirred at rt for 1 h, and then compound P44 (0.46 g, 1.7 mmol) was added. The resulting mixture was stirred at 90 °C for 14 h. The mixture was evaporated and purified by column chromatography on silica gel. The yield of compound P45 was 0.41 g (48%). LCMS ESI (m / z): 505.5 ([M+1] + ),431.6.

[1777] Prepare 46,3-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}propionic acid (P46).

[1778] A mixture of compound P45 (0.41 g, 0.8 mmol) and NaOH (0.05 g, 1.2 mmol) in 10 mL of EtOH and 2 mL of H2O was stirred at 60 °C for 14 h and then evaporated. The residue was diluted with water and acidified with 6 M HCl to pH 3–4. The resulting solid was filtered off and dried. The yield of compound P46 was 0.32 g (83%). 1H 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] + ).

[1779] Synthesis of ethyl 5-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]valerate (P49)

[1780]

[1781] Preparation of 47-ethyl 6-({[(1Z)-amino(3-methyl-5-nitropyridin-2-yl)methylene]amino}oxy)-6-oxohexanoate (P47)

[1782] Et3N (1.5 mL, 10.2 mmol) was added to a solution of 6-ethoxy-6-oxohexanoic acid (0.60 g, 3.4 mmol) in 20 mL of DCM. The mixture was stirred at rt for 10 min. 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 h. 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.

[1783] Preparation of 48-ethyl 5-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]valerate (P48).

[1784] The solution of compound P47 in 50 mL of dioxane was refluxed and stirred for 96 h. The mixture was evaporated and purified by column chromatography on silica gel. The yield of compound P48 in both steps (P47 and P48) was 0.58 g (51%). LCMS ESI (m / z): 335.5 ([M+1)) + ),289.3.

[1785] Preparation of 49-ethyl 5-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]valeric acid (P49).

[1786] Fe powder (1.0 g, 17 mmol) was added to a solution of compound P48 (0.58 g, 1.7 mmol) in 20 mL of acetic acid. The suspension was stirred at 70 °C for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL), and filtered through diatomaceous earth. 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 column chromatography on silica gel. Yield of compound P49 (0.47 g, 84%). LCMS ESI (m / z): 305.5 ([M+1) + ),149.4.

[1787] Synthesis of 5-formyl-4-methyl-1H-indol-2-carboxynitrile N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(5-oxopentyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P53)

[1788]

[1789] Prepare 50-ethyl 5-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}valerate (P50).

[1790] Et3N (0.9 mL, 6.4 mmol) was added to a solution of compound P36 (0.36 g, 1.6 mmol) in 20 mL of toluene. The mixture was stirred at rt for 10 min. Then, DPPA (0.4 mL, 2.0 mmol) was added. The mixture was stirred at rt for 1 h, and then compound P49 (0.47 g, 1.6 mmol) was added. The resulting mixture was stirred at 90 °C for 14 h. The mixture was evaporated and purified by column chromatography on silica gel. The yield of compound P50 was 0.52 g, 63%. LCMS ESI (m / z): 533.5 ([M+1] + ),377.5.

[1791] Prepare 51.5-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}valeric acid (P51).

[1792] A mixture of compound P50 (0.52 g, 1.0 mmol), NaOH (0.06 g, 1.5 mmol), and 10 mL of EtOH and 2 mL of H2O was stirred at 60 °C for 14 h and then evaporated. The residue was diluted with water and acidified with 6 M HCl to pH 3–4. The resulting solid was filtered off and dried. Yield of compound P51 (0.45 g, 92%). LCMS (m / z): 505.5 ([M+1]) + ).

[1793] Prepare 52.N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{6-[5-(5-hydroxypentyl)-1,2,4-oxadiazol-3-yl]-5-methylpyridin-3-yl}urea (P52).

[1794] Et3N (0.16 mL, 1.17 mmol) was added to a solution of compound P51 (0.45 g, 0.9 mmol) in 10 mL THF. The mixture was stirred at rt for 10 min. Then, ethyl chloroformate (0.11 mL, 1.17 mmol) was added at 0–5 °C. The mixture was stirred at rt for 1 h. The resulting solid was filtered off, and the filtrate was added dropwise to a solution of sodium borohydride (0.17 g, 4.5 mmol) in water (10 mL) at 0–5 °C. The resulting mixture was stirred at ambient temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P52 (0.34 g, 78%). LCMS (m / z): 491.4 ([M+1]) + ).

[1795] Prepare 53.N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(5-oxopentyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P53).

[1796] At -70 °C, a solution of dimethyl sulfoxide (0.14 mL, 1.88 mmol) in DCM (0.1 mL) was added to a stirred solution of trifluoroacetic anhydride (0.2 mL, 1.37 mmol) in DCM (10 mL). 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 min, and the mixture was stirred for another 3.5 h. Triethylamine (0.5 mL, 3.42 mmol) was added dropwise while stirring for 15 min, and the mixture was heated to rt. 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)) + ).

[1797] Synthesis of N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(3-oxopropyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P55)

[1798]

[1799] Prepare 54.N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{6-[5-(3-hydroxypropyl)-1,2,4-oxadiazol-3-yl]-5-methylpyridin-3-yl}urea (P54).

[1800] Et3N (0.16 mL, 1.04 mmol) was added to a solution of compound P46 (0.4 g, 0.8 mmol) in 10 mL of THF. The mixture was stirred at rt for 10 min. Subsequently, ethyl chloroformate (0.1 mL, 1.04 mmol) was added at 0–5 °C. The mixture was stirred at rt for 1 h. The solid formed 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 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel to obtain compound P54 (0.22 g, 57%). 1H 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]) + ).

[1801] Prepare 55.N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(3-oxopropyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P55).

[1802] At -70°C, a solution of DMSO (0.03 mL, 0.43 mmol) in DCM (0.1 mL) was added to a stirred solution of trifluoroacetic anhydride (0.045 mL, 0.31 mmol) in DCM (10 mL). A solution of compound P54 (0.06 g, 0.13 mmol) in DCM (1.0 mL) was added dropwise to the prepared solution over 15 min, and the mixture was stirred for another 3.5 h. Triethylamine (0.11 mL, 0.78 mmol) was added dropwise while stirring for 15 min, and the mixture was heated 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)) + ).

[1803] N-(3-chloro-7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(3-oxypropyl)-

[1804] Synthesis of 1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P56)

[1805]

[1806] Prepare 56.N-(3-chloro-7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(3-oxopropyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P56).

[1807] At -70°C, a solution of DMSO (0.06 mL, 0.80 mmol) in DCM (0.1 mL) was added to a stirred solution of oxaloyl 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 min, and the mixture was stirred for another 3.5 h. Triethylamine (0.20 mL, 1.44 mmol) was added dropwise while stirring for 15 min, and the mixture was heated 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)) + ).

[1808] N-(3-chloro-7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(4-oxobutyl)-

[1809] Synthesis of 1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P58)

[1810]

[1811] Prepare 57.N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{6-[5-(4-hydroxybutyl)-1,2,4-oxadiazol-3-yl]-5-methylpyridin-3-yl}urea (P57).

[1812] Et3N (0.1 mL, 0.72 mmol) was added to a solution of compound P41 (0.27 g, 0.55 mmol) in 10 mL THF. The mixture was stirred at rt for 10 min. Then, ethyl chloroformate (0.07 mL, 0.72 mmol) was added at 0–5 °C. The mixture was stirred at rt for 1 h. The solid formed was filtered off, and the filtrate was added dropwise to a solution of sodium borohydride (0.1 g, 2.75 mmol) in water (10 mL) at 0–5 °C. The resulting mixture was stirred at ambient temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P57: 0.20 g, 76%. LCMS ESI (m / z): 477.6 ([M+1]) + ),377.4.

[1813] Prepare 58.N-(3-chloro-7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(4-oxobutyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P58).

[1814] At -70°C, a solution of DMSO (0.05 mL, 0.66 mmol) in DCM (0.1 mL) was added to a stirred solution of oxaloyl 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 min, and the mixture was stirred for another 3.5 h. Triethylamine (0.2 mL, 1.20 mmol) was added dropwise while stirring for 15 min, and the mixture was heated to rt. 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]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(4-oxobutyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P59)

[1815]

[1816] Preparation of 59.N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-{5-methyl-6-[5-(4-oxobutyl)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}urea (P59)

[1817] At -70°C, a solution of DMSO (0.025 mL, 0.33 mmol) in DCM (0.1 mL) was added to a stirred solution of trifluoroacetic anhydride (0.036 mL, 0.24 mmol) in DCM (10 mL). A solution of compound P57 (0.05 g, 0.1 mmol) in DCM (1.0 mL) was added dropwise over 15 min to the above-prepared solution, and the mixture was stirred for another 3.5 h. Triethylamine (0.09 mL, 0.60 mmol) was added dropwise while stirring for 15 min, and the entire mixture was heated to rt. 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-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P8) - Second Choice

[1818]

[1819] Preparation of 60-ethyl 7-{[(E)-(oxime)(3-methyl-5-nitropyridin-2-yl)methyl]amino}-7-oxoheptane ester (P60)

[1820] N-ethyl-N-isopropylpropyl-2-amine (0.645 g, 4.98 mmol) was added to a solution of 7-ethoxy-7-oxoheptanoic acid (0.78 g, 4.2 mmol) in 40 mL of 1,4-dioxane. The solution was stirred for 5 min, and then N'-hydroxy-3-methyl-5-nitropyridine-2-formamidinium P6 (0.816 g, 4.2 mmol) was added, and the mixture was stirred for 10 min. 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphonane 2,4,6-trioxide (1.98 g, 6.3 mmol, 50 wt% solution in EtOAc) was poured into a reaction flask, and the reaction mixture was stirred at rt for 12 h. After the reaction was complete as indicated by TLC, the reaction mixture was concentrated under vacuum, dissolved in ethyl acetate, washed with water, and evaporated. The residue (P60) was used for the next step without further purification. LCMS(m / z): 366.3([M+1] + ).

[1821] Preparation of 8a. ethyl 6-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate (P8)

[1822] Ethyl 7-{[(E)-(oxime)(3-methyl-5-nitropyridin-2-yl)methyl]amino}-7-oxoheptane P60 (0.815 g, 4.16 mmol) was dissolved in 50 mL of 1,4-dioxane. The solution was refluxed for 96 h. After the reaction was complete as indicated by TLC, the reaction mixture was concentrated under vacuum. The residue was purified on silica gel by elution with EtOAc / hexane, 1:10, to provide ethyl 6-[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate P8 (0.55 g). The yields of both steps (Preparation 60 and Preparation 8a) were 38%. 1 H 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).

[1823] Synthesis of 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid (P62)

[1824]

[1825] Preparation of 61-ethyl 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate (P61).

[1826] Triethylamine (0.166 g, 1.64 mmol) was added to a suspension of 7-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.095 g, 0.41 mmol) in 40 mL of toluene. The mixture was stirred for 5 min. Then, DPPA (1.136 g, 0.49 mmol) was added and the mixture was stirred at rt for 60 min. Subsequently, ethyl 6-[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]hexanoate P9 (0.13 g, 0.41 mmol) was added, and the mixture was refluxed for 12 h. The reaction was monitored by LCMS. The mixture was quenched with water, and the separated toluene was dried over Na2SO4 and evaporated. The residue was purified on silica gel by elution with hexane / ethyl acetate at a 1:1 ratio, thereby providing ethyl 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate P61 (0.129 g, 57%). 1 H NMR (400MHz, DMSO-d6), δ: 9.35 (s, 1H), 8.62 (d, J = 2.2Hz, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.23 ​​(d, J = 2.3 Hz,1H),8.00(s,1H),6.75(d,J=2.3Hz,1H),4.04(q,J=7.1Hz,2H),3.94-3.78(m,1H),3.00(t,J=7.5Hz ,2H),2.47(s,3H),2.34(d,J=11.0Hz,2H),2.30(t,J=7.3Hz,2H),1.99(s,2H),1.86(s,2H),1.78(dd,J =15.4,7.5Hz,2H),1.71(s,2H),1.57(dd,J=15.3,7.3Hz,2H),1.44-1.33(m,2H),1.16(t,J=7.1Hz,3H).

[1827] Prepare 62,6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid (P62).

[1828] An aqueous solution of NaOH (0.026 g, 0.46 mmol) was added to a solution of ethyl 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoate P61 (0.127 g, 0.23 mmol) in 10 mL of ethanol. The mixture was stirred at 50 °C for 12 h. After complete hydrolysis of the ester, the mixture was cooled to ambient temperature. The ethanol was evaporated and the reaction mixture was acidified to pH 7 with hydrochloric acid, and the product was extracted with ethyl acetate. The product solution in ethyl acetate was dried with Na₂SO₄ and evaporated. Solid 6-{3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}hexanoic acid P62 (0.102 g, 84%) was obtained. 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).

[1829] Synthesis of tert-butyl(4-azidobutoxy)acetic acid (P64)

[1830]

[1831] Preparation of 63-tert-butyl{4-[(methylsulfonyl)oxy]butoxy}acetate (P63).

[1832] At 0 °C, methanesulfonyl chloride (0.673 g, 5.87 mmol) was added to a solution of tert-butyl(4-hydroxybutoxy)acetate (1.0 g, 4.9 mmol) and triethylamine (0.743 g, 7.4 mmol) in anhydrous DCM (30 mL). The mixture was stirred overnight and then washed with water, 1 M hydrochloric acid, 5% sodium bicarbonate aqueous solution, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to provide tert-butyl{4-[(methanesulfonyl)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).

[1833] Preparation of 64-tert-butyl(4-azidobutoxy)acetic acid ester (P64).

[1834] Sodium azide (1.15 g, 17.5 mmol) was added to a solution of tert-butyl{4-[(methanesulfonyl)oxy]butoxy}acetate in DMF (30 mL). The mixture was heated at 80 °C for 18 hours with stirring. When the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The product was purified by column chromatography on silica gel. Eluent: hexane / ethyl acetate, 40:1. Tert-butyl(4-azidobutoxy)acetate (0.395 g) was obtained in 48% yield. 1 H NMR (400MHz, DMSO-d6), δ: 3.94 (s, 2H), 3.45 (t, J = 5.9Hz, 2H), 3.35 (t, J = 6.6Hz, 2H), 1.68-1.49 (m, 4H), 1.42 (s, 9H).

[1835] (4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridine

[1836] Synthesis of [-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetic acid (P66)

[1837]

[1838] Preparation of 65-tert-butyl(4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetate (P65).

[1839] N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(6-ethynyl-5-methylpyridin-3-yl)urea P30 (0.232 g, 0.64 mmol) and tert-butyl(4-azidobutoxy)acetate (0.147 g, 0.64 mmol) were dissolved in 20 mL of a solvent consisting of equal volumes 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 a flask and the reaction mixture was stirred at rt for 12 h. After the reaction was complete as indicated by LCMS, the product was extracted with ethyl acetate and concentrated. Purification of the residue on silica gel by elution with EtOAc / MeOH, 40:1, yielded tert-butyl(4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetate P65 (0.157 g, 41%). LCMS ESI (m / z): 590.5 ([M+1) + ),534.3.

[1840] Preparation of 66.(4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetic acid (P66).

[1841] 0.157 g (0.27 mmol) of tert-butyl(4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetate P65 was dissolved in 10 mL of DCM (0.303 g, 2.66 mmol) containing TFA. The solution was stirred at rt for 15 h. TLC control was used. The product was concentrated under vacuum and evaporated by dioxane saturated with HCl. 0.15 g (4-{4-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1H-1,2,3-triazol-1-yl}butoxy)acetate hydrochloride P66 was obtained in 98% yield. LCMS ESI (m / z): 534.5 ([M+1]) + ).

[1842] Synthesis of [4-(benzoyl)butoxy]acetic acid (P68)

[1843]

[1844] Prepare 67.4-(2-tert-butoxy-2-oxyethoxy)benzoate butyl ester (P67).

[1845] Et3N (1.7 mL, 12.3 mmol) was added to a solution of tert-butyl-2-(4-hydroxybutoxy)acetate (1.0 g, 4.9 mmol) in 20 mL of DCM. Then, benzoyl chloride (0.7 mL, 5.9 mmol) was added at 0–5 °C. The mixture was stirred at rt for 14 h. The mixture was diluted with DCM, washed with saturated NaHCO3 (aqueous solution), dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P67: 1.0 g, 68%. 1 H 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).

[1846] Preparation of 68-[4-(benzoic acid)butoxy]acetic acid (P68).

[1847] TFA (2.6 mL, 33.0 mmol) was added to a solution of compound P67 (1.0 g, 3.3 mmol) in 15 mL of DCM. The mixture was stirred at rt for 14 h. The mixture was then 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).

[1848] 4-{[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]methoxy}butylbenzoate

[1849] Synthesis of (P70)

[1850]

[1851] Preparation of 69.4-{[3-(3-methyl-5-nitropyridin-2-yl)-1,2,4-oxadiazol-5-yl]methoxy}butylbenzoate (P69)

[1852] CDI (0.6 g, 3.7 mmol) was added to a solution of compound P68 (0.84 g, 3.3 mmol) in 20 mL of dioxane. The mixture was stirred at 60 °C for 4 h. Then, compound P6 (0.65 g, 3.3 mmol) was added, and the mixture was refluxed and stirred for 72 h. The mixture was evaporated. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na₂SO₄ and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P69: 0.25 g, 18%. LCMS ESI (m / z): 413.5 ([M+1]) + ),291.5.

[1853] Prepare 70,4-{[3-(5-amino-3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]methoxy}butylbenzoate (P70).

[1854] Fe powder (0.3 g, 6.0 mmol) was added to a solution of compound P69 (0.25 g, 0.6 mmol) in 10 mL of acetic acid. The suspension was stirred at 70 °C for 1 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (100 mL), and filtered through diatomaceous earth. 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 column chromatography on silica gel. Yield of compound P70: 0.14 g, 60%. LCMS ESI (m / z): 383.5 ([M+1)) + ).

[1855] Synthesis of N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(5-methyl-6-{5-[(4-oxybutoxy)methyl]-1,2,4-oxadiazol-3-yl}pyridin-3-yl)urea (P73)

[1856]

[1857] Prepare 71,4-({3-[5-({[(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)amino]carbonyl}amino)-3-methylpyridin-2-yl]-1,2,4-oxadiazol-5-yl}methoxy)butyl benzoate (P71).

[1858] Et3N (0.2 mL, 0.140 mmol) was added to a solution of compound P36 (0.08 g, 0.035 mmol) in 10 mL of toluene. The mixture was stirred at rt for 10 min. Then, DPPA (0.09 mL, 0.042 mmol) was added. The mixture was stirred at rt for another 1 h, and then compound P70 (0.13 g, 0.035 mmol) was added. The resulting mixture was stirred at 90 °C for 14 h. The mixture was evaporated and purified by column chromatography on silica gel. Yield of compound P71: 0.13 g, 58%. LCMS ESI (m / z): 611.5 ([M+1]) + ).

[1859] Preparation of 72.N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(6-{5-[(4-hydroxybutoxy)methyl]-1,2,4-oxadiazol-3-yl}-5-methylpyridin-3-yl)urea (P72).

[1860] K₂CO₃ (0.12 g, 0.84 mmol) was added to a solution of compound P71 (0.13 g, 0.21 mmol) in 5 mL of MeOH. The mixture was stirred at 60 °C for 4 h. The mixture was evaporated. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over Na₂SO₄ and evaporated. Yield of compound P72: 0.085 g, 80%. LCMS ESI (m / z): 507.5 ([M+1]) + ).

[1861] Preparation of 73,N-(7-cyclopentylpyrazolo[1,5-a]pyrimidin-6-yl)-N'-(5-methyl-6-{5-[(4-oxybutoxy)methyl]-1,2,4-oxadiazol-3-yl}pyridin-3-yl)urea (P73)

[1862] At -70 °C, a solution of dimethyl sulfoxide (0.04 mL, 0.5 mmol) in DCM (0.1 mL) was added to a stirred solution of oxaloyl 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 min, and the mixture was stirred for another 3.5 h. Triethylamine (0.13 mL, 0.90 mmol) was added dropwise while stirring for 15 min, and the entire mixture was heated to rt. 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)) + ).

[1863] Synthesis of 3-[2-(benzoyl)ethoxy]propionic acid (P75)

[1864]

[1865] Prepare ethyl 74,2-(3-tert-butoxy-3-oxypropoxy)benzoate (P74).

[1866] Et3N (1.9 mL, 13.3 mmol) was added to a solution of tert-butyl 3-(2-hydroxyethoxy)propionate (1.0 g, 5.3 mmol) in 20 mL of DCM. Subsequently, benzoyl chloride (0.7 mL, 5.9 mmol) was added at 0–5 °C. The mixture was stirred at rt for 14 h. The mixture was diluted with DCM, washed with saturated NaHCO3 (aqueous solution), dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel. Yield of compound P74: 1.2 g, 80%. 1 H NMR (400MHz, DMSO-d6), δ: 7.96 (d, J = 7.8Hz, 2H), 7.66 (t, J = 7.4Hz, 1H), 7.53 (t, J = 7.6Hz, 2H), 4.38 (d, J =4.5Hz,2H),3.73(d,J=4.5Hz,2H),3.66(t,J=6.1Hz,2H),2.43(t,J=6.1Hz,2H),1.37(d,J=13.7Hz,9H).

[1867] Preparation of 75,3-[2-(benzoic acid)ethoxy]propionic acid (P75).

[1868] TFA (3.2 mL, 41.0 mmol) was added to a solution of compound P74 (1.2 g, 4.1 mmol) in 15 mL of DCM. The mixture was stirred at rt for 14 h. The mixture was then 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).

[1869] Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2-phenylethyl)quinazoline (P78)

[1870]

[1871] Prepare 76,2-[3-({[(1E)-amino(3-methyl-5-nitropyridin-2-yl)methylene]amino}oxy)-3-oxypropoxy]ethyl benzoate (P76).

[1872] Et3N (0.9 mL, 6.0 mmol) was added to a solution of compound P75 (0.48 g, 2.0 mmol) in 20 mL of DCM. The mixture was stirred at rt for 10 min....

Claims

1. A compound of formula (A): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, in: Each X is independently selected from N and CH; Y is selected from -NR5C(O)NR5- and -NR5C(O)-; Ring A is selected from cycloalkyl, aryl, heterocyclyl and heteroaryl; Ring B is selected from cycloalkyl, aryl, heterocyclyl and heteroaryl; Ring C is selected from cycloalkyl, aryl, heterocyclyl and heteroaryl; M is selected from -CH2-, -C(O)-, -C(O)NR L -, -C(O)O-, -NR L -, -NR L C(O)-, -NR L C(O)NR L -, -NR L C(O)O-, -NR L SO2-, -O-, -OC(O)-, -OC(O)NR L -, -OC(O)O-, -S(O)2NR L -, -S- and -S(O)2-; L1 and L2 are independently selected from a bond, a C1-C 12 Alkanediyl, C2-C 12 Alkenyl, C2-C 12 Alkynedyl, C3-C8 cycloalkanediyl, C3-C8 cycloalkanediyl-(CH2) p -、C1-C 12 Alkoxyalkenyl and -((CH2) 1-6 O) o -(CH2) p -;or M and L2 together are a bond; or L1-M-L2 is the key; L3 and L4 are independently selected from a bond, a C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynediyl, C1-C 12 Alkoxyalkenyl, -((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-; R1 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CH2-OC(O)C1-C6 alkyl, -CH2-OP(O)(OC1-C6 alkyl)2, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 11 replace; Each of 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 are optionally replaced by one or more R 11 replace; or Two R3 are =O; Each of R4, R6, R7 and R 10 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 are optionally replaced by one or more R 11 replace; Each R5 is independently selected from hydrogen and C1-C6 alkyl; R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 11 replace; Each R 11 independently selected from 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; Each R L independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; R 12 and R 13 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and g is an integer selected from 0, 1 and 2; m and n are integers independently selected from 0, 1, 2 and 3; o is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; t is an integer selected from 0 and 1; u is an integer selected from 0, 1 and 2; w is an integer selected from 0, 1 and 2; The condition is that if t is 0, then L4 is a bond; The condition is that at least one of L3 and L4 is not a bond, in, Cycloalkyl is a saturated or partially saturated C3-C 10 Single ring, C5-C 18 Fused, bridged or spiro bicyclic or C6-C 18 fused, bridged or spiro tricyclic ring systems; Aryl is a cycloaromatic hydrocarbon ring system comprising 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially saturated 3-10 membered monocyclic, 7-12 membered fused, bridged or spiro bicyclic or 11-14 membered fused, bridged or spiro tricyclic ring system containing 1-7 heteroatoms selected from O, N, S, P, Se or B; and Heteroaryl is a monovalent monocyclic or polycyclic aromatic ring system containing 5 to 24 ring atoms, wherein 1-7 ring atoms are heteroatoms selected from N, O, S, P or B and the remaining ring atoms are C.

2. The compound according to claim 1, wherein The compound has the chemical formula (I): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, in: Each X is independently selected from N and CH; Y is selected from -NR5C(O)NR5- and -NR5C(O)-; Ring A is selected from cycloalkyl, aryl, heterocyclyl and heteroaryl; Ring B is selected from cycloalkyl, aryl, heterocyclyl and heteroaryl; M is selected from -CH2-, -C(O)-, -C(O)NR L -, -C(O)O-, -NR L -, -NR L C(O)-, -NR L C(O)NR L -, -NR L C(O)O-, -NR L SO2-, -O-, -OC(O)-, -OC(O)NR L -, -OC(O)O-, -S(O)2NR L -, -S- and -S(O)2-; L1 and L2 are independently selected from a bond, a C1-C 12 Alkanediyl, C2-C 12 Alkenyl, C2-C 12 Alkynedyl, C3-C8 cycloalkanediyl, C3-C8 cycloalkanediyl-(CH2) p -、C1-C 12 Alkoxyalkenyl and -((CH2) 1-6 O) o -(CH2) p -;or M and L2 together are a bond; or L1-M-L2 is the key; L3 and L4 are independently selected from a bond, a C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynedyl, C3-C8 cycloalkanediyl, C1-C 12 Alkoxyalkenyl, -((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-; R1 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CH2-OC(O)C1-C6 alkyl, -CH2-OP(O)(OC1-C6 alkyl)2, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 11 replace; Each of 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 are optionally replaced by one or more R 11 replace; or Two R3 are =O; Each of R4, R6, R7 and R 10 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 are optionally replaced by one or more R 11 replace; Each R5 is independently selected from hydrogen and C1-C6 alkyl; R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 11 replace; Each R 11 independently selected from 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; Each R L independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; R 12 and R 13 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and m and n are integers independently selected from 0, 1, 2 and 3; o is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; t is an integer selected from 0 and 1; u is an integer selected from 0, 1 and 2; w is an integer selected from 0, 1 and 2; The condition is that if t is 0, then L4 is a bond; The condition is that at least one of L3 and L4 is not a bond.

3. The compound according to claim 2, wherein The compound has the chemical formula (II): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

4. The compound according to claim 2, wherein The compound has the chemical formula (I-II): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

5. The compound according to claim 2, wherein The compound has the chemical formula (IA) or (IB): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

6. A compound according to any one of the preceding claims, wherein L3 is selected from a bond and -NR L C(O)NR L -.

7. A compound according to any one of the preceding claims, wherein L4 is selected from a bond and -NR L C(O)NR L -.

8. A compound according to any one of the preceding claims, wherein At least one of L3 and L4 is -NR L C(O)NR L - and the other is a key.

9. A compound according to any one of the preceding claims, wherein L3 is a bond and t is 1.

10. The compound according to claim 2, wherein The compound has the chemical formula (IIA-1-a-1-IA) or (IIB-2-a-1-IA): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

11. The compound according to claim 1, wherein Ring A is selected from 6-10 membered aryl or 5-10 membered heteroaryl containing 1-5 heteroatoms selected from N, O, S.

12. The compound according to claim 1, wherein Ring B is selected from 6-10 membered aryl or 5-10 membered heteroaryl containing 1-5 heteroatoms selected from N, O, S.

13. The compound according to claim 1, wherein R8 is selected from C1-C6 alkyl, 3-10 membered cycloalkyl, 6-10 membered aryl, 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S and 5-10 membered heteroaryl containing 1-5 heteroatoms selected from N, O, S, wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, -CN, -NO2, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, aryl, heterocyclyl and heteroaryl.

14. The compound according to claim 2, wherein The compound has chemical formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15) or (I-16): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, wherein in each of the chemical formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15) and (I-16), n is an integer selected from 0 and 1; and both R3 are H, or both R 3 Formation = O.

15. The compound according to claim 1, wherein The compound has the chemical formula (II): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, in: Each X is independently selected from N and CH; Y is selected from -NR5C(O)NR5- and -NR5C(O)-; Ring A is selected from cycloalkyl, aryl, heterocyclyl and heteroaryl; Ring B is selected from cycloalkyl, aryl, heterocyclyl and heteroaryl; M is selected from -CH2-, -C(O)-, -C(O)NR L -, -C(O)O-, -NR L -, -NR L C(O)-, -NR L C(O)NR L -, -NR L C(O)O-, -NR L SO2-, -O-, -OC(O)-, -OC(O)NR L -, -OC(O)O-, -S(O)2NR L -, -S- and -S(O)2-; L1 and L2 are independently selected from a bond, a C1-C 12 Alkanediyl, C2-C 12 Alkenyl, C2-C 12 Alkynedyl, C3-C8 cycloalkanediyl, C3-C8 cycloalkanediyl-(CH2) p -、C1-C 12 Alkoxyalkenyl and -((CH2) 1-6 O) o -(CH2) p -;or M and L2 together are a bond; or L1-M-L2 is the key; L3 and L4 are independently selected from a bond, a C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynediyl, C1-C 12 Alkoxyalkenyl, -((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-; R1 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CH2-OC(O)C1-C6 alkyl, -CH2-OP(O)(OC1-C6 alkyl)2, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 11 replace; Each of R2 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 are optionally replaced by one or more R 11 replace; R4, R6, R7 and R 10 Each of which is independently selected from 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 are optionally replaced by one or more R 11 replace; Each R5 is independently selected from hydrogen and C1-C6 alkyl; R8 is selected from H, C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 11 replace; Each R 11 Independently selected from 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; Each R L independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; R 12 and R 13 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and m and n are integers independently selected from 0, 1, 2 and 3; o is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Each p is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; t is an integer selected from 0 and 1; u is an integer selected from 0, 1 and 2; w is an integer selected from 0, 1 and 2; The condition is that if t is 0, then L4 is a bond; The condition is that at least one of L3 and L4 is not a bond.

16. The compound according to claim 15, wherein The compound has the chemical formula (II-A): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

17. The compound according to claim 15, wherein The compound has the chemical formula (II-B): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

18. A compound selected from: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19, further comprising other pharmaceutically active agents.

21. A method for degrading MALT1, the method comprising administering to a subject a compound according to any one of claims 1-18 or a pharmaceutical composition according to any one of claims 19 or 20.

22. A method of treating a disease or condition associated with MALT1, the method comprising administering to a subject a compound according to any one of claims 1-18 or a pharmaceutical composition according to any one of claims 19 or 20.

23. A method of treating a disease or condition selected from lymphoma and immunodeficiency, the method comprising administering to a subject in need of treatment a compound according to any one of claims 1-18 or a pharmaceutical composition according to any one of claims 19 or 20.

24. The method according to any one of claims 21 to 23, wherein: The subject is a mammal.

25. The method according to claim 24, wherein: The subject is a human.

Images