Macrocyclic compounds and uses thereof

Abstract

The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat diseases such as cancer.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 050,559, filed July 10, 2020; U.S. Provisional Application No. 63 / 143,569, filed January 29, 2021; and U.S. Provisional Application No. 63 / 217,950, filed July 2, 2021, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] This disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat diseases such as cancer. Background Technology

[0004] Protein kinases are tightly regulated signaling proteins that coordinate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G et al., The protein kinase complement of the human genome., Science, 2002, 298: 1912-34). Dysregulation of kinase activity is associated with many diseases, including cancer, as well as cardiovascular diseases, degenerative diseases, immune diseases, infectious diseases, inflammatory diseases, and metabolic diseases (Levitzki, A., Protein kinase inhibitors as a therapeutic modality., Acc. Chem. Res., 2003, 36: 462-469). The molecular basis of various diseases includes gain-of-function and loss-of-function mutations of kinases, gene amplification and deletion, splicing alterations, and translocations (Wilson LJ et al., New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome., Cancer Res. 2018, 78: 15-29). The important role of kinases in cancer and other diseases makes them an attractive target for drug development, with 52 small molecule kinase inhibitors already approved, 46 of which are used in targeted cancer therapies (Roskoski R Jr., Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2020 Update., Pharmacol Res. 2020, 152: 104609). Despite the great success of kinase inhibitors in targeted cancer therapy, the development of treatment resistance remains a challenge for small molecule kinase inhibitors.Acquired secondary mutations within the kinase domain during treatment often lead to resistance to kinase inhibitors (Pottier C et al., Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy, *Cancers (Basel)*, 2020, 12: 731). Therefore, it is necessary to invent kinase inhibitors that not only target kinase-induced oncogenic drivers but also overcome the most common resistance mutations to achieve better efficacy and longer-lasting disease control.

[0005] Non-small cell lung cancer (NSCLC) is a leading cause of cancer death worldwide (World Health Organization Cancer Fact Sheet 2017). Activated EGFR mutations have been reported in approximately 10% to 15% of adenocarcinoma cases in white patients and 50% in Asian patients (Chan BA, Hughes BG, Targeted therapy for non-small cell lung cancer: current standards and the promise of the future, *Transl. Lung Cancer Res* 2015; 4: 36-54). The two most common EGFR alterations found in NSCLC tumors are short-frame deletions in exon 19 of the EGFR gene (del19) and a single missense mutation L858R in exon 21 (Konduri K. et al., EGFR Fusions as Novel Therapeutic Targets in Lung Cancer., Cancer Discovery, 2016, 6: 601-11). First-generation reversible EGFR inhibitors erlotinib and gefitinib have shown superiority over chemotherapy in patients with advanced EGFR mutation-positive (Del19 or L858R) NSCLC and have been used as first-line standard of care in this condition. However, as treatment progresses, most patients will develop resistance to gefitinib or erlotinib, with 50% to 70% of tumors exhibiting EGFR T790M gatekeeper mutations (Sequist LV et al., Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors., Sci Transl Med 2011; 3: 75ra26).

[0006] Second-generation EGFR inhibitors afatinib and dacomitinib are covalent, irreversible EGFR inhibitors. They also inhibit HER2 and ERB4 of the ERB family. (Li D et al., BIBW2992, an irreversible EGFR / HER2 inhibitor highly effective in preclinical lung cancer models., *Oncogene* 2008; 27: 4702-11; Ou SH, Soo RA., Dacomitinib in lung cancer: a “lost generation” EGFR tyrosine-kinase inhibitor from a bygone era?, *Drug Design, Development and Therapy*.) (Ther) 2015; 9: 5641-53). Although afatinib and dacomitinib are more effective EGFR inhibitors than gefitinib and erlotinib and have been approved as first-line therapy for advanced EGFR mutation-positive (Del19 or L858R) NSCLC with longer progression-free survival (PFS), EGFR T790M has been generated during afatinib treatment (Tanaka K et al., Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations., Onco-target 2017; 8: 68123-30).EGFR T790M exhibits resistance to dacomitinib in in vitro studies (Kobayashi Y et al., EGFR T790M and C797S mutations as mechanisms of acquired resistance to dacomitinib. J Thorac Oncol 2018; 13: 727-31).

[0007] The third-generation EGFR inhibitor osimertinib is also an irreversible inhibitor. It targets both EGFR activating mutations (Del19 and L858R) and T790M resistance double mutations, exhibiting greater selectivity than wild-type EGFR (Finlay MR et al.). The discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild-type form of the receptor (JMed Chem, 2014; 57: 8249-67). Osimertinib was first approved for patients with metastatic EGFR T790M mutation-positive NSCLC after failure of first-line EGFR inhibitors, and was subsequently approved for first-line treatment of EGFR mutation-positive NSCLC patients following the phase III FLAURA trial and head-to-head trials compared with erlotinib or gefitinib (Soria JC et al., Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer., The New England Journal of Medicine 2018;378:113-25). The mutation C797S has been detected at the EGFR covalently binding residue of the irreversible EGFR inhibitor osimertinib in patients resistant to osimertinib (Ramalingam SS et al., Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study., ESMO, 2018).

[0008] Genetic alterations in transfected rearranged (RET) genes occur in various cancers, including non-small cell lung cancer and thyroid cancer (Drilon A et al., Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes., *Nature Reviews Clin Oncol.* 2018, 15: 151-167). Multiple kinase inhibitors lenvatinib, sorafenib, and cabozantinib have been approved for certain thyroid cancers. Recently, highly selective RET inhibitors selpercatinib and pralsetinib have been approved for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced / metastatic RET-altered medullary thyroid carcinoma (MTC), and papillary thyroid carcinoma (PTC). Acquired resistance RET mutations have been reported in patients or cell lines with RET mutations after treatment with multiple kinase inhibitors or selective RET inhibitors, including gate factor mutations V804M and V804L; hinge mutations Y806N and Y806C; solvent front mutations G810A, G810C, G810S, G810V and G810R; and other RET kinase domain mutations, such as V738A and S904F (Subbiah V et al., Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations, Ann Oncol., 5 November 2020: S0923-7534(20)43127-8). Acquired compound mutations, such as RET M918T / V804M, M918T / V804M / G810C, V804M / G810C, or other combinations, may be difficult to treat clinically with current multiplex kinase and selective RET inhibitors under sequential treatment with multiple RET inhibitors. Therefore, there is a need to develop next-generation RET inhibitors that can target primary and secondary RET mutations in patients with RET mutations, whether or not they have been treated with approved RET inhibitors.

[0009] Chronic myeloid leukemia (CML) is characterized by a Philadelphia chromosome (Ph) resulting from a balanced reciprocal translocation of the t(9;22)(q34;q11) chromosome, leading to the production of the BCR-ABL oncogene, which encodes the chimeric BCR-ABL1 oncoprotein. (Salesse S, Verfaillie CM, BCR / ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia, Oncogene, 2002, 21(56): 8547-59). Imatinib (a selective BCR-ABL1 kinase inhibitor) was the first approved tyrosine kinase inhibitor, revolutionizing the treatment and outcomes for CML patients. However, mutations in the BCR-ABL1 kinase domain can lead to resistance to imatinib treatment. More than 50 mutation sites and more than 70 individual mutations conferring varying levels of resistance have been identified in CML patients (Apperley J: Part I: Mechanisms of resistance to imatinib in chronic myeloid leukemia, Lancet Oncol 2007, 8: 1018-1029). Although more effective second-generation BCR-ABL1 inhibitors have been approved, none of them are effective against all imatinib resistance mutations. Y253H, E255V, F359V, and Q252H exhibit moderate resistance to nilotinib, while E255V, F317L, and Q252H show moderate resistance to dasatinib. T315I, however, is resistant to nilotinib, dasatinib, and besutinib (O'Hare T et al., Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia, *Blood*, 2007, 110, 2242-2249). The third-generation BCR-ABL1 inhibitor ponatinib is effective against T315I but ineffective against T315L and T315M.Multiple complex mutations following sequential treatment with various BCR-ABL1 inhibitors pose new challenges to currently approved BCR-ABL1 inhibitors (Zabriskie MS et al., Extreme mutational selectivity of axitinib limits its potential use as a targeted therapeutic for BCR-ABL1-positive leukemia, *Leukemia*, 2016, 30(6): 1418-21). Furthermore, none of the currently available BCR-ABL1 inhibitors are absolutely safe, and the widespread prescribing of second- or third-generation BCR-ABL1 inhibitors is hampered by their toxicity. Therefore, it is necessary to develop next-generation BCR-ABL1 inhibitors that can target both BCR-ABL1 fusion proteins and acquired mutations with a better safety profile.

[0010] FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is normally expressed by hematopoietic stem cells or progenitor cells and plays an important role in the early stages of bone marrow and lymphoid lineage development. FLT3 mutations are found in approximately 30% of newly diagnosed AML cases, and occur as internal tandem repeats (ITDs) (≈25%) or point mutations in the tyrosine kinase domain (TKD) (7–10%) (Daver N et al., Targeting FLT3 mutations in AML: review of current knowledge and evidence., Leukemia, 2019, 33(2): 299–312). Both FLT3-ITD and FLT3-TKD mutations constitutively activate FLT3 kinase activity, leading to AML proliferation and survival. The multi-kinase inhibitor midostaurin is approved in combination with induction chemotherapy for first-line treatment of patients with FLT3-mutant (ITD or TKD) AML, and the second-generation selective FLT3 inhibitor gilteritinib in single-agent form is approved for patients with relapsed or refractory FLT3-mutant AML. Despite the encouraging results of FLT3 inhibitor-based therapy, many patients still fail to respond to FLT3 inhibitor therapy or subsequently relapse. One resistance mechanism is secondary mutations in the FLT3 kinase domain, including mutations at activating residues (e.g., D835, I836, D839, Y842) or gate residues (e.g., F691) (Short NJ et al., Advances in the Treatment of Acute Myeloid Leukemia: New Drugs and New Challenges., Cancer Discov., April 2020; 10(4): 506-525). Therefore, it is necessary to develop next-generation FLT3 inhibitors that can target primary and secondary FLT3 mutations in FLT3-mutant cancer patients who have been treated with or have not been treated with approved FLT3 inhibitors.

[0011] Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract and account for 18% of all human sarcomas (Corless CL et al., Gastrointestinal stromal tumors: Origin and molecular oncology., *Nature Reviews Cancer*, 2011, 11: 865-878). Gain-of-function mutations of the KIT or PDGFRA receptor tyrosine kinase have been characterized as oncogenic driver mutations in approximately 80-90% of GISTs (O'Brien KM et al., Gastrointestinal stromal tumors, somatic mutations and candidate genetic risk variants., *PLoS One*, 8: e621192013). KIT and the PDGFRA inhibitor imatinib have been approved as first-line therapy for patients with unresectable, recurrent, or metastatic GIST, except for those with the PDGFRA D842V mutation. Most patients who initially experience clinical benefit from imatinib eventually progress after 20–24 months of treatment (Blanke et al., Long-term results from a randomized phase II trial of standard-versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT., *Journal of Clinical Oncology*, 2008, 26, 620–625).Due to the reactivation of KIT signaling in tumor subclones with heterogeneous secondary KIT mutations, oncogenic activated KIT remains a key driver of GIST proliferation and survival in up to 90% of patients after imatinib treatment failure (Serrano C et al., Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumors, *British Journal of Cancer*, 2019, 120: 612-620). Sunitinib and regorafenib exhibit inhibitory activity against only certain secondary mutations, resulting in limited efficacy as second-line and third-line therapies, respectively. Therefore, for GIST patients treated with or without approved KIT and / or PDGFRA inhibitors, there is a need to develop next-generation KIT and / or PDGFRA inhibitors that target both primary and full-spectrum secondary mutations.

[0012] Overall, there is an urgent need to develop next-generation kinase inhibitors that target primary mutations and clinically emerging secondary mutations to achieve better efficacy and longer duration of treatment as first-line therapy, or to overcome resistance mutations in refractory patients. For example, it is necessary to develop next-generation reversible EGFR inhibitors that are effective against oncogenic driver EGFR mutations such as L858R, Del19, L858R / T790M, Del19 / T790M, L858R / C979S, and Del19 / C979S, as well as other emerging and established resistance mutations, while maintaining good selectivity for wild-type EGFR. Summary of the Invention

[0013] In one respect, this disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof.

[0015] in

[0016] A is a 5- to 10-membered heteroaryl group or a C6-C group. 10 Alpha-aryl;

[0017] Each L is independently -C(R) 3 (R) 4 -, -C(O)-, -O-, -N(R) 5 -, -S-, -S(O)- or -S(O)2-, with the constraint that (L)n Excluding -OO-, -OS-, or -ON(R) 5 )-key;

[0018] X is N or C(R) 6 );

[0019] X 1 Is it N or C(R)? 7 );

[0020] X 2 Is it N or C(R)? 8 );

[0021] X 3 Is it N or C(R)? 9 );

[0022] X 4 Is it N or C(R)? 10 );

[0023] Y and Y 1 Each can be either O or S independently;

[0024] Y 2 It is -O-, -N(R) 11 - or -S-;

[0025] Z is a 3- to 7-membered heterocyclic alkylene group, C3-C6 heterocyclic alkylene group, C6-C6 heterocyclic alkylene group. 10 aryl, 5- to 10-membered heteroaryl, -C(R) 12 (R) 13 -, -C(O)-, -O-, -N(R) 14 -, -S-, -S(O)- or -S(O)2-, wherein 3 to 7 member heterocyclic alkylene groups, C 3- C6 cycloalkylene, C6-C 10 Each hydrogen atom in the arylene and 5- to 10-membered heteroarylene groups is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2Re -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0026] Z 1 Yes -NR 2 C(Y 1 )-、-C(Y 1 )NR 2 -、-O-、-N(R 2 -, -S-, -S(O)- or -S(O)2-;

[0027] Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a-OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0028] R 2 R 5 R 11 Or R 14 Each of the following is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl or 5- to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PRe R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e′ -CN or -NO2;

[0029] Each R 3 R 4 R 12 and R 13 Independently, it is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=N)NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=N)NR c R d -NRc S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=N)NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN, -NO2, or R 3 R 4 R 12 and R 13 Both of these, together with one or more carbons attached to them, form C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocyclic alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e Rf -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0030] R 6 It is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -CN;

[0031] R 7 and R 8 Each independently consists of a bond with Z, H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2Ra -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NRe R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; the limiting condition is that R 7 Or R 8 One of them is the Z-bond;

[0032] R 9 and R 10Each of the following is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a-P(O)2OR a -CN or -NO2; or R 8 and R 9 Or R 9 and R 10 Together with the carbon it is attached to, it forms C4-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-C 10 aryl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PRe R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0033] Each R a R b R c R d R e and R f Independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkyl-C6-C 10 Aryl and 5- to 10-membered heteroaryl groups;

[0034] m is 0, 1, 2, 3, or 4; and

[0035] n is 2, 3, 4, 5, 6, 7 or 8.

[0036] In some embodiments, this disclosure provides a compound of formula II or a pharmaceutically acceptable salt thereof.

[0038] Where R 1 R 2 A, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Y 2 Z, m, and n are as described in this article.

[0039] In some embodiments, this disclosure provides a compound of formula III or a pharmaceutically acceptable salt thereof.

[0041] Where R 1 A, L, X, X 1 X 2 X 3 X 4 Y, Y 2 Z, Z 1 m and n are as described in this article.

[0042] In some embodiments, this disclosure provides a compound of formula IV or a pharmaceutically acceptable salt thereof.

[0044] Where R 1 R 2 A, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Y 2 Z, m, and n are as described in this article.

[0045] In some embodiments, this disclosure provides a compound of formula V or a pharmaceutically acceptable salt thereof.

[0047] Where R 1 A, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Z, Z 1 m and n are as described in this article.

[0048] In some embodiments, this disclosure provides a compound of formula VI or a pharmaceutically acceptable salt thereof.

[0050] Where R 1 R 2 A, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Y 2 Z, m, and n are as described in this article.

[0051] In some embodiments, this disclosure provides a compound of formula VII or a pharmaceutically acceptable salt thereof.

[0053] Where R 1 R 2 A, B, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Y 2 Z, m, and n are as described in this article.

[0054] In some embodiments, this disclosure provides a compound of formula VIII or a pharmaceutically acceptable salt thereof.

[0056] Where R 1 R 2 A, B, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Y 2 Z, m, and n are as described in this article.

[0057] In some aspects of each of the above embodiments, ring B(Z) is not

[0058] In some aspects of the embodiments herein, C(R) 9 ) is H. In some aspects of the embodiments herein, C(R) 9 ) is not -Cl. In some embodiments, C(R) 10 ) is H. In some aspects of the embodiments herein, C(R) 10 It is not -Cl.

[0059] In some aspects of the embodiments herein, the compound is not a compound in which ring B(Z) is

[0060] In some embodiments of the foregoing, the compounds of formulas (I)-(VIII) are compounds selected from those species described or exemplified in the following embodiments.

[0061] In other respects, this disclosure relates to a pharmaceutical composition comprising at least one compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to this disclosure may additionally comprise a pharmaceutically acceptable excipient.

[0062] In other respects, this disclosure relates to compounds of formulas (I)-(VIII) or pharmaceutically acceptable salts thereof used as pharmaceutical agents.

[0063] In other respects, this disclosure relates to a method of treating a disease such as cancer, comprising administering to an individual in need of such treatment an effective amount of at least one compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof.

[0064] In other respects, this disclosure relates to the use of compounds of formulas (I)-(VIII) or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating diseases such as cancer, and the use of such compounds and salts for treating such diseases.

[0065] In other respects, this disclosure relates to a method of inhibiting a tyrosine kinase (e.g., EGFR) comprising contacting a cell containing one or more kinases with an effective amount of at least one compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof and / or with at least one pharmaceutical composition of this disclosure, wherein said contact is in vitro, ex vivo or in vivo.

[0066] Other embodiments, features, and advantages of this disclosure will become apparent from the following description and from practice of this disclosure. The compounds disclosed herein may be described as embodiments in any of the categories listed below. It should be understood that any embodiment described herein may be used in conjunction with any other embodiment described herein to the extent that the embodiments do not contradict each other.

[0067] 1. A compound of formula I or a pharmaceutically acceptable salt thereof,

[0069] in

[0070] A is a 5- to 10-membered heteroaryl group or a C6-C group. 10 Alpha-aryl;

[0071] Each L is independently -C(R) 3 (R) 4 -, -C(O)-, -O-, -N(R) 5 -, -S-, -S(O)- or -S(O)2-, with the constraint that (L) n Excluding -OO-, -OS-, or -ON(R) 5 )-key;

[0072] X is N or C(R) 6 );

[0073] X 1 Is it N or C(R)? 7 );

[0074] X 2 Is it N or C(R)? 8 );

[0075] X 3 Is it N or C(R)? 9 );

[0076] X 4 Is it N or C(R)? 10 );

[0077] Y and Y 1 Each can be either O or S independently;

[0078] Y 2 It is -O-, -N(R) 11 - or -S-;

[0079] Z is a 3- to 7-membered heterocyclic alkylene group, C3-C6 heterocyclic alkylene group, C6-C6 heterocyclic alkylene group. 10 aryl, 5- to 10-membered heteroaryl, -C(R) 12 (R) 13 -, -C(O)-, -O-, -N(R) 14 -, -S-, -S(O)- or -S(O)2-, wherein the 3 to 7-membered heterocyclic alkylene, C3-C6 heterocyclic alkylene, C6-C 10 Each hydrogen atom in the arylene and 5- to 10-membered heteroarylene groups is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e Rf -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0080] Z 1 Yes -NR 2 C(Y 1 )-、-C(Y 1 )NR 2 -、-O-、-N(R 2 -, -S-, -S(O)- or -S(O)2-,

[0081] Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR aS(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NRe C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0082] R 2 R 5 R 11 Or R 14 Each of the following is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl or 5- to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e-S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e′ -CN or -NO2;

[0083] Each R 3 R 4 R 12 and R 13 Independently, it is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=N)NR c Rd 、-OS(O)R c 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=N)NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=N)NR c R d 、-PR c R d 、-P(O)R c R d 、-P(O)2R c R d 、-P(O)NR c R d 、-P(O)2NR c R d 、-P(O)OR c 、-P(O)2OR c-CN, -NO2, or R 3 R 4 R 12 and R 13 Both of these, together with one or more carbons attached to them, form C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocyclic alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e Rf -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0084] R 6 It is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -CN;

[0085] R 7 and R 8 Each independently consists of a bond with Z, H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR aS(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NRe S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; the limiting condition is that R 7 Or R 8 One of them is the Z-bond;

[0086] R 9 and R 10 Each of the following is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b-NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or R 8 and R 9 Or R 9 and R 10 Together with the carbon it is attached to, it forms C4-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-C 10 aryl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2Re -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0087] Each R a R b R c R d R e and R f Independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkyl-C6-C 10 Aryl and 5- to 10-membered heteroaryl groups;

[0088] m is 0, 1, 2, 3, or 4; and

[0089] n is 2, 3, 4, 5, 6, 7 or 8.

[0090] 2. The compound as described in clause 1, having formula IV

[0092] Or its pharmaceutically acceptable salt.

[0093] 3. The compound as described in clause 1, having formula VI

[0095] Or its pharmaceutically acceptable salt.

[0096] 4. The compound of any one of clauses 1 to 3 or a pharmaceutically acceptable salt thereof, wherein A is phenylene, furanyl, thiopheneyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl.

[0097] 5. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein A is a pyridine group.

[0098] 6. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein A is

[0099] 7. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein A is

[0100] 8. The compound or its pharmaceutically acceptable salt as described in any of the preceding clauses, each R 1 It is -CN or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f-NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0101] 9. The compound or its pharmaceutically acceptable salt as described in any of the preceding clauses, each R 1 It is -CN or methyl.

[0102] 10. The compound or its pharmaceutically acceptable salt as described in any of the preceding clauses, R 1a It is a methyl group.

[0103] 11. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 2 It is H or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e-OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e′ -CN or -NO2.

[0104] 12. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 2 It is H or methyl.

[0105] 13. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein Z is a 5- or 6-membered heteroaryl group, wherein each hydrogen atom in the 5- or 6-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e-P(O)2OR e -CN or -NO2.

[0106] 14. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein Z is an imidazolyl, imoxazolyl, imidazolyl, imidaridyl, pyrimidinyl, or imidarid-2-one group, wherein each hydrogen atom in the imidazolyl, imoxazolyl, imidazolyl, imidaridyl, or imidarid-2-one group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2Re R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0107] 15. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein Z is

[0108] 16. A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 12, wherein Z is C6-C 10 Aromatic compounds, of which C6-C 10 Each hydrogen atom in the arylene group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f-C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0109] 17. A compound or a pharmaceutically acceptable salt thereof as described in any one of clauses 1 to 12 or 16, wherein Z is a phenylene, wherein each hydrogen atom in the phenylene is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e Rf -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0110] 18. The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 12, 16 or 17, wherein Z is

[0111] 19. A compound or a pharmaceutically acceptable salt thereof as described in any one of clauses 1 to 12, wherein Z is a 3- to 7-membered heterocyclic alkyl group, wherein each hydrogen atom in the 3- to 7-membered heterocyclic alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NRe R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0112] 20. A compound or a pharmaceutically acceptable salt thereof as described in any one of clauses 1 to 12 or 19, wherein Z is a pyridine group or a aziridine group, wherein each hydrogen atom in the pyridine group and the aziridine group is optionally independently substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR eC(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0113] 21. A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 12, wherein Z is -C(R 12 (R) 13 )-、-O-、-N(R 14 -, -S-, -S(O)- or -S(O)2-.

[0114] 22. The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 12 or 21, wherein Z is -C(R 12 (R) 13 )-.

[0115] 23. The compound as described in any of the preceding clauses, wherein R 12 and R 13 Independently select from the following groups: H, deuterium, fluorine, chlorine, bromine, --OR e and C1-C6 alkyl; or R 12 and R 13Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or the 4- to 6-membered heterocycloalkyl is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e-P(O)2OR e -CN or -NO2.

[0116] 24. The compound as described in any of the preceding clauses, wherein R 12 It is H and R 13 It is a methyl group.

[0117] 25. The compound as described in any of the preceding clauses, wherein R 12 It is methyl and R 13 It is H.

[0118] 26. The compound as described in any of the preceding clauses, wherein R 12 and R 13 It is H.

[0119] 27. The compound as described in any of the preceding clauses, wherein R 12 It is methyl and R 13 It is -OH.

[0120] 28. The compound as described in any of the preceding clauses, wherein R 12 It is -OH and R 13 It is a methyl group.

[0121] 29. The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 12 or 21, wherein Z is -O-.

[0122] 30. The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 12 or 21, wherein Z is -N(R 14 )-.

[0123] 31. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 14 It is H, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl.

[0124] 32. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 14 It is H, methyl, or cyclopropyl.

[0125] 33. The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 12 or 21, wherein Z is -S-.

[0126] 34. The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 12 or 21, wherein Z is -S(O)2-.

[0127] 35. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein n is 3.

[0128] 36. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein n is 4.

[0129] 37. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein n is 5.

[0130] 38. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein n is 6.

[0131] 39. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein n is 7.

[0132] 40. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein each L is independently selected from the group consisting of: -C(O)-, -O-, -CH2-, -C(H)(CH3)-, -C(H)(OH)-, -C(H)(C(O)OR c )-、-C(H)(C(O)NR c R d -, -NH- and -NCH3-.

[0133] 41. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein X is a C(R) compound. 6 ).

[0134] 42. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 6 It is H.

[0135] 43. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein Y is O.

[0136] 44. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein Y 1 It is O.

[0137] 45. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein Y 2 It is -N(R) 11 )-.

[0138] 46. ​​A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein X 1 When it exists and X 3 It is N.

[0139] 47. A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 45, wherein X 1 When it exists and X 4 It is N.

[0140] 48. A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 45, wherein X 3 and X 4 It is N.

[0141] 49. A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 45, wherein X 1 It is N when it exists.

[0142] 50. A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 45, wherein X 2 It is N when it exists.

[0143] 51. The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 45, wherein X 3 It is N.

[0144] 52. The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 45, wherein X 4 It is N.

[0145] 53. The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 45, wherein X 1 It is C(R) 7 ), X 3 It is C(R) 9 ), and X 4 It is C(R) 10 ).

[0146] 54. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein C(R) 7 When present, it is independently H, deuterium, fluorine, chlorine, -CN, or methyl.

[0147] 55. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein C(R) 8 When present, it is independently H, deuterium, fluorine, chlorine, -CN, or methyl.

[0148] 56. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein C(R) 9 When present, it is independently H, deuterium, fluorine, chlorine, -CN, or methyl.

[0149] 57. The compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein C(R) 10 When it exists, it is H.

[0150] 58. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein -(L) n- is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -C(O)NH-(CH2)2O(CH2)2-, -C(O)N(CH3)-(CH2)2O(CH2)2-, -NHC(O)CH2O(CH2)2-, -N(CH3)-C(O)CH2O(CH2)2-, -CH2O(CH2)2-, -(CH2)2O(CH2)2-, -(CH2)2S(CH2)2-, -O(CH2)2S(CH2)2-, -(CH2)2SO2(CH2)2-, -O(CH2)2SO2(CH2)2-, -(CH2)2SO(CH2)2-, -O(CH2)2SO(CH2)2-, -(CH2)2O(C(H)(C(O)N(H)(azetidin-3-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(CH3))-CH2-, -(CH2)2O(C(H)(C(O)N(CH3)2)-CH2-, -(CH2)2O(C(H)(C(O)N(H)(piperidin-4-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(pyrrolidin-3-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(4-methylpiperazin-1-yl))-CH2-, -(CH2)2O(C(H)(C(O)OCH3)-CH2-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)3-, -CH2CH(CH3)-O(CH2)2-, -CH(CH3)-CH2O(CH2)2-, -O(CH2)2-, -O-(CH2)3-, -OCH2O(CH2)2-, -O-CH2CH(OH)CH2-, -O-(CH2)2O(CH2)2-, -O-CH2CH(CH3)-O(CH2)2-, -O-CH(CH3)-CH2O(CH2)2-, -O-(CH2)2NH-(CH2)2-, -O-CH2CH(CH3)-NH-(CH2)2-, -O-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -O-(CH2)2N(CH3)-(CH2)2-, -O-CH2CH(CH3)-N(CH3)-(CH2)2-, -O-CH(CH3)-CH2N(CH3)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -CH2N(CH2CH3)-(CH2)2--CH2N(CH(CH3))-(CH2)2-, -(CH2)2N(CH3)-(CH2)2-, -CH2CH(CH3)-N(CH3)-(CH2)2-, or -O-CH(CH3)-CH2N(CH3)-(CH2)2-. ,

[0151] 59. The compound as described in paragraph 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [3a(4)Z]-10,11-dihydro-2H,13H-16,1-(methazine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4,11]oxadiazacyclotetradecyne-3,8(5H,9H)-dione;

[0152] [3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(nitromethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecadeyn-3,8(2H,5H)-dione;

[0153] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(nitromethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecadeyn-3,8(2H,5H)-dione;

[0154] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(diazanediyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazaheterocyclic pentadecylyn-3,8(2H,5H)-dione;

[0155] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0156] [3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(nitromethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonide-3,8(2H,5H)-dione;

[0157] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(nitromethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonide-3,8(2H,5H)-dione;

[0158] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazaheterocyclic pentadecylyn-3,8(2H,5H)-dione;

[0159] [3a(4)Z,11S]-11-hydroxy-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecadeyn-3,8(2H,5H)-dione;

[0160] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H,12H-15,17-(ethylenedimethyl)pyrazolo[4,3-p]dipyrrolo[3,2-i:3′,4′-l][1,4,7,14]dioxadiazacycloheptadecyn-4,19(5H,18H)-dione;

[0161] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0162] [3a(4)Z]-3,8-dioxo-2,3,5,8,9,10,11,12-octahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylene-6-carboxylonitrile;

[0163] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)imidazo[4,5-i]pyrazolo[3,4-b]pyrrolo[3,4-f][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0164] [3a(4)Z]-6,15-dimethyl-9,10,11,12-tetrahydro-15H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0165] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclopentadecanyne-3,8(2H,5H)-dione;

[0166] [3a(4)Z]-6,16-dimethyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclopentadecanyne-3,8(2H,5H)-dione;

[0167] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethylenedimethyl)dipyrrolo[3,4-f:2′,3′-i][1,2]thiazo[3,4-b][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0168] [3a(4)Z]-6,9-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0169] [3a(4)Z]-6,9-dimethyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclopentadecanyne-3,8(2H,5H)-dione;

[0170] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0171] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclopentadecanyne-3,8(2H,5H)-dione;

[0172] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethylenedimethyl)pyrazolo[5,1-c]dipyrrolo[3,2-j:3′,4′-m][1,4,8]triazacyclotetradecyne-3,8(2H,5H)-dione;

[0173] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-17,1-(nitromethyl)pyrazolo[1,5-e]dipyrrolo[3,4-i:2′,3′-l][1,5]diazacyclic tetradecyne-3,8(2H,5H)-dione;

[0174] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(ethylenedimethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,19(5H,18H)-dione;

[0175] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(nitromethamine)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,14]oxadiazacyclic hexadecyne-4,19(5H,18H)-dione;

[0176] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(nitromethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,19(5H,18H)-dione;

[0177] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(ethylenedimethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,14]oxadiazacyclohexadecyne-4,19(5H,18H)-dione;

[0178] [10R,19a(20)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethylenedimethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,14]oxadiazacyclohexadecyne-4,19(5H,18H)-dione;

[0179] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethylenedimethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,14]oxadiazacyclohexadecyne-4,19(5H,18H)-dione;

[0180] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(nitromethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,19(5H,18H)-dione;

[0181] [19a(20)Z]-2-methyl-5,6,7,8,9,10-hexahydro-15,17-(ethylenedimethyl)pyrazolo[1,5-g]dipyrrolo[3,4-k:2′,3′-n][1,4,7]triazacyclohexadecyne-4,19(1H,18H)-dione;

[0182] [19a(20)Z]-2,5-dimethyl-5,6,7,8,9,10-hexahydro-15,17-(ethylenedimethyl)pyrazolo[1,5-g]dipyrrolo[3,4-k:2′,3′-n][1,4,7]triazacyclohexadecyne-4,19(1H,18H)-dione;

[0183] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4,11]oxadiazacyclic pentadecylyn-3,8(5H,9H)-dione;

[0184] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-17,1-(nitromethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadeyn-3,8(5H,9H)-dione;

[0185] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadeyn-3,8(5H,9H)-dione;

[0186] [3a(4)Z]-6,9-dimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadeyn-3,8(5H,9H)-dione;

[0187] [3a(4)Z]-6,9,16-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadenyne-3,8(5H,9H)-dione;

[0188] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0189] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0190] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0191] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0192] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0193] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0194] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0195] [3a(4)Z]-20-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0196] [3a(4)Z]-19-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0197] [3a(4)Z]-6,9,20-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecyne-3,8(2H,5H)-dione;

[0198] [3a(4)Z]-9,20-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclopentadecanyne-3,8(2H,5H)-dione;

[0199] [3a(4)Z]-6,16-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0200] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0201] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecyne-3,8(2H,5H)-dione;

[0202] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclopentadecanyne-3,8(2H,5H)-dione;

[0203] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-17,1-(nitromethamine)[1,2]oxazolo[4,5-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(5H,9H)-dione;

[0204] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-17,1-(nitromethamine)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(5H,9H)-dione;

[0205] [3a(4)Z]-6,14-dimethyl-10,11,13,14-tetrahydro-2H-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonide-pentadecanyne-3,8(5H,9H)-dione;

[0206] [3a(4)Z]-6,9,14-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadeyn-3,8(5H,9H)-dione;

[0207] [3a(4)Z]-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0208] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0209] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0210] [3a(4)Z]-6,9,16-trimethyl-10,11-dihydro-2H,13H-1,17-(ethylenediamide)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazolocyclic pentadecylyn-3,8(5H,9H)-dione;

[0211] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-1,17-(ethylenediamide)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(5H,9H)-dione;

[0212] [3a(4)Z]-6,9,12,14,16-pentamethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0213] [3a(4)Z]-6,9,14,16-tetramethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonidedecadeyn-3,8(2H,5H)-dione;

[0214] [3a(4)Z]-6,9,14,16-tetramethyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadenyne-3,8(5H,9H)-dione;

[0215] [3a(4)Z]-9,14,16-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonidedecadeyn-3,8(2H,5H)-dione;

[0216] [3a(4)Z]-9,14,16-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadenyne-3,8(5H,9H)-dione;

[0217] [3a(4)Z]-12-ethyl-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0218] [3a(4)Z]-6,9,14-trimethyl-12-(propyl-2-yl)-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0219] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-10,11-dihydro-2H,13H-1,17-(ethylenediamide)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazolocyclic pentadecylyn-3,8(5H,9H)-dione;

[0220] [3a(4)Z]-9,14-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0221] [3a(4)Z]-6,9-dimethyl-16-(propyl-2-yl)-10,11-dihydro-2H,13H-1,17-(ethylenediamide)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazolocyclic pentadecylyn-3,8(5H,9H)-dione;

[0222] [3a(4)Z]-9-methyl-16-(propyl-2-yl)-10,11-dihydro-2H,13H-1,17-(ethylenediamide)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazolocyclic pentadecylyn-3,8(5H,9H)-dione;

[0223] [3a(4)Z]-6,9,14-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonidedecadeyn-3,8(2H,5H)-dione;

[0224] [3a(4)Z]-9,14-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonidedecadeyn-3,8(2H,5H)-dione;

[0225] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0226] [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0227] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclic pentadecylyn-3,8(2H,5H)-dione; and

[0228] [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclopentadecanyne-3,8(2H,5H)-dione.

[0229] 60. The compound as described in paragraph 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,18-(ethylenedimethyl)dipyrrolo[3,2-g:3′,4′-j][1,5,12]benzoxazadiazepine-3,8(2H,5H)-dione;

[0230] [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,11]benzoxazadiazetadecylene-3,8(5H,9H)-dione;

[0231] [3a(4)Z]-6-methyl-10,11-dihydro-2H-17,1-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4]benzoxazazaheteroyltetradecyne-3,8(5H,9H)-dione;

[0232] [3a(4)Z]-16-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,11]benzoxazadiazetadecylene-3,8(5H,9H)-dione;

[0233] [3a(4)Z]-15-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,11]benzoxazadiazetadecylene-3,8(5H,9H)-dione;

[0234] [3a(4)Z]-14-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,11]benzoxazadiazetadecylene-3,8(5H,9H)-dione;

[0235] [3a(4)Z]-13-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,11]benzoxazadiazetadecylene-3,8(5H,9H)-dione; and

[0236] [3a(4)Z]-6,9,12-trimethyl-10,11,12,13-tetrahydro-2H-1,18-(ethylenedimethyl)dipyrrolo[3,2-g:3′,4′-j][2,5]benzodioxane-3,8(5H,9H)-dione.

[0237] 61. The compound as described in paragraph 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)pyrido[3,2-m]dipyrrolo[3,2-f:3′,4′-i][1,4,11]oxadiazacyclotetradecyne-3,8(5H,9H)-dione;

[0238] [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)pyrimido[5,4-m]dipyrrolo[3,2-f:3′,4′-i][1,4,11]oxadiazacyclic tetradetyne-3,8(5H,9H)-dione;

[0239] [3a(4)Z]-6,16-dimethyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)pyrido[3,4-m]dipyrrolo[3,2-f:3′,4′-i][1,4,11]oxadiazacyclic tetradetyne-3,8(5H,9H)-dione;

[0240] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,18-(ethylenedimethyl)pyrido[2,1-c]dipyrrolo[3,2-j:3′,4′-m][1,4,8]triazacyclotetradecyne-3,8,14(2H,5H)-trione;

[0241] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-18,1-(nitromethamine)pyrido[1,2-e]dipyrrolo[3,4-i:2′,3′-l][1,5]diazacyclic tetradecyne-3,8,14(2H,5H)-trione;

[0242] Or its pharmaceutically acceptable salt.

[0243] 62. The compound as described in paragraph 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [3a(4)Z,13aR]-6-methyl-10,11,12,13,13a,14,15,16-octahydro-2H-18,1-(nitromethamine)tripyrrolo[1,2-a:3′,2′-i:3″,4″-l][1,4,7]triazacyclopentadecanyne-3,8(5H,9H)-dione;

[0244] [3a(4)Z,13aR]-6-methyl-9,10,11,12,13,13a,14,15-octahydro-17,1-(nitromethamine)azacyclobutano[1,2-a]dipyrrolo[3,2-i:3′,4′-l][1,4,7]triazacyclopentadecanyne-3,8(2H,5H)-dione;

[0245] [16a(17)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(nitromethamine)dipyrrolo[3,4-g:2′,3′-j][1,4,6,13]oxatriazacyclopentadecanyne-4,16(5H,15H)-dione;

[0246] [16a(17)Z]-2,5,11-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,13]oxadiazacyclic pentadecadeyn-4,16(5H,15H)-dione;

[0247] [17a(18)Z]-2,12-dimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,13]oxadiazacyclic hexadecyne-4,17(5H,16H)-dione;

[0248] [17a(18)Z]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,13]oxadiazacyclic hexadecyne-4,17(5H,16H)-dione;

[0249] [17a(18)Z]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,11,13]oxatriazacyclohexadecyne-4,17(5H,16H)-dione;

[0250] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-i:3′,4′-l][1,4,7]triazacyclic pentadecylyn-4,16(5H,15H)-dione;

[0251] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-k:3′,4′-n][1,3,6,9]tetraazacyclopentadecanyne-4,16(5H,15H)-dione;

[0252] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-k:3′,4′-n][1,3,6,9]tetraazacyclopentadecanyne-4,16(5H,15H)-dione;

[0253] [16a(17)Z]-11-cyclopropyl-2,5-dimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-k:3′,4′-n][1,3,6,9]tetraazacyclopentadecanyne-4,16(5H,15H)-dione;

[0254] [16a(17)Z]-11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-k:3′,4′-n][1,3,6,9]tetraazacyclopentadecanyne-4,16(5H,15H)-dione;

[0255] [10R,16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-i:3′,4′-l][1,4,7]triazacyclic pentadecylyn-4,16(5H,15H)-dione;

[0256] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-i:3′,4′-l][1,4,7]triazacyclic pentadecylyn-4,16(5H,15H)-dione;

[0257] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,13]oxadiazacyclic pentadecadeyn-4,16(5H,15H)-dione;

[0258] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(nitromethamine)dipyrrolo[3,4-g:2′,3′-j][1,4,6,13]oxatriazacyclopentadecanyne-4,16(5H,15H)-dione;

[0259] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadecanyne-4,16(5H,15H)-dione;

[0260] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(nitromethamine)dipyrrolo[3,4-d:2′,3′-g][1,13,3,10]dioxadiazacyclopentadecanyne-4,16(5H,15H)-dione;

[0261] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,4-d:2′,3′-g][1,13,3,10]dioxadiazacyclopentadecanyne-4,16(5H,15H)-dione;

[0262] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(nitromethamine)dipyrrolo[3,4-d:2′,3′-g][1,3,10,13]oxatriazacyclopentadecanyne-4,16(1H,15H)-dione;

[0263] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,4-d:2′,3′-g][1,3,10,13]oxatriazacyclopentadecanyne-4,16(1H,15H)-dione;

[0264] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(nitromethamine)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxadiazacyclic pentadecadeyn-4,16(1H,15H)-dione;

[0265] [9R,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(nitromethamine)dipyrrolo[3,4-d:2′,3′-g][1,13,3,10]dioxadiazacyclopentadecanyne-4,16(5H,15H)-dione;

[0266] [9S,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(nitromethamine)dipyrrolo[3,4-d:2′,3′-g][1,13,3,10]dioxadiazacyclopentadecanyne-4,16(5H,15H)-dione;

[0267] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0268] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0269] [10R,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadenyne-4,16(5H,15H)-dione;

[0270] [10S,16a(17)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0271] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxadiazacyclopentadecanyne-4,16(1H,15H)-dione;

[0272] [9R,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0273] [9S,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadenyne-4,16(5H,15H)-dione;

[0274] [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-13,15-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,13,4]oxasulfurazine-pentadecantyne-4,17(5H,16H)-dione;

[0275] [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H-13,15-(ethylenediamide)-12λ6-dipyrrolo[3,2-f:3′,4′-i][1,13,4]oxasulfurazine-pentadecanyne-4,12,12,17(5H,9H,16H)-tetraone;

[0276] [17a(18)Z]-2-methyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonohexadecyne-4,17(5H,16H)-dione;

[0277] [12R,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonohexadecyne-4,17(5H,16H)-dione;

[0278] [12S,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonohexadecyne-4,17(5H,16H)-dione;

[0279] [12S,17a(18)Z]-2,5,12-trimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonohexadecyne-4,17(5H,16H)-dione;

[0280] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0281] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(nitromethamine)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0282] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,14]oxadiazacyclic hexadecylene-4,10,17(5H,9H,16H)-trione;

[0283] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0284] [12S,17a(18)Z]-2,5,12-trimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0285] [17a(18)Z]-2-methyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0286] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0287] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0288] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(nitromethamine)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0289] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,14]oxadiazacyclic hexadecyne-4,10,17(5H,9H,16H)-trione;

[0290] [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0291] [18a(19)Z]-2,5-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0292] [18a(19)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0293] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0294] [13R,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0295] [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(nitromethamine)dipyrrolo[3,4-i:2′,3′-l][1,4,8,15]oxatriazacycloheptadecyn-4,12,18(5H,13H,17H)-trione;

[0296] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,4-i:2′,3′-l][1,4,8,15]oxatriazacycloheptadecyn-4,12,18(5H,13H,17H)-trione;

[0297] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0298] [13S,18a(19)Z]-13-hydroxy-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0299] [16a(17)Z]-2-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0300] [16a(17)Z]-19-chloro-2-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0301] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0302] [7R,16a(17)Z]-19-chloro-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonide-pentadecanyne-methyl 7-carboxylate;

[0303] [7R,16a(17)Z]-N-(azacyclobutane-3-yl)-19-chloro-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazacyclopentadecanyne-7-carboxamide;

[0304] [7R,16a(17)Z]-19-chloro-2,5-dimethyl-4,16-dioxo-N-(piperidin-4-yl)-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidecyclopentadecanyne-7-carboxamide;

[0305] [7R,16a(17)Z]-19-chloro-N,2,5-trimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidecyclopentadecanyne-7-carboxamide;

[0306] [7R,16a(17)Z]-19-chloro-2,5-dimethyl-4,16-dioxo-N-[(3R)-pyrrolidine-3-yl]-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidecyclopentadecanyne-7-carboxamide;

[0307] [7R,16a(17)Z]-19-chloro-N,N,2,5-tetramethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidecyclopentadecanyne-7-carboxamide;

[0308] [7R,16a(17)Z]-19-chloro-2,5-dimethyl-7-(4-methylpiperazin-1-carbonyl)-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonide-pentadecanyne-4,16(5H,15H)-dione;

[0309] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0310] [10S,16a(17)Z]-19-chloro-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadenyne-4,16(5H,15H)-dione;

[0311] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0312] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxasulfurazine-pentadecanyne-4,16(5H,15H)-dione;

[0313] [16a(17)Z]-19-chloro-2,5-dimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxadiazacyclic pentadecylyn-4,16(1H,15H)-dione;

[0314] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14-(ethylenediamide)-8λ6-dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxasulfurazine-pentadecanyne-4,8,8,16(1H,5H,15H)-tetraone;

[0315] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14-(ethylenediamide)-8λ4-dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxasulfurazine-pentadecanyne-4,8,16(1H,5H,15H)-trione;

[0316] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxasulfurazine-pentadecanyne-4,16(5H,15H)-dione;

[0317] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxasulfurazine-pentadecanyne-4,16(5H,15H)-dione;

[0318] [16a(17)Z]-2,5-dimethyl-6,7-dihydro-1H,9H-12,14-(ethylenediamide)-11λ6-dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxasulfurazine-pentadecanyne-4,11,11,16(5H,10H,15H)-tetraone;

[0319] [16a(17)Z]-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxasulfurazine-pentadecanyne-4,16(5H,15H)-dione;

[0320] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)pyrazolo[4,3-i]pyrrolo[3,4-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0321] [16a(17)Z]-19-chloro-5-methyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxadiazacyclic pentadecylyn-4,16(1H,15H)-dione;

[0322] [16a(17)Z]-19-chloro-2,5,8-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxadiazacyclic pentadecylyn-4,16(1H,15H)-dione;

[0323] [16a(17)Z]-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonide-19-carboxynitrile;

[0324] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxasulfurazine-pentadecanyne-4,16(5H,15H)-dione;

[0325] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxathionazinecyclopentadecanyne-4,16(5H,15H)-dione; and

[0326] [16a(17)Z]-19-chloro-5-methyl-6,7-dihydro-1H,9H-12,14-(ethylenediamide)-11λ6-dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxasulfurazine-pentadecanyne-4,11,11,16(5H,10H,15H)-tetraone.

[0327] 63. A pharmaceutical composition comprising at least one compound as described in any one of paragraphs 1 to 62 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0328] 64. A method of treating a disease such as cancer, comprising administering to an individual in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 62.

[0329] 65. The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 62, used in a method of treating cancer in an individual.

[0330] 66. A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs 1 to 62, used to treat cancer in an individual.

[0331] 67. Use of a compound as described in any one of paragraphs 1 to 62, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in an individual. Detailed Implementation

[0332] Before further describing this disclosure, it should be understood that this disclosure is not limited to the specific embodiments described, and therefore variations are naturally possible. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting, as the scope of this disclosure will be limited only by the appended claims.

[0333] For the sake of brevity, all publications (including patents) cited in this specification are incorporated herein by reference. 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, applications, published applications, and other publications mentioned herein are incorporated herein by reference in their entirety. If any definition set forth in this section contradicts or otherwise disagrees with a definition set forth in a patent, application, or other publication incorporated herein by reference, the definition set forth in this section shall prevail over the definition incorporated herein by reference.

[0334] Unless the context clearly indicates otherwise, the singular forms “a / an” and “the” as used herein and in the appended claims include multiple indicators. It should also be noted that the claims may be drafted to exclude any optional elements. Therefore, this statement is intended, in combination with the description of the claimed element, to serve as an exclusive term such as “solely / only” and similar expressions, or as a presupposition for the use of negative limitations.

[0335] As used herein, the terms “including,” “containing,” and “comprise” are used in their open, non-restrictive sense.

[0336] To provide a more concise description, some quantitative expressions given herein are not limited by the term "about". It should be understood that, whether or not the term "about" is explicitly used, each quantity given herein is intended to refer to an actual given value, and also to an approximation of the given value based on reasonable deduction by a person skilled in the art, including equivalent and approximate values ​​obtained due to the experimental and / or measurement conditions of the given value. Whenever the yield is given as a percentage, the yield refers to the mass of the same entity relative to the maximum amount of the entity obtainable under specific stoichiometric conditions, where the yield is given for the entity. Unless otherwise indicated, concentrations given as percentages refer to mass ratios.

[0337] Unless otherwise specified, 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. While any methods and materials similar to or equivalent to those described and used herein may be used to implement or test this disclosure, preferred methods and materials are described here. All publications referenced herein are incorporated by way of citation to disclose and describe methods and / or materials relating to the cited publications.

[0338] Unless otherwise specified, the methods and techniques of embodiments of this disclosure are generally performed according to conventional methods well known in the art and described in various general and more specific references cited and discussed throughout this specification. See, for example, Loudon, Organic Chemistry, 4th ed., New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., Wiley-Interscience, 2001.

[0339] The chemical names of the compounds described in this article are generally obtained using a commercially available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0340] It should be understood that certain features of this disclosure described in the context of individual embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of this disclosure described in the context of individual embodiments for brevity may also be provided individually or in any suitable sub-combination. All combinations of embodiments relating to chemical groups represented by variables are particularly included in this disclosure and disclosed herein with respect to compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), as if each combination were individually and explicitly disclosed herein. In addition, all sub-combinations of chemical groups listed in embodiments describing such variables are also particularly included in this disclosure and disclosed herein, as if each such sub-combination of chemical groups were individually and explicitly disclosed herein.

[0341] Chemical definition

[0342] The term "alkyl" refers to a straight-chain or branched monovalent hydrocarbon group. The term "alkylene" refers to a straight-chain or branched divalent hydrocarbon group. In some embodiments, it may be advantageous to limit the number of atoms in "alkyl" or "alkylene" to a specific atomic range, such as C1-C. 20 Alkyl or C1-C 20 Alkylene, C1-C 12 Alkyl or C1-C 12 Alkylene or C1-C6 alkylene or C1-C6 alkylene. Examples of alkyl groups include: methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups considered equivalent to any of the foregoing examples by general knowledge in the fundamental art and the teachings provided herein. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n-propylene ((-CH2-)3), isopropylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), and similar groups. It should be understood that, as described herein, alkyl or alkylene groups may be unsubstituted or substituted. Alkyl or alkylene groups may be substituted by any substituents in the various examples described herein, including one or more of such substituents.

[0343] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having one or more double bonds. The term "alkenylene" refers to a straight-chain or branched divalent hydrocarbon group having one or more double bonds. In some embodiments, it may be advantageous to limit the number of atoms in "alkenyl" or "alkenylene" to a specific atomic range, such as C2-C. 20 alkenyl or C2-C 20 alkenyl, C2-C 12 alkenyl or C2-C 12Alkenyl or C2-C6 alkenyl or C2-C6 alkenyl. Examples of alkenyl groups include ethenyl, allyl, and but-3-en-1-yl. Examples of alkenyl groups include ethenylene (-CH=CH-), propenylene (-CH=CHCH2-), isopropenylene (-CH=CHCH3-), and similar groups. This term includes cis and trans isomers and mixtures thereof. It should be understood that, as described herein, alkenyl or alkenyl groups may be unsubstituted or substituted. Alkenyl or alkenyl groups may be substituted by any substituents in the various embodiments described herein, including one or more of such substituents.

[0344] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having one or more triple bonds. The term "ynynyl" refers to a straight-chain or branched divalent hydrocarbon group having one or more triple bonds. In some embodiments, it may be advantageous to limit the number of atoms in "alkynyl" or "ynynyl" to a specific range of atoms, such as C2-C. 20 Alkyne group or C2-C 20 alkyne group, C2-C 12 Alkyne group or C2-C 12 The alkynyl group may be either a C2-C6 alkynyl group or a C2-C6 alkynyl group. Examples of alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), and similar groups. It should be understood that, as described herein, the alkynyl or alkynyl group may be unsubstituted or substituted. The alkynyl or alkynyl group may be substituted by any substituent in the various embodiments described herein, including one or more of such substituents.

[0345] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic monovalent carbon ring. The term "cycloalkylene" refers to a saturated or partially saturated monocyclic or polycyclic divalent carbon ring. In some embodiments, it may be advantageous to limit the number of atoms in "cycloalkyl" or "cycloalkylene" to a specific atomic range, for example, having 3 to 12 ring atoms. Polycyclic carbon rings include fused, bridged, and spirocyclic systems. Illustrative examples of cycloalkyl include monovalent groups of the following entities, while cycloalkylene includes divalent groups of the following entities, in the form of a suitable bonded moiety:

[0348] Specifically, the cyclopropyl moiety can be derived from the structural formula

[0349] The term "halogen" or "halogen group" refers to chlorine, fluorine, bromine, or iodine.

[0350] The term "haloalkyl" refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include -CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F. The term "haloalkylene" refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include -CF2-, -C(H)(F)-, -C(H)(Br)-, -CH2CF2-, and -CH2C(H)(F)-.

[0351] The term "aryl" refers to a monovalent, all-carbon monocyclic or fused-ring polycyclic group having a fully conjugated π-electron system. The term "arylene" refers to a monovalent, all-carbon monocyclic or fused-ring polycyclic group having a fully conjugated π-electron system. In some embodiments, it may be advantageous to limit the number of atoms in "aryl" or "arylene" to a specific range, such as monovalent, all-carbon monocyclic or fused-ring polycyclic groups with 6 to 14 carbon atoms (C6-C4). 14 Aryl groups, monovalent all-carbon monocyclic or fused-ring polycyclic groups with 6 to 10 carbon atoms (C6-C50, C ... 10 Aryl groups, divalent all-carbon monocyclic or fused-ring polycyclic groups with 6 to 14 carbon atoms (C6-C50, C ... 14 arylene groups, divalent all-carbon monocyclic or fused-ring polycyclic groups with 6 to 10 carbon atoms (C6-C50, C ... 10 (Arylidene). Examples of aryl groups are, but not limited to, phenyl, naphthyl, and anthracene. Examples of aryl groups are, but not limited to, phenylene, naphthylene, and anthracene. It should be understood that, as described herein, aryl or arylidene groups may be unsubstituted or substituted. Aryl or arylidene groups may be substituted by any substituents in the various embodiments described herein, including one or more of such substituents.

[0352] The term "heterocyclic alkyl" refers to a saturated or partially saturated monovalent monocyclic or polycyclic ring structure having one or more non-carbon ring atoms. The term "heterocyclic alkylene" refers to a saturated or partially saturated monovalent monocyclic or polycyclic ring structure having one or more non-carbon ring atoms. In some embodiments, it may be advantageous to limit the number of atoms in the "heterocyclic alkyl" or "heterocyclic alkylene" to a specific range of ring atoms, such as 3 to 12 ring atoms (3 to 12-membered), or 3 to 7 ring atoms (3 to 7-membered), or 3 to 6 ring atoms (3 to 6-membered), or 4 to 6 ring atoms (4 to 6-membered), or 5 to 7 ring atoms (5 to 7-membered). In some embodiments, it may be advantageous to limit the number and type of cyclic heteroatoms in the "heterocyclic alkyl" or "heterocyclic alkylene" to a specific range or type of heteroatoms, such as 1 to 5 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Polycyclic systems include fused, bridged, and spirocyclic systems. The ring structure may optionally contain an oxygen atom on a carbocyclic member or up to two oxygen atom on a sulfide ring member. Illustrative examples of heterocyclic alkyl groups include monovalent groups of the following entities, while heterocyclic alkylene groups include divalent groups of the following entities, in the form of a suitable bonded moiety:

[0354] Three-membered heterocycles may contain at least one heteroatom ring atom, wherein the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of three-membered heterocyclic groups include monovalent and divalent groups of ethylene oxide, aziridine, and thietane. Four-membered heterocycles may contain at least one heteroatom ring atom, wherein the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocyclic groups include monovalent and divalent groups of azitidine, oxtenane, and thietane. Five-membered heterocycles may contain up to four heteroatom ring atoms, wherein (a) at least one ring atom is oxygen and sulfur, and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heterocyclic groups include the following monovalent and divalent groups: pyrrolidine, tetrahydrofuran, 2,5-dihydro-1H-pyrrole, pyrazolidine, thiazolylidine, 4,5-dihydro-1H-imidazol, dihydrothiophene-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolylidine-2-one, pyrrolidine-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolane-2-one, and oxazolidine-2-one. A six-membered heterocycle may contain up to four heteroatomic ring atoms, wherein (a) at least one ring atom is oxygen and sulfur, and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocyclic groups include the following monovalent or divalent groups: piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxazyrazine-2-one, piperazine-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A "heterobicyclic" is a fused bicyclic system comprising a heterocycle fused to a cycloalkyl group or another heterocycle.

[0355] It should be understood that, as described herein, heterocyclic or heterocyclic alkyl groups may be unsubstituted or substituted. Heterocyclic or heterocyclic alkyl groups may be substituted by any substituents in the various embodiments described herein, including one or more of such substituents.

[0356] The term "heteroaryl" refers to a fully unsaturated monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (having a ring structure with ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having 3 to 12 ring atoms per heterocycle. The term "hybrid aryl" refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (having a ring structure with ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having 3 to 12 ring atoms per heterocycle. In some embodiments, it may be advantageous to limit the number of ring atoms in "heteroaryl" or "hybrid aryl" to a specific range of atomic members, such as 5 to 10-membered heteroaryls or 5 to 10-membered hybrid aryls. In some cases, a 5 to 10-membered heteroaryl may be a monocyclic or fused bicyclic having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, such as N, O, or S. In some cases, 5- to 10-membered heteroaryl groups can be monocyclic or fused bicyclic with 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, such as N, O, or S. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent groups of the following entities, while examples of 5- to 10-membered heteroaryl groups include divalent groups of the following entities, in the form of a suitable bonded moiety:

[0358] In some embodiments, the "monocyclic" heteroaryl group may be an aromatic five- or six-membered heterocycle. A five-membered heteroaryl or heteroalkylene group may contain up to four heteroatomic ring atoms, wherein (a) at least one ring atom is oxygen and sulfur, and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include monovalent groups of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetraazole. Non-limiting examples of five-membered heteroalkylene groups include divalent groups of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetraazole. A six-membered heteroaryl or heteroaryl group may contain up to four heteroatom ring atoms, wherein (a) at least one ring atom is oxygen and sulfur, and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent groups of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of six-membered heteroaryl groups include divalent groups of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” or “bicyclic heteroaryl” is a fused bicyclic system comprising a heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent groups of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthidine, 1,8-naphthidine, isoquinoline-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzi[d]imidazolium, benzo[d]oxazole, and benzo[d]thiazole. Non-limiting examples of bicyclic heteroaryl groups include divalent groups of quinoline, isoquinoline, quinazoline, quinoline, 1,5-naphthidine, 1,8-naphthidine, isoquinoline-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzi[d]imidazolium, benzo[d]oxazole, and benzo[d]thiazole.

[0359] Specifically, the pyrrole moiety can be derived from the structural formula

[0360] It should be understood that, as described herein, heteroaryl or heteroalkylene groups may be unsubstituted or substituted. Heteroaryl or heteroalkylene groups may be substituted by any substituents in the various embodiments described herein, including one or more of such substituents.

[0361] The term "oxo" stands for carbonyl oxygen. For example, a cyclopentyl group substituted with oxygen is cyclopentanone.

[0362] The term "substituted" means that a specified group or portion carries one or more substituents. The term "unsubstituted" means that a specified group does not carry any substituents. When the term "substituted" is used to describe a structural system, substitution means that it occurs at any position on the system where the valence is allowed. In some embodiments, "substituted" means that a specific group or portion carries one, two, or three substituents. In other embodiments, "substituted" means that a specific group or portion carries one or two substituents. In still other embodiments, "substituted" means that a specific group or portion carries one substituent.

[0363] Any formula described herein is intended to represent a compound with the stated structure, as well as certain variations or forms. For example, the formulas given herein are intended to include racemic forms or one or more enantiomers, diastereomers, or geometric isomers, or mixtures thereof. Additionally, any formula given herein is also intended to refer to hydrates, solvates, or polymorphs of such compounds, or mixtures thereof.

[0364] Any formula given herein is intended to represent both the unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure described by the chemical formulas given herein, differing in that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, 36 Cl and 125 I. These isotopically labeled compounds are suitable for metabolic studies (preferably using...) 14 C); Reaction kinetic studies (using, for example) 2 H or 3 H); detection or imaging techniques [e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT)], including drug or substrate tissue distribution determination; or radiotherapy applicable to the patient. Additionally, using, for example, deuterium (i.e., 2Substitution with heavier isotopes such as H) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents through the procedures disclosed in the examples and preparation methods described below or in the embodiments.

[0365] The term "(ATOM)" for j > i i-j "When applied herein to a class of substituents, it is intended to refer to the following embodiments of this disclosure: wherein each of the numbers of atomic members i to j (inclusive) is independently realized. For example, the term C..." 1-3 The examples refer independently to embodiments having one carbon member (C1), embodiments having two carbon members (C2), and embodiments having three carbon members (C3).

[0366] Where more than one attachment possibility is permitted, any disubstituent mentioned herein is intended to encompass a variety of such possibilities. For example, the disubstituent -AB- (where A ≠ B) herein refers to a disubstituent having A connected to a first substituted member and B connected to a second substituted member, and it also refers to a disubstituent having A connected to a second substituted member and B connected to a first substituted member. For example, in some embodiments, where applicable, the compound moiety -(L) of the formula -CH(CH3)-CH2NH-(CH2)2- that connects two groups A and B. n - This should be understood as -CH(CH3)-CH2NH-(CH2)2- including both Examples A-CH(CH3)-CH2NH-(CH2)2-B and B-CH(CH3)-CH2NH-(CH2)2-A. More specifically, in the case of the present invention, it has linking groups -Z- and -NR. 2 The compound part of the formula -CH(CH3)-CH2NH-(CH2)2- is -(L). n The compounds of formula (I)-(VIII) should be understood to include those in the example -Z-CH(CH3)-CH2NH-(CH2)2-NR 2 -and-NR 2 -CH(CH3)-CH2NH-(CH2)2-A Both.

[0367] This disclosure also includes compounds represented by formulas (I)-(VIII), pharmaceutically acceptable salts of preferably the above-described compounds and specific compounds illustrated herein, pharmaceutical compositions comprising such salts, and methods of using such salts.

[0368] "Pharmaceutically acceptable salt" is intended to mean a salt of the free acid or base of the compounds described herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to an individual. See generally S.M. Berge et al., "Pharmaceutical Salts," *J. Pharm. Sci.*, 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for use in contact with individual tissues without excessive toxicity, irritation, or anaphylactic reactions. The compounds described herein may have sufficiently acidic groups, sufficiently basic groups, two types of functional groups, or more than one of each type, and thus react with a variety of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts.

[0369] Examples of pharmaceutically acceptable salts include: sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptarates, propynates, oxalates, malonates, succinates, sebates, trans-butenedioic acid salts, and maleic acid salts. Butyn-1,4-diacid salt, hexyn-1,6-diacid salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985.

[0370] For compounds of formulas (I)-(VIII) containing basic nitrogen, pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example by treating the free base with the following acids: inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, ammonium sulfonic acid, nitric acid, boric acid, phosphoric acid and similar acids; or organic acids, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, hydroxyethyl sulfonic acid, succinic acid, valeric acid, trans-butenedioic acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, etc. Lauric acid, pyranoic acid (e.g., glucuronic acid or galacturonic acid), α-hydroxy acid (e.g., mandelic acid, citric acid or tartaric acid), amino acid (e.g., aspartic acid or glutamic acid), aromatic acid (e.g., benzoic acid, 2-acetoxybenzoic acid, naphtholic acid or cinnamic acid), sulfonic acid (e.g., laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid); any compatible mixture of acids, such as those given as examples herein; and any other acids and mixtures thereof considered equivalent or acceptable substitutes according to a general level of skill in this art.

[0371] This disclosure also relates to pharmaceutically acceptable prodrugs of formulas (I)-(VIII) and treatment methods employing such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a specified compound that, upon administration to an individual, produces the compound in vivo through a chemical or physiological process (e.g., solvent degradation or enzymatic cleavage) or under physiological conditions (e.g., a prodrug is converted to a compound of formula (I)-(VIII) upon reaching a physiological pH). A "pharmaceutically acceptable prodrug" is a non-toxic, biologically tolerable, and otherwise biologically suitable for administration to an individual. Illustrative procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

[0372] This disclosure also relates to pharmaceutically active metabolites of compounds of formulas (I)-(VIII), and the use of such metabolites in the methods of this disclosure. "Pharmacoactive metabolite" means a pharmacologically active product of a compound of formulas (I)-(VIII) or a salt thereof metabolized in vivo. The prodrugs and active metabolites of the compounds can be determined using conventional techniques known or available in the art. See, for example, Bertolini et al., *Journal of Medicinal Chemistry*, 1997, 40, 2011-2016; Shan et al., *Journal of Pharmaceutical Science*, 1997, 86(7), 765-767; Bagshawe, *Drug Discovery Research*, 1995, 34, 220-230; Bodor, *Advanced Drug Delivery Review*, 1984, 13, 255-331; Bondgard, *Design of Prodrugs* (Elsevier Press, 1985); and Larsen, *Design and Application of Prodrugs*, *Drug Design and Development*. Development (edited by Krogsgaard-Larsen et al., Harwood Academic Publishers, 1991).

[0373] As used herein, the term "protecting group" or "PG" refers to any group commonly known to those skilled in the art that can be introduced into a molecule by chemical modification of a functional group (e.g., an amine or a hydroxyl group) to achieve chemoselectivity in subsequent chemical reactions. It should be understood that such protecting groups can subsequently be removed from the functional group at a later point in the synthesis to provide further opportunities for reaction at such functional group, or, in the case of the final product, to mask such functional group. Protecting groups have been described, for example, in *Wuts PGM*, *Greene TW*, *Greene TW*, and *John Wiley & Sons* (2006). *Greene's protective groups in organic synthesis*, Hoboken, NJ: Wiley Online Journal. Those skilled in the art will readily understand the chemical process conditions under which such protecting groups can be mounted on functional groups. Suitable amine protecting groups applicable in conjunction with this disclosure include, but are not limited to: 9-fluorenylmethyl-carbonyl (FMOC), tert-butylcarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl (Ac), trifluoroacetyl, phthalimide, benzyl (Bn), triphenylmethyl (triphenylmethyl, Tr), benzylene, and p-toluenesulfonyl (tolylamide, Ts).

[0374] Representative Examples

[0375] In some embodiments, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0377] Where R 1 A, L, X, X 1 X 2 X 3 X 4 Y, Y 2 Z, Z 1 m and n are as described in this article.

[0378] In some embodiments, this disclosure provides a compound of formula II or a pharmaceutically acceptable salt thereof.

[0380] Where R 1 R 2 A, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Y 2Z, m, and n are as described in this article.

[0381] In some embodiments, this disclosure provides a compound of formula III or a pharmaceutically acceptable salt thereof.

[0383] Where R 1 A, L, X, X 1 X 2 X 3 X 4 Y, Y 2 Z, Z 1 m and n are as described in this article.

[0384] In some embodiments, this disclosure provides a compound of formula IV or a pharmaceutically acceptable salt thereof.

[0386] Where R 1 R 2 A, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Y 2 Z, m, and n are as described in this article.

[0387] In some embodiments, this disclosure provides a compound of formula V or a pharmaceutically acceptable salt thereof.

[0389] Where R 1 A, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Z, Z 1 m and n are as described in this article.

[0390] In some embodiments, this disclosure provides a compound of formula VI or a pharmaceutically acceptable salt thereof.

[0392] Where R 1 R 2 A, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Y 2 Z, m, and n are as described in this article.

[0393] In some embodiments, this disclosure provides a compound of formula VII or a pharmaceutically acceptable salt thereof.

[0395] Where R 1 R 2 A, B, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Y 2 Z, m, and n are as described in this article.

[0396] In some embodiments, this disclosure provides a compound of formula VIII or a pharmaceutically acceptable salt thereof.

[0398] Where R 1 R 2 A, B, L, X, X 1 X 2 X 3 X 4 Y, Y 1 Y 2 Z, m, and n are as described in this article.

[0399] In some embodiments, ring A is a 5- to 10-membered heteroaryl group and Z is a 3- to 7-membered heterocyclic alkyl group, C3-C6 heterocyclic alkyl group, or C6-C6 heterocyclic alkyl group. 10 A arylene or a 5- to 10-membered heteroarylene (also known as ring B). In some embodiments, ring A is a 5- to 10-membered heteroarylene and ring B is a 5- to 10-membered heteroarylene. In some embodiments, ring A is a 5- to 10-membered heteroarylene and ring B is a 3- to 7-membered heterocyclic alkyl. In some embodiments, ring A is a 5- to 10-membered heteroarylene and ring B is a C3-C6 heterocyclic alkyl. In some embodiments, ring A is a 5- to 10-membered heteroarylene and ring B is a C6-C6 heterocyclic alkyl. 10 Alpha-aryl.

[0400] In some embodiments, ring A is C6-C. 10 The arylene group and Z is a 3- to 7-membered heterocyclic alkylene group, a C3-C6 heterocyclic alkylene group, or a C6-C6 heterocyclic alkylene group. 10 A arylene or a 5- to 10-membered heteroarylene (also known as ring B). In some embodiments, ring A is C6-C. 10 The ring is arylene and ring B is a 5- to 10-membered heteroarylene. In some embodiments, ring A is C6-C. 10 The arylene group and ring B are 3 to 7-membered heterocyclic alkylene groups. In some embodiments, ring A is C6-C. 10 The arylene group and ring B are C3-C6 cycloalkylene groups. In some embodiments, ring A is C6-C6. 10 The aryl group and ring B are C6-C 10 Alpha-aryl.

[0401] In some embodiments, ring A is a 5- or 6-membered heterocyclic alkylene group, and Z is a 3- to 7-membered heterocyclic alkylene group, a C3-C6 heterocyclic alkylene group, or a C6-C6 heterocyclic alkylene group. 10 A arylene or a 5- to 10-membered heteroarylene (also known as ring B). In some embodiments, ring A is a 5- or 6-membered heteroarylene and ring B is a 5- to 10-membered heteroarylene. In some embodiments, ring A is a 5- or 6-membered heteroarylene and ring B is a 3- to 7-membered heterocyclic alkyl. In some embodiments, ring A is a 5- or 6-membered heteroarylene and ring B is a C3-C6 cycloalkyl. In some embodiments, ring A is a 5- or 6-membered heteroarylene and ring B is a C6-C6 cycloalkyl. 10 Alpha-aryl.

[0402] In some embodiments, ring A is a 5- or 6-membered heteroaryl group containing 1, 2, or 3 nitrogen ring atoms. In some embodiments, ring A is furanyl, thiopheneyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, ring A is pyrrolyl. In some embodiments, ring B is a 5- or 6-membered heteroaryl group containing 1 or 2 nitrogen ring atoms. In some embodiments, ring B is pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and pyridin-2-one. In some embodiments, ring A is pyrrolyl, and ring B is pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and pyridin-2-one.

[0403] In some embodiments, ring A has the following formula:

[0405] Where R 1a It is a C1-C6 alkyl group, -C(O)R a -C(O)OR a -C(O)NR a R b or -P(O)2OR a Each hydrogen atom in the C1-C6 alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f-SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0406] In some embodiments, ring A has the following formula:

[0408] In some embodiments, ring B(Z) has the following formula:

[0410] In some embodiments, ring B(Z) has the following formula:

[0412] In some embodiments, ring B(Z) has the following formula:

[0414] In some embodiments, ring B(Z) is not

[0415] In some embodiments, ring B(Z) is C6-C 10 Aromatic compounds, of which C6-C 10 Each hydrogen atom in the aryl group is independently and optionally substituted with: C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f-P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0416] In some embodiments, ring B is a phenylene, wherein each hydrogen atom in the phenylene is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f-P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0417] In some embodiments, ring B has the following formula:

[0419] In some embodiments, cyclobola B(Z) is a 3- to 7-membered heterocyclic alkyl group, wherein each hydrogen atom in the 3- to 7-membered heterocyclic alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f-PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0420] In some embodiments, ring B is a pyridine ketone group or azathionyl butyl group, wherein each hydrogen atom in the pyridine ketone group and the azathionyl butyridinyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NReR f -C(O)R e -C(O)OR e-C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0421] In some embodiments, ring A is a 5- or 6-membered heteroaryl group, and Z is -C(R) 12 (R) 13 -O-, -N(R) 14 -, -S-, -S(O)- or -S(O)2-.

[0422] In some embodiments, each R 1 When present, it is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NRa S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f-NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2

[0423] In some embodiments, R 1 When present, it is -CN or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR eC(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2. In some embodiments, R 1 When present, it is -CN or methyl.

[0424] In some embodiments, R 1a When present, it is a C1-C6 alkyl group, -C(O)R a -C(O)OR a -C(O)NR a R b or -P(O)2OR a Each hydrogen atom in the C1-C6 alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e Rf -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2. In some embodiments, R 1a It is a methyl group when present.

[0425] In some embodiments, R 2 Independently, it is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl or 5- to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e′ -CN or -NO2.

[0426] In some embodiments, R 2 It is H or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f-P(O)OR e -P(O)2OR e′ -CN or -NO2. In some embodiments, R 2 It is H or methyl.

[0427] In some embodiments, each L is independently -C(R) 3 (R) 4 -, -C(O)-, -O-, -N(R) 5 -, -S-, -S(O)- or -S(O)2-, with the constraint that (L) n Excluding -OO-, -OS-, or -ON(R) 5 )-key.

[0428] In some embodiments, each R 3 R 4 R 12 and R 13 Independently, it is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=N)NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NRc C(=N)NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=N)NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN, -NO2, or R 3 R 4 R 12 and R 13 Both of these, together with one or more carbons attached to them, form C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocyclic alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e-S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0429] In some embodiments, R 12 and R 13 When present, it can be independently selected from the following groups: H, deuterium, fluorine, chlorine, bromine, -OR e and C1-C6 alkyl; or R 12 and R 13 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or the 4- to 6-membered heterocycloalkyl is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NRe R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0430] In some embodiments, R 12 It is H and R 13 It is methyl. In some embodiments, R is present when present. 12It is methyl and R 13 It is H. In some embodiments, R, when present 12 and R 13 It is H. In some embodiments, R, when present 12 It is methyl and R 13 It is -OH. In some embodiments, R, when present, 12 It is -OH and R 13 It is a methyl group.

[0431] In some embodiments, each L is independently selected from the group consisting of: -C(O)-, -O-, -CH2-, -C(H)(CH3)-, -C(H)(OH)-, -NH-, and -NCH3-. In some embodiments, -(L) n- is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -C(O)NH-(CH2)2O(CH2)2-, -C(O)N(CH3)-(CH2)2O(CH2)2-, -NHC(O)CH2O(CH2)2-, -N(CH3)-C(O)CH2O(CH2)2-, -CH2O(CH2)2-, -(CH2)2O(CH2)2-, -(CH2)2S(CH2)2-, -O(CH2)2S(CH2)2-, -(CH2)2SO2(CH2)2-, -O(CH2)2SO2(CH2)2-, -(CH2)2SO(CH2)2-, -O(CH2)2SO(CH2)2-, -(CH2)2O(C(H)(C(O)N(H)(azetidin-3-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(CH3))-CH2-, -(CH2)2O(C(H)(C(O)N(CH3)2)-CH2-, -(CH2)2O(C(H)(C(O)N(H)(piperidin-4-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(pyrrolidin-3-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(4-methylpiperazin-1-yl))-CH2-, -(CH2)2O(C(H)(C(O)OCH3)-CH2-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)3-, -CH2CH(CH3)-O(CH2)2-, -CH(CH3)-CH2O(CH2)2-, -O(CH2)2-, -O-(CH2)3-, -OCH2O(CH2)2-, -O-CH2CH(OH)CH2-, -O-(CH2)2O(CH2)2-, -O-CH2CH(CH3)-O(CH2)2-, -O-CH(CH3)-CH2O(CH2)2-, -O-(CH2)2NH-(CH2)2-, -O-CH2CH(CH3)-NH-(CH2)2-, -O-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -O-(CH2)2N(CH3)-(CH2)2-, -O-CH2CH(CH3)-N(CH3)-(CH2)2-, -O-CH(CH3)-CH2N(CH3)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -CH2N(CH2CH3)-(CH2)2--CH2N(CH(CH3))-(CH2)2-, -(CH2)2N(CH3)-(CH2)2-, -CH2CH(CH3)-N(CH3)-(CH2)2-, or -O-CH(CH3)-CH2N(CH3)-(CH2)2-. In some embodiments, -Z-(L), n -Z 1 -Do not include -OO-, -OS-, or -ON(R) x )-key.

[0432] In some embodiments, R 5 It is H or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e Rf -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e′ -CN or -NO2. In some embodiments, R 5 It is H or methyl.

[0433] In some embodiments, X is -N-. In some embodiments, X is C(R) 6 In some embodiments, R 6 When present, it is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, or -CN. In some embodiments, R 6 It is H when it exists.

[0434] In some embodiments, X 1 Is it N or C(R)? 7 ); and X 2 Is it N or C(R)? 8 Its constraint is that R 7 Or R 8 One of them is the key with Z. In some embodiments, X 1 Is it N or C(R)? 7 In some embodiments, X 1 It is N. In some embodiments, X 1 It is C(R) 7 In some embodiments, X 2 Is it N- or C(R) 8 In some embodiments, X 2 It is N. In some embodiments, X 2 It is C(R) 8 In some embodiments, X 3 Is it N or C(R)? 9 In some embodiments, X 3 It is N. In some embodiments, X 3 It is C(R) 9 In some embodiments, X 4 Is it N or C(R)? 10 In some embodiments, X 4 It is N. In some embodiments, X 4 It is C(R)10 In some embodiments, X 1 and X 3 It is N. In some embodiments, X 1 and X 4 It is N. In some embodiments, X 3 and X 4 It is N. In some embodiments, X 1 It is C(R) 7 ), X 3 It is C(R) 9 ), and X 4 It is C(R) 10 In some embodiments, the compound is not a compound in which X 1 It is C(R) 7 ), X 3 It is C(R) 9 ), and X 4 It is C(R) 10 ), and R 10 Not H. In some embodiments, the compound is not a compound in which X... 1 It is C(R) 7 ), X 3 It is C(R) 9 ), and X 4 It is C(R) 10 ), and R 9 Not H. In some embodiments, the compound is not a compound in which X... 1 It is C(R) 7 ), X 3 It is C(R) 9 ), and X 4 It is C(R) 10 ), and R 9 and R 10 Not H.

[0435] In some embodiments, R 7 and R 8 Each independently consists of a bond with Z, H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2Ra -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2Re -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; the limiting condition is that R 7 Or R 8 One of them is the Z-bond;

[0436] In some embodiments, R 9 and R 10Each of the following is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a-P(O)2OR a -CN or -NO2; or R 8 and R 9 Or R 9 and R 10 Together with the carbon it is attached to, it forms C4-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-C 10 aryl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PRe R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0437] In some embodiments, R 9 and R 10 Each of them is not deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a Rb -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or R 8 and R 9 Or R 9 and R 10 Together with the carbon it is attached to, it forms C4-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-C 10 aryl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NRe R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)ORe, -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0438] In some embodiments, C(R) 7 ) is H, deuterium, fluorine, chlorine, -CN, or methyl. In some embodiments, C(R) 8 ) is H, deuterium, fluorine, chlorine, -CN, or methyl. In some embodiments, each C(R) 9 ) is H, deuterium, fluorine, chlorine, -CN, or methyl. In some embodiments, C(R) 10 ) is H, deuterium, fluorine, chlorine, -CN, or methyl. In some embodiments, C(R) 9 ) is H. In some embodiments, C(R) 9 ) is not -Cl. In some embodiments, C(R) 10 ) is H. In some embodiments, C(R) 10 It is not -Cl.

[0439] In some embodiments, the compound is not a compound in which ring B(Z) is...

[0440] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0441] In some embodiments, n is 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8.

[0442] In some embodiments, this disclosure provides compounds selected from the group consisting of: [3a(4)Z]-10,11-dihydro-2H,13H-16,1-(methazine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4,11]oxadiazacyclic tetradecyne-3,8(5H,9H)-dione;

[0443] [3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(nitromethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecadeyn-3,8(2H,5H)-dione;

[0444] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(nitromethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecadeyn-3,8(2H,5H)-dione;

[0445] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(diazanediyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazaheterocyclic pentadecylyn-3,8(2H,5H)-dione;

[0446] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0447] [3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(nitromethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonide-3,8(2H,5H)-dione;

[0448] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(nitromethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonide-3,8(2H,5H)-dione;

[0449] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazaheterocyclic pentadecylyn-3,8(2H,5H)-dione;

[0450] [3a(4)Z,11S]-11-hydroxy-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecadeyn-3,8(2H,5H)-dione;

[0451] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H,12H-15,17-(ethylenedimethyl)pyrazolo[4,3-p]dipyrrolo[3,2-i:3′,4′-l][1,4,7,14]dioxadiazacycloheptadecyn-4,19(5H,18H)-dione;

[0452] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0453] [3a(4)Z]-3,8-dioxo-2,3,5,8,9,10,11,12-octahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylene-6-carboxylonitrile;

[0454] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)imidazo[4,5-i]pyrazolo[3,4-b]pyrrolo[3,4-f][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0455] [3a(4)Z]-6,15-dimethyl-9,10,11,12-tetrahydro-15H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0456] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclopentadecanyne-3,8(2H,5H)-dione;

[0457] [3a(4)Z]-6,16-dimethyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclopentadecanyne-3,8(2H,5H)-dione;

[0458] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethylenedimethyl)dipyrrolo[3,4-f:2′,3′-i][1,2]thiazo[3,4-b][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0459] [3a(4)Z]-6,9-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0460] [3a(4)Z]-6,9-dimethyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclopentadecanyne-3,8(2H,5H)-dione;

[0461] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0462] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2′,3′-i][1,5,12]oxadiazacyclopentadecanyne-3,8(2H,5H)-dione;

[0463] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethylenedimethyl)pyrazolo[5,1-c]dipyrrolo[3,2-j:3′,4′-m][1,4,8]triazacyclotetradecyne-3,8(2H,5H)-dione;

[0464] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-17,1-(nitromethyl)pyrazolo[1,5-e]dipyrrolo[3,4-i:2′,3′-l][1,5]diazacyclic tetradecyne-3,8(2H,5H)-dione;

[0465] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(ethylenedimethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,19(5H,18H)-dione;

[0466] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(nitromethamine)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,14]oxadiazacyclic hexadecyne-4,19(5H,18H)-dione;

[0467] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(nitromethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,19(5H,18H)-dione;

[0468] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(ethylenedimethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,14]oxadiazacyclohexadecyne-4,19(5H,18H)-dione;

[0469] [10R,19a(20)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethylenedimethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,14]oxadiazacyclohexadecyne-4,19(5H,18H)-dione;

[0470] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethylenedimethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,14]oxadiazacyclohexadecyne-4,19(5H,18H)-dione;

[0471] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(nitromethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,19(5H,18H)-dione;

[0472] [19a(20)Z]-2-methyl-5,6,7,8,9,10-hexahydro-15,17-(ethylenedimethyl)pyrazolo[1,5-g]dipyrrolo[3,4-k:2′,3′-n][1,4,7]triazacyclohexadecyne-4,19(1H,18H)-dione;

[0473] [19a(20)Z]-2,5-dimethyl-5,6,7,8,9,10-hexahydro-15,17-(ethylenedimethyl)pyrazolo[1,5-g]dipyrrolo[3,4-k:2′,3′-n][1,4,7]triazacyclohexadecyne-4,19(1H,18H)-dione;

[0474] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4,11]oxadiazacyclic pentadecylyn-3,8(5H,9H)-dione;

[0475] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-17,1-(nitromethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadeyn-3,8(5H,9H)-dione;

[0476] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadeyn-3,8(5H,9H)-dione;

[0477] [3a(4)Z]-6,9-dimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadeyn-3,8(5H,9H)-dione;

[0478] [3a(4)Z]-6,9,16-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadenyne-3,8(5H,9H)-dione;

[0479] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0480] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0481] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0482] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0483] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0484] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0485] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0486] [3a(4)Z]-20-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0487] [3a(4)Z]-19-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0488] [3a(4)Z]-6,9,20-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecyne-3,8(2H,5H)-dione;

[0489] [3a(4)Z]-9,20-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclopentadecanyne-3,8(2H,5H)-dione;

[0490] [3a(4)Z]-6,16-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0491] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0492] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecyne-3,8(2H,5H)-dione;

[0493] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4j dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclopentadecanyne-3,8(2H,5H)-dione;

[0494] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-17,1-(nitromethamine)[1,2]oxazolo[4,5-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(5H,9H)-dione;

[0495] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-17,1-(nitromethamine)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(5H,9H)-dione;

[0496] [3a(4)Z]-6,14-dimethyl-10,11,13,14-tetrahydro-2H-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonide-pentadecanyne-3,8(5H,9H)-dione;

[0497] [3a(4)Z]-6,9,14-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadeyn-3,8(5H,9H)-dione;

[0498] [3a(4)Z]-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0499] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0500] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0501] [3a(4)Z]-6,9,16-trimethyl-10,11-dihydro-2H,13H-1,17-(ethylenediamide)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazolocyclic pentadecylyn-3,8(5H,9H)-dione;

[0502] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-1,17-(ethylenediamide)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(5H,9H)-dione;

[0503] [3a(4)Z]-6,9,12,14,16-pentamethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0504] [3a(4)Z]-6,9,14,16-tetramethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonidedecadeyn-3,8(2H,5H)-dione;

[0505] [3a(4)Z]-6,9,14,16-tetramethyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadenyne-3,8(5H,9H)-dione;

[0506] [3a(4)Z]-9,14,16-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonidedecadeyn-3,8(2H,5H)-dione;

[0507] [3a(4)Z]-9,14,16-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazonidedecadenyne-3,8(5H,9H)-dione;

[0508] [3a(4)Z]-12-ethyl-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0509] [3a(4)Z]-6,9,14-trimethyl-12-(propyl-2-yl)-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0510] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-10,11-dihydro-2H,13H-1,17-(ethylenediamide)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazolocyclic pentadecylyn-3,8(5H,9H)-dione;

[0511] [3a(4)Z]-9,14-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0512] [3a(4)Z]-6,9-dimethyl-16-(propyl-2-yl)-10,11-dihydro-2H,13H-1,17-(ethylenediamide)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazolocyclic pentadecylyn-3,8(5H,9H)-dione;

[0513] [3a(4)Z]-9-methyl-16-(propyl-2-yl)-10,11-dihydro-2H,13H-1,17-(ethylenediamide)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]oxazolocyclic pentadecylyn-3,8(5H,9H)-dione;

[0514] [3a(4)Z]-6,9,14-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonidedecadeyn-3,8(2H,5H)-dione;

[0515] [3a(4)Z]-9,14-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethylenedimethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonidedecadeyn-3,8(2H,5H)-dione;

[0516] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0517] [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecylyn-3,8(2H,5H)-dione;

[0518] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclic pentadecylyn-3,8(2H,5H)-dione; and

[0519] [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4-f]dipyrrolo[3,4-j:2′,3′-m][1,4,9]triazacyclopentadecanyne-3,8(2H,5H)-dione;

[0520] Or its pharmaceutically acceptable salt.

[0521] In other embodiments, this disclosure provides compounds selected from the group consisting of: [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,18-(ethylenedimethyl)dipyrrolo[3,2-g:3′,4′-j][1,5,12]benzoxazadiazepine-3,8(2H,5H)-dione;

[0522] [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,11]benzoxazadiazetadecylene-3,8(5H,9H)-dione;

[0523] [3a(4)Z]-6-methyl-10,11-dihydro-2H-17,1-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4]benzoxazazaheteroyltetradecyne-3,8(5H,9H)-dione;

[0524] [3a(4)Z]-16-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,11]benzoxazadiazetadecylene-3,8(5H,9H)-dione;

[0525] [3a(4)Z]-15-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,11]benzoxazadiazetadecylene-3,8(5H,9H)-dione;

[0526] [3a(4)Z]-14-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,11]benzoxazadiazetadecylene-3,8(5H,9H)-dione;

[0527] [3a(4)Z]-13-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,11]benzoxazadiazetadecylene-3,8(5H,9H)-dione; and

[0528] [3a(4)Z]-6,9,12-trimethyl-10,11,12,13-tetrahydro-2H-1,18-(ethylenedimethyl)dipyrrolo[3,2-g:3′,4′-j][2,5]benzodioxane-3,8(5H,9H)-dione or a pharmaceutically acceptable salt thereof.

[0529] In other embodiments, this disclosure provides compounds selected from the group consisting of: [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)pyrido[3,2-m]dipyrrolo[3,2-f:3′,4′-i][1,4,11]oxadiazacyclotetradecyne-3,8(5H,9H)-dione;

[0530] [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)pyrimido[5,4-m]dipyrrolo[3,2-f:3′,4′-i][1,4,11]oxadiazacyclic tetradetyne-3,8(5H,9H)-dione;

[0531] [3a(4)Z]-6,16-dimethyl-10,11-dihydro-2H-1,17-(ethylenedimethyl)pyrido[3,4-m]dipyrrolo[3,2-f:3′,4′-i][1,4,11]oxadiazacyclic tetradetyne-3,8(5H,9H)-dione;

[0532] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,18-(ethylenedimethyl)pyrido[2,1-c]dipyrrolo[3,2-j:3′,4′-m][1,4,8]triazacyclotetradecyne-3,8,14(2H,5H)-trione;

[0533] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-18,1-(nitromethamine)pyrido[1,2-e]dipyrrolo[3,4-i:2′,3′-l][1,5]diazacyclic tetradecyne-3,8,14(2H,5H)-trione;

[0534] Or its pharmaceutically acceptable salt.

[0535] In other embodiments, this disclosure provides compounds selected from the group consisting of: [3a(4)Z,13aR]-6-methyl-10,11,12,13,13a,14,15,16-octahydro-2H-18,1-(nitromethamine)tripyrrolo[1,2-a:3′,2′-i:3″,4″-l][1,4,7]triazacyclic pentadecylyn-3,8(5H,9H)-dione;

[0536] [3a(4)Z,13aR]-6-methyl-9,10,11,12,13,13a,14,15-octahydro-17,1-(nitromethamine)azacyclobutano[1,2-a]dipyrrolo[3,2-i:3′,4′-l][1,4,7]triazacyclopentadecanyne-3,8(2H,5H)-dione;

[0537] [16a(17)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(nitromethamine)dipyrrolo[3,4-g:2′,3′-j][1,4,6,13]oxatriazacyclopentadecanyne-4,16(5H,15H)-dione;

[0538] [16a(17)Z]-2,5,11-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,13]oxadiazacyclic pentadecadeyn-4,16(5H,15H)-dione;

[0539] [17a(18)Z]-2,12-dimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,13]oxadiazacyclic hexadecyne-4,17(5H,16H)-dione;

[0540] [17a(18)Z]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,13]oxadiazacyclic hexadecyne-4,17(5H,16H)-dione;

[0541] [17a(18)Z]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,11,13]oxatriazacyclohexadecyne-4,17(5H,16H)-dione;

[0542] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-i:3′,4′-l][1,4,7]triazacyclic pentadecylyn-4,16(5H,15H)-dione;

[0543] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-k:3′,4′-n][1,3,6,9]tetraazacyclopentadecanyne-4,16(5H,15H)-dione;

[0544] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-k:3′,4′-n][1,3,6,9]tetraazacyclopentadecanyne-4,16(5H,15H)-dione;

[0545] [16a(17)Z]-11-cyclopropyl-2,5-dimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-k:3′,4′-n][1,3,6,9]tetraazacyclopentadecanyne-4,16(5H,15H)-dione;

[0546] [16a(17)Z]-11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-k:3′,4′-n][1,3,6,9]tetraazacyclopentadecanyne-4,16(5H,15H)-dione;

[0547] [10R,16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-i:3′,4′-l][1,4,7]triazacyclic pentadecylyn-4,16(5H,15H)-dione;

[0548] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-i:3′,4′-l][1,4,7]triazacyclic pentadecylyn-4,16(5H,15H)-dione;

[0549] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,13]oxadiazacyclic pentadecadeyn-4,16(5H,15H)-dione;

[0550] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(nitromethamine)dipyrrolo[3,4-g:2′,3′-j][1,4,6,13]oxatriazacyclopentadecanyne-4,16(5H,15H)-dione;

[0551] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(nitromethamine)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadecanyne-4,16(5H,15H)-dione;

[0552] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(nitromethamine)dipyrrolo[3,4-d:2′,3′-g][1,13,3,10]dioxadiazacyclopentadecanyne-4,16(5H,15H)-dione;

[0553] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,4-d:2′,3′-g][1,13,3,10]dioxadiazacyclopentadecanyne-4,16(5H,15H)-dione;

[0554] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(nitromethamine)dipyrrolo[3,4-d:2′,3′-g][1,3,10,13]oxatriazacyclopentadecanyne-4,16(1H,15H)-dione;

[0555] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,4-d:2′,3′-g][1,3,10,13]oxatriazacyclopentadecanyne-4,16(1H,15H)-dione;

[0556] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(nitromethamine)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxadiazacyclic pentadecadeyn-4,16(1H,15H)-dione;

[0557] [9R,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(nitromethamine)dipyrrolo[3,4-d:2′,3′-g][1,13,3,10]dioxadiazacyclopentadecanyne-4,16(5H,15H)-dione;

[0558] [9S,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(nitromethamine)dipyrrolo[3,4-d:2′,3′-g][1,13,3,10]dioxadiazacyclopentadecanyne-4,16(5H,15H)-dione;

[0559] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0560] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0561] [10R,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadenyne-4,16(5H,15H)-dione;

[0562] [10S,16a(17)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0563] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxadiazacyclopentadecanyne-4,16(1H,15H)-dione;

[0564] [9R,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0565] [9S,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadenyne-4,16(5H,15H)-dione;

[0566] [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-13,15-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,13,4]oxasulfurazine-pentadecantyne-4,17(5H,16H)-dione;

[0567] [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H-13,15-(ethylenediamide)-12λ6-dipyrrolo[3,2-f:3′,4′-i][1,13,4]oxasulfurazine-pentadecanyne-4,12,12,17(5H,9H,16H)-tetraone;

[0568] [17a(18)Z]-2-methyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonohexadecyne-4,17(5H,16H)-dione;

[0569] [12R,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonohexadecyne-4,17(5H,16H)-dione;

[0570] [12S,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonohexadecyne-4,17(5H,16H)-dione;

[0571] [12S,17a(18)Z]-2,5,12-trimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonohexadecyne-4,17(5H,16H)-dione;

[0572] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0573] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(nitromethamine)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0574] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,14]oxadiazacyclic hexadecylene-4,10,17(5H,9H,16H)-trione;

[0575] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0576] [12S,17a(18)Z]-2,5,12-trimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0577] [17a(18)Z]-2-methyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0578] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0579] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0580] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(nitromethamine)dipyrrolo[3,4-h:2′,3′-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0581] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,14]oxadiazacyclic hexadecyne-4,10,17(5H,9H,16H)-trione;

[0582] [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0583] [18a(19)Z]-2,5-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0584] [18a(19)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0585] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0586] [13R,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0587] [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(nitromethamine)dipyrrolo[3,4-i:2′,3′-l][1,4,8,15]oxatriazacycloheptadecyn-4,12,18(5H,13H,17H)-trione;

[0588] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,4-i:2′,3′-l][1,4,8,15]oxatriazacycloheptadecyn-4,12,18(5H,13H,17H)-trione;

[0589] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(nitromethamine)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0590] [13S,18a(19)Z]-13-hydroxy-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenedimethyl)dipyrrolo[3,2-f:3′,4′-i][1,4,15]oxadiazacyclic heptadecanyne-4,12,18(5H,13H,17H)-trione;

[0591] [16a(17)Z]-2-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0592] [16a(17)Z]-19-chloro-2-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0593] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0594] [7R,16a(17)Z]-19-chloro-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonide-pentadecanyne-methyl 7-carboxylate;

[0595] [7R,16a(17)Z]-N-(azacyclobutane-3-yl)-19-chloro-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazacyclopentadecanyne-7-carboxamide;

[0596] [7R,16a(17)Z]-19-chloro-2,5-dimethyl-4,16-dioxo-N-(piperidin-4-yl)-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidecyclopentadecanyne-7-carboxamide;

[0597] [7R,16a(17)Z]-19-chloro-N,2,5-trimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidecyclopentadecanyne-7-carboxamide;

[0598] [7R,16a(17)Z]-19-chloro-2,5-dimethyl-4,16-dioxo-N-[(3R)-pyrrolidine-3-yl]-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidecyclopentadecanyne-7-carboxamide;

[0599] [7R,16a(17)Z]-19-chloro-N,N,2,5-tetramethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidecyclopentadecanyne-7-carboxamide;

[0600] [7R,16a(17)Z]-19-chloro-2,5-dimethyl-7-(4-methylpiperazin-1-carbonyl)-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonide-pentadecanyne-4,16(5H,15H)-dione;

[0601] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0602] [10S,16a(17)Z]-19-chloro-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadenyne-4,16(5H,15H)-dione;

[0603] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0604] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxasulfurazine-pentadecanyne-4,16(5H,15H)-dione;

[0605] [16a(17)Z]-19-chloro-2,5-dimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxadiazacyclic pentadecylyn-4,16(1H,15H)-dione;

[0606] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14-(ethylenediamide)-8λ6-dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxasulfurazine-pentadecanyne-4,8,8,16(1H,5H,15H)-tetraone;

[0607] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14-(ethylenediamide)-8λ4-dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxasulfurazine-pentadecanyne-4,8,16(1H,5H,15H)-trione;

[0608] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxasulfurazine-pentadecanyne-4,16(5H,15H)-dione;

[0609] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxasulfurazine-pentadecanyne-4,16(5H,15H)-dione;

[0610] [16a(17)Z]-2,5-dimethyl-6,7-dihydro-1H,9H-12,14-(ethylenediamide)-11λ6-dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxasulfurazine-pentadecanyne-4,11,11,16(5H,10H,15H)-tetraone;

[0611] [16a(17)Z]-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxasulfurazine-pentadecanyne-4,16(5H,15H)-dione;

[0612] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)pyrazolo[4,3-i]pyrrolo[3,4-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione;

[0613] [16a(17)Z]-19-chloro-5-methyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxadiazacyclic pentadecylyn-4,16(1H,15H)-dione;

[0614] [16a(17)Z]-19-chloro-2,5,8-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxadiazacyclic pentadecylyn-4,16(1H,15H)-dione;

[0615] [16a(17)Z]-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonide-19-carboxynitrile;

[0616] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxasulfurazine-pentadecanyne-4,16(5H,15H)-dione;

[0617] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxathionazinecyclopentadecanyne-4,16(5H,15H)-dione; and

[0618] [16a(17)Z]-19-chloro-5-methyl-6,7-dihydro-1H,9H-12,14-(ethylenediamide)-11λ6-dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxasulfurazine-pentadecanyne-4,11,11,16(5H,10H,15H)-tetraone.

[0619] Or its pharmaceutically acceptable salt.

[0620] The following are illustrative examples of compounds represented by formula (I):

[0651] And its pharmaceutically acceptable salts.

[0652] Those skilled in the art will recognize that the species listed or described herein are not exhaustive, and other species within the scope of these defined terms may also be selected.

[0653] Pharmaceutical Composition

[0654] For therapeutic purposes, pharmaceutical compositions comprising the compounds described herein may additionally comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are substances that are non-toxic and otherwise biologically suited to the individual administering the compound. Such excipients facilitate the administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, build-up agents, emulsifiers, or flavor modifiers. In a preferred embodiment, the pharmaceutical composition according to this disclosure is a sterile composition. The pharmaceutical composition may be prepared using compounding techniques known or available to those skilled in the art.

[0655] This disclosure also covers sterile compositions, including compositions that comply with national and regional regulations governing such compositions.

[0656] The pharmaceutical compositions and compounds described herein can be formulated into solutions, emulsions, suspensions, or dispersions suitable for use in pharmaceutical solvents or carriers, or formulated together with solid carriers known in the art for preparing various dosage forms into pills, tablets, lozenges, suppositories, capsules, sugar-coated pills, granules, powders, reconstitution powders, or capsules. The pharmaceutical compositions of this disclosure can be administered via a suitable route of delivery (e.g., oral, parenteral, rectal, nasal, topical, or ocular) or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0657] For oral administration, the compounds of this disclosure may be provided in solid form (e.g., tablets or capsules) or in the form of solutions, emulsions, or suspensions. To prepare oral compositions, the compounds of this disclosure may be formulated to produce doses, for example, about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. Oral tablets may include the active ingredient mixed with pharmaceutically acceptable compatible excipients such as diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, and preservatives. Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and analogues. Exemplary liquid oral excipients include ethanol, glycerol, water, and analogues. Starch, polyvinylpyrrolidone (PVP), sodium glycolate starch, microcrystalline cellulose, and alginate are exemplary disintegrants. Binders may include starch and gelatin. If present, lubricants may be magnesium stearate, stearic acid, or talc. If necessary, tablets may be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0658] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules. To prepare hard gelatin capsules, the active ingredient can be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules can be prepared by mixing the active ingredient with water, oil (e.g., peanut oil or olive oil), liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0659] Liquids intended for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dried product reconstituted with water or other suitable mediators prior to use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and the like); non-aqueous mediators, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethanol, or water; preservatives (e.g., methylparaben or propylparaben or sorbic acid); wetting agents, such as lecithin; and, where necessary, flavoring or coloring agents.

[0660] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the pharmaceutical preparations disclosed herein may be provided as sterile aqueous solutions or suspensions buffered to an appropriate pH and isotonic, or as parenteral acceptable oil forms. Suitable aqueous media include Ringer's solution and isotonic sodium chloride. Such forms may be provided as single-dose forms, such as ampoules or disposable injection devices; multi-dose forms, such as vials from which appropriate doses can be dispensed; or as solid or pre-concentrated forms suitable for preparing injectable formulations. Indicative infusion doses range from about 1 to 1000 μg / kg of the mixture of pharmaceutical preparation and drug carrier per minute over time periods ranging from minutes to days.

[0661] For nasal, inhalation, or oral administration, the pharmaceutical compositions of the present invention can be administered using, for example, a spray formulation containing a suitable carrier. The compositions of the present invention can be formulated for rectal administration in suppository form.

[0662] For surface application, the compounds of this disclosure are preferably formulated as creams or ointments or similar mediators suitable for surface application. For surface application, the compounds of the present invention may be mixed with a drug carrier at a concentration of about 0.1% to about 10% drug:carrier. Another mode of application of the pharmaceutical agents of this disclosure may be achieved through transdermal delivery using patch formulations.

[0663] As used herein, the term "treat / treatment" encompasses both "preventive" and "curative" treatment. "Preventive" treatment aims to delay the development of a disease, its symptoms, or a medical condition; suppress potential symptoms; or reduce the risk of disease or symptom development or recurrence. "Cure" treatment includes reducing the severity of an existing disease, its symptoms, or a condition, or suppressing its worsening. Therefore, treatment includes improving existing disease symptoms or preventing their worsening; preventing the occurrence of other symptoms; improving or preventing underlying systemic causes of symptoms; suppressing a condition or disease, such as curbing its development; alleviating a condition or disease; causing a condition or disease to subside; relieving symptoms caused by a disease or disease; or stopping the symptoms of a disease or disease.

[0664] The term "individual" refers to a mammalian patient, such as a human, who requires this type of treatment.

[0665] Examples of diseases include cancer, pain, neurological disorders, autoimmune diseases, and inflammation. As used herein, the term "cancer" includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastoma, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. +Breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, degenerative thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, epithelial hemangioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, spitzoid neoplasms, sarcoma, astrocytoma, lower-grade glioma of the brain, secretory breast cancer, breast-like carcinoma, acute myeloid leukemia, congenital mesodermal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, melanoma of the skin, squamous cell carcinoma of the head and neck, pediatric glioma (CML), prostate cancer, squamous cell carcinoma of the lung, serous cystadenocarcinoma of the ovary, melanoma of the skin, castration-resistant prostate cancer, Hodgkin's lymphoma, and serous and clear cell endometrial carcinoma. In some embodiments, cancer includes lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophageal-gastric cancer, glioblastoma, head and neck cancer, inflammatory myofibroblastic tumor, and multimorphic large cell lymphoma. Pain includes pain from any source or cause, including cancer pain, pain from chemotherapy, neuropathic pain, pain from injury, or pain from other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren's syndrome, type 1 diabetes, and lupus. Exemplary neurological diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. Exemplary inflammatory diseases include atherosclerosis, allergies, and inflammation resulting from infection or injury.

[0666] In one aspect, the compounds and pharmaceutical compositions disclosed herein specifically target tyrosine receptor kinases, particularly EGFR. Therefore, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow down, or inhibit the activity of one or more of these kinases. In a preferred embodiment, the treatment method targets cancer. In other embodiments, the method is used to treat lung cancer or non-small cell lung cancer.

[0667] In the inhibition methods disclosed herein, "effective amount" means an amount sufficient to inhibit the target protein. Such target regulation can be measured using conventional analytical methods, such as those described below. This type of regulation is applicable to various situations, including in vitro assays. In such methods, the cells are preferably cancer cells exhibiting aberrant signaling due to EGFR upregulation.

[0668] In the treatment methods according to this disclosure, "effective amount" means an amount or dose that is generally sufficient to produce the desired therapeutic benefit in an individual requiring such treatment. The effective amount or dose of the compounds of this disclosure can be determined by conventional methods, such as modeling, dose escalation, or clinical trials, taking into account conventional factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the individual's health status, symptoms and weight, and the judgment of the treating physician. Example doses range from about 0.1 mg to 1 g daily, or from about 1 mg to 50 mg daily, or from about 50 to 250 mg daily, or from about 250 mg to 1 g daily. The total dose can be administered in a single or divided dose unit (e.g., BID, TID, QID).

[0669] Once a patient's condition improves, the dosage can be adjusted for prevention or maintenance therapy. For example, the dosage or frequency of administration, or both, may be reduced to a level necessary to maintain the desired therapeutic or preventative effect, depending on changes in symptoms. Of course, treatment can be discontinued if symptoms have subsided to an appropriate level. However, patients may request long-term intermittent treatment whenever symptoms recur. Patients may also require long-term continuous treatment.

[0670] Drug combination

[0671] The compounds of this invention described herein can be combined with one or more other active ingredients in pharmaceutical compositions or methods to treat the diseases and conditions described herein. Other active ingredients include other therapies or agents that mitigate adverse effects of treatments for the intended disease target. Such combinations can be used to improve efficacy, alleviate other disease symptoms, reduce one or more side effects, or reduce the desired dosage of the compounds of this invention. Other active ingredients can be administered separately from the compounds disclosed herein in a single pharmaceutical composition or may be included together with the compounds disclosed herein in a single pharmaceutical composition. Other active ingredients may be administered simultaneously, before, or after the administration of the compounds disclosed herein.

[0672] Combination agents include other active ingredients known or found to be effective in treating the diseases and conditions described herein, including active ingredients active against another target associated with said disease. For example, the compositions and formulations and treatments of this disclosure may additionally include other drugs or agents, such as other active agents suitable for treating or alleviating a target disease or related symptoms or conditions. For cancer indications, other such agents include, but are not limited to, kinase inhibitors, such as ALK inhibitors (e.g., crizotinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib); standard chemotherapy agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum-based drugs, mitotic inhibitors, antibodies, hormone therapy, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory drugs, such as NSAIDs. The pharmaceutical compositions of this disclosure may additionally include one or more of these active agents, and treatments may additionally include administration of an effective amount of one or more of these active agents.

[0673] Chemical synthesis methods

[0674] The following examples are provided for illustrative purposes and are not intended to limit this disclosure. Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified to obtain other compounds of formulas (I)-(VIII) by selecting suitable starting materials and reagents.

[0675] In some embodiments, this disclosure provides compounds of formula (IX).

[0677] A′ is a 5- to 10-membered heteroaryl group or a C6-C group. 10 aryl groups, optionally substituted with one or more of the following: deuterium, halogen, -OC1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR aR b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(S)R a -C(S)OR a -C(S)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein -OC1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NRe R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0678] Z′ is a 3- to 7-membered heterocyclic alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -C(R a (R) b )H、-C(O)R a -OR a -NR a R b -SRa -S(O)R a or -S(O)2R a Among them, 3 to 7-membered heterocyclic alkyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f-P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0679] X is -N- or -C(R) 6 )-;

[0680] X 1 It is -N-, -C(R) 7 - or the key with Z′; X 2 It is -N-, -C(R) 8 - or the bond with Z′; the constraint is that X 1 or X 2 One of them is the bond with Z′;

[0681] X 3 Is it -N- or -C(R)? 9 )-;

[0682] X 4 Is it -N- or -C(R)? 10 )-;

[0683] Y is either -O- or -S-;

[0684] Y 2 It is -O-, -N(R) 11 - or -S-;

[0685] R 6 It is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -CN;

[0686] R 7 R 8 R 9 and R 10 Each of the following is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -OC1-C6 alkyl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a-S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or R 3 and R 4 Or R 4 and R 5 Together with the carbon it is attached to, it forms C4-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-C 10 aryl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e-CN or -NO2;

[0687] R 11 Independently, it is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl or 5- to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)Re R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e′ -CN or -NO2;

[0688] Each R a R b R c R d R e and R f Independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkyl-C6-C 10 aryl and 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkyl-C6-C 10Each hydrogen atom in the aryl group and the 5- to 10-membered heteroaryl group is independently and optionally substituted with one of the following: -OH, -OPG, -CN, -OC1-C6 alkyl, -NH2, -NHPG, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6) Alkyl)2, -N(C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, -NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O) 2NH2, -NHS(O)NH (C1-C6 alkyl), -NHS(O)2NH (C1-C6 alkyl), -NHS(O)N (C1-C6 alkyl)2, -NHS(O)2N (C1-C6 alkyl)2, -N (C1-C6 alkyl)S(O)NH (C1-C6 alkyl), -N (C1-C6 alkyl)S(O)2NH (C1-C6 alkyl), -N (C1-C6 alkyl)S(O)N (C1-C6 alkyl)2, -N (C1-C6 alkyl)S(O)2N (C1-C6 alkyl)2, -CO2H, -COOPG, -C(O)OC1 -C6 alkyl, -C(O)NH2, -C(O)NHPG, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl or 3 to 7-membered heterocyclic alkyl; and

[0689] PG is a protective base.

[0690] Abbreviations: The examples described herein use materials that are described using, but are not limited to, the following abbreviations known to those skilled in the art:

[0693] General Method A

[0695] A mixture of hydroxyindole A1-1 (1.0 eq.), aldehyde A2-1 (1.0 eq.), and piperidine (2.0 eq.) in ethanol (0.4 M) was refluxed until the reaction was complete. The mixture was cooled to ambient temperature, and the precipitated solid was collected by vacuum filtration, washed with ethanol, and dried to give A-1. If no precipitate formed after cooling of the reaction mixture, the mixture was concentrated and purified by column chromatography.

[0696] Intermediates A-1 to A-26 can be prepared using the corresponding starting materials A1 and A2 as shown in the table below, via general method A:

[0703] General Methodology BI

[0705] Step 1. Add Cs₂CO₃ (2.0 eq.) to a solution of B1-1 (1.0 eq.) and B2-1 (1.5 eq.) in DMF (0.25 M), and heat the mixture at 60-80 °C under nitrogen until the reaction is complete. Add water (5 equivalent volumes of DMF) to the cooled DMF solution, and extract the product three times with ethyl acetate (1 equivalent volume of water). Wash the combined extracts with water, aqueous HCl solution (1N), and brine, and dry over magnesium sulfate. After filtration and condensation, purify the crude product on a silica gel column to obtain pure product B3-1.

[0706] Alternative Step 1: At ambient temperature, add B1-1 (1.0 eq.) to a suspension of NaH (60% in mineral oil, 1.1 eq.) in THF (0.5 M). After 30 minutes, add B2-1 (1.0 eq.) to the suspension. After the reaction is complete, quench the reactants with a saturated ammonium chloride aqueous solution and extract three times with EtOAe. Wash the combined extracts with brine, dry with Na2SO4, filter, concentrate, and purify on a silica gel column to obtain B3-1.

[0707] Step 2. Add N-bromosuccinimide (1.05 eq.) to a solution of B3-1 (1.0 eq.) in anhydrous acetonitrile (0.25 M) and stir the solution at ambient temperature until the reaction is complete. Quench the reactants with an aqueous solution of sodium thiosulfate (0.1 N), and then remove the acetonitrile under vacuum. Dissolve the residue in water and extract with ethyl acetate. Wash the combined extracts with water and brine, and then dry over magnesium sulfate. After filtration and condensation, purify the crude product on a silica gel column to obtain pure product B4-1.

[0708] Step 3. A mixture of B4-1 (1.0 eq), bis(pinacol)diborane (1.2 eq), KOAc (3.0 eq), and catalyst Pd(dppf)Cl2 / CH2Cl2 (0.05 eq) in anhydrous DMF (0.5 M) was purged with nitrogen. The mixture was heated at approximately 95 °C under nitrogen for approximately 15 hours. The reaction solution was cooled and diluted with ethyl acetate (5 volumes of DMF), filtered through a silica gel column, and concentrated. The residue was further purified by rapid silica gel chromatography to obtain the pure product BI-1.

[0709] Using the corresponding starting materials B1 and B2, the following pinacol boronic esters BI-1 to BI-16 were prepared by the general method BI:

[0713] General Method B-II

[0715] Step 1. Add Cs₂CO₃ (2 eq.) to a solution of B5-1 (1.0 eq.) and B2-2 (1.5 eq.) in DMF (0.25 M), and heat the mixture at 60–80 °C under nitrogen until the reaction is complete. Add water (5 volumes of DMF) to the cooled DMF solution, and extract the product three times with ethyl acetate (1 volume of water). Wash the combined extracts with water, HCl aqueous solution (1 N), and brine, and dry over magnesium sulfate. After filtration and condensation, purify the crude product on a silica gel column to obtain pure product B6-1.

[0716] Step 2. A mixture of B6-1 (1.0 eq), bis(pinacol)diborane (1.2 eq), KOAc (3.0 eq), and catalyst Pd(dppf)Cl2 / CH2Cl2 (0.05 eq) in anhydrous DMF (0.5 M) was purged with nitrogen. The mixture was heated at approximately 95 °C under nitrogen for approximately 15 hours. The reaction solution was cooled and diluted with ethyl acetate (5 volumes of DMF), filtered through a silica gel column, and concentrated. The residue was further purified by rapid silica gel chromatography to give pure product B-II-1.

[0717] Using the corresponding starting materials B5 and B2 shown in the table below, the following pinacol boronic esters B-II-1 to B-II-10 were prepared by general method B-II:

[0720] General Method B-III

[0722] Step 1. At ambient temperature, add B7-1 (1.0 eq.) to a suspension of NaH (60% in mineral oil, 1.1 eq.) in THF (0.5 M). After 30 minutes, add B8-1 (1.0 eq.) to the suspension. Stir the mixture at ambient temperature until the reaction is complete, quench with saturated ammonium chloride aqueous solution, and extract three times with EtOAc. Wash the combined extracts with brine, dry with Na2SO4, filter, concentrate, and purify on a silica gel column to obtain B9-1.

[0723] Step 2. At 0°C, n-BuLi (2.5M in hexane, 1.1 eq.) was added to a solution of B9-1 (1.0 eq.) in anhydrous THF (0.2 M). The reaction solution was stirred at ambient temperature for 1 hour, then cooled to -78°C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoboronane (1.05 eq.) was added to the reaction solution. After 15 minutes at -78°C, the reactants were heated to 0°C over 1 hour. The reactants were diluted with saturated NH4Cl solution and extracted with DCM. The organic matter was dried over Na2SO4, concentrated, and purified on a silica gel column to give B-III-1.

[0724] Using the corresponding starting materials B7 and B8 shown in the table below, the following pinacol boronic esters B-III-1 to B-III-6 were prepared by general method B-III:

[0727] General Method B-IV

[0729] Step 1. At ambient temperature, add B11-1 (1 eq.) and NaCNBH3 (2 eq.) to a solution of B10-1 (1 eq.) in methanol (0.2 M) and acetic acid (1.5 eq.). Stir the mixture for 1 hour and allow it to partition between water and ethyl acetate. Separate the organic phase, wash successively with saturated NaHCO3 and brine, concentrate and dry under vacuum. Dissolve the residue in CH2Cl2 (0.2 M) and cool the solution to 0°C. Add di(tert-butyl dicarbonate) (1.2 eq.) partically to the solution. Remove the ice bath and stir the mixture overnight at ambient temperature. Dilute the reaction solution with dichloromethane, wash with water, and dry over magnesium sulfate. After filtration and condensation, purify the residue on a silica gel column to give B12-1.

[0730] Steps 2 and 3 are the same as steps 2 and 3 in the general method BI, resulting in B-IV-1.

[0731] Using the corresponding starting materials B10 and B11 shown in the table below, the following pinacol boronic esters B-IV-1 to B-IV-7 were prepared by the general method B-IV:

[0734] General Method C

[0736] Under N2 conditions, Pd(PPh3)2Cl2 (0.05 eq.) was added to a solution of A-1 (1.0 eq.), B-1 (1.2 eq.), and Cs2CO3 (3 eq.) in DME / H2O (5:1, 0.2 M). The mixture was stirred overnight at 85 °C, cooled to ambient temperature, and quenched with H2O. The resulting mixture was extracted three times with EtOAc. The combined extracts were washed with brine and dried over anhydrous Na2SO4. After filtration and condensation, the residue was purified by silica gel column chromatography to give the desired product C-1.

[0737] The following intermediates C-1 to C-66 are prepared using the two corresponding starting materials A and B shown in the table below, via general method C:

[0754] General Method D

[0756] Under nitrogen atmosphere, D1-1 (1.5 eq.), sodium tert-butoxide (3 eq.), BINAP (0.05 eq.), and Pd(OAc)2 (0.05 eq.) were added to a stirred solution of A-9 (1.0 eq.) in toluene (0.2 M). The mixture was heated at 85 °C for 20 hours and then cooled to ambient temperature. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined extracts were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified on a silica gel column to give D-1.

[0757] The following intermediates D-1 to D-16 were prepared using the two corresponding starting materials A and D1 shown in the table below via general method D:

[0762] General Method E

[0764] Cs₂CO₃ (2.0 eq.) was added to a solution of A-23 (1.0 eq.) and E1-1 (1.5 eq.) in DMF (0.25 M), and the mixture was heated under nitrogen at 60–80 °C until the reaction was complete. Water (5 volumes of DMF) was added to the cooled DMF solution, and the product was extracted three times with ethyl acetate (1 volume of water). The combined extracts were washed with water, aqueous HCl (1 N), and brine, and dried over magnesium sulfate. After filtration and condensation, the crude product was purified on a silica gel column to give pure product E-1.

[0765] The following intermediates E-1 to E-16 were prepared using the two corresponding starting materials A and E1 shown in the table below via general method E:

[0770] General Method F

[0772] At 0 °C, m-chloroperbenzoic acid (m-CPBA) (3 eq.) was added to a solution of E-16 (1.0 eq.) in DCM (0.2 M). The reaction mixture was heated to ambient temperature and stirred for 4 hours. The mixture was quenched with an aqueous solution of sodium thiosulfate (1 M) and extracted with DCM. The combined extracts were washed with brine and dried over sodium sulfate. After filtration and condensation, the residue was purified by silica gel rapid column chromatography to give F-1.

[0773] General method G

[0775] Step 1. Add MsCl (3 eq.) to a solution of Al-19 (1.0 eq.) in DCM (0.2 M) and Et3N (4 eq.) in an ice bath, and stir the mixture overnight at 0°C to ambient temperature. Dilute the reactants with DCM, wash with ice water and brine, and dry with Na2SO4. After filtration and condensation, dry the residue under vacuum to obtain G1-1, which is used without further purification.

[0776] Step 2. At ambient temperature, G2-1 (1.0 eq.) was added to a solution of NaH (60% in mineral oil, 1.2 eq.) in anhydrous THF (0.5 M). After 30 minutes, G1-1 (1.0 eq.) was added to the suspension. After the reaction was complete, the reactants were quenched with a saturated ammonium chloride aqueous solution and extracted three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and vacuum dried. The residue was dissolved in THF / water (1:1, 0.5 M) and an aqueous solution of NaOH (6 M, 3 eq.) was added to the mixture. The mixture was stirred at 60 °C until hydrolysis was complete. The reaction solution was cooled to ambient temperature, diluted with EtOAC, washed with brine, and dried over Na2SO4. After filtration and condensation, the residue was purified by silica gel column chromatography to obtain G3-1.

[0777] Step 3. Following general procedure A, react G3-1 with A2-2 to obtain G-1.

[0778] The following intermediates G-1 to G-4 were prepared using the two corresponding starting materials A1 and G2 shown in the table below, via general method G:

[0781] General Method H

[0783] Step 1. Add DIPEA (3 eq.) and pentafluorophenyl diphenyl phosphate (FDPP) (1.1 eq.) to a solution of A1-22 (1.0 eq.) and H1-1 (1.0 eq.) in DMF (0.2 M). Stir the solution at ambient temperature until amide formation is complete. Dilute the mixture with water and extract three times with EtOAc. Wash the combined extracts three times with water, aqueous HCl (1N), saturated aqueous Na2CO3 solution, and brine, dry over Na2SO4, and concentrate. Purify the residue by silica gel column chromatography to obtain H2-1.

[0784] Step 2. Following the general procedure A, react H2-1 with A2-2 to obtain H-1.

[0785] The following intermediates H-1 to H-10 were prepared using the two corresponding starting materials A1 and H1 shown in the table below, via general method H:

[0789] General Method I

[0791] Step 1. Add DIPEA (3 eq.) and pentafluorophenyl diphenyl phosphate (FDPP) (1.1 eq.) to a solution of A1-31 (1.0 eq.) and D1-13 (1.0 eq.) in DMF (0.2 M). Stir the solution at ambient temperature until amide formation is complete. Dilute the mixture with water and extract three times with EtOAc. Wash the combined extracts three times with water, aqueous HCl (1N), saturated aqueous Na2CO3 solution, and brine, dry over Na2SO4, and concentrate. Purify the residue by silica gel column chromatography to obtain I1-1.

[0792] Step 2. Following the general procedure A, react I1-1 with A2-2 to obtain I-1.

[0793] The following intermediates I-1 to I-5 were prepared using the two corresponding starting materials A1 and D1 shown in the table below, via general method I:

[0797] General Method J

[0799] Step 1. Add H₂O (1M) containing LiOH (3 eq) to a solution of C-1 (1.0 eq.) in MeOH (0.2 M). Stir the mixture at 60 °C until hydrolysis is complete. Cool the solution to ambient temperature, concentrate to remove methanol, acidify with an aqueous HCl solution (1N) until pH is approximately 4-5, and then extract with CH₂Cl₂. Dry the combined extracts with Na₂SO₄, concentrate, and vacuum dry. Dissolve the resulting crude solid in CH₂Cl₂ (0.2 M) and add HCl to the solution in a solution of dioxane (4 eq HCl). Stir the solution at 40 °C until de-Boc is complete. Remove the solvent in a rotary evaporator and vacuum dry the residue to give crude product J-1, which is used in the next step without purification.

[0800] Step 2. Add DIPEA (3 eq.) and pentafluorophenyl diphenyl phosphate (FDPP) (1.1 eq.) to a solution of J-1 (1 eq.) in DMF (0.2 M). Stir the solution at ambient temperature until amide formation is complete. Dilute the mixture with water and extract three times with EtOAc. Wash the combined extracts three times with water, aqueous HCl (1N), saturated aqueous Na2CO3 solution, and brine, dry over Na2SO4, and concentrate. Purify the residue by silica gel column chromatography to give compound 1.

[0801] Following general procedure J, compounds 1-66 are prepared from corresponding C-1 to C-66, compounds 67-82 are prepared from D-1 to D-16, compounds 83-98 are prepared from E-1 to E-16, compound 99 is prepared from F-1, compounds 100-103 are prepared from G-1 to G-4, compounds 104-113 are prepared from H-1 to H-10, and compounds 114-122 are prepared from I-1 to I-9.

[0802] General Method K

[0804] Under nitrogen atmosphere, Pd(PPh3)2Cl2 (0.1 eq) was added to a mixture of [2-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]ethyl]pyrazol-3-yl]boronic acid (1 eq), 5-bromoindoline-2-one (1.3 eq), and Cs2CO3 (3 eq) in dioxane and H2O. The mixture was stirred at 100 °C under N2 for 16 hours, then cooled and concentrated under vacuum. The residue was purified by column chromatography (SiO2) to give N-methyl-N-[2-[2-[5-(2-oxoindoline-5-yl)pyrazol-1-yl]ethoxy]ethyl]tert-butyl carbamate (K-1).

[0805] General Method I

[0807] Under nitrogen atmosphere, Pd(dppf)Cl2 (0.1 eq) and an aqueous solution of Na2CO3 (2 M, 3.0 eq) were added to a solution of N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate tert-butyl ester (1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indoline-2-one (1.5 eq) in dioxane (17 mL). The mixture was stirred at 100 °C under nitrogen atmosphere for 2 hours. After completion, the mixture was concentrated under vacuum to give the crude compound in title. The residue was purified by silica gel column chromatography to give N-methyl-N-[2-[[2-methyl-4-(2-oxoindoline-5-yl)pyrazol-3-yl]methoxy]ethyl]carbamate tert-butyl ester (L-1).

[0808] General Method M

[0810] In an ice bath, DIAD (2.2 eq) was added to a solution of 5-hydroxyindolin-2-one (1 eq), PPh3 (2.2 eq), and N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-tert-butyl carbamate (2.0 eq) in 2-MeTHF. The mixture was stirred at 50 °C for 16 hours, quenched with MeOH, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give N-methyl-N-[2-[2-(2-oxoindolin-5-yl)oxyethoxy]ethyl]tert-butyl carbamate (M-1).

[0811] General Method N

[0813] Step 1. HCl / dioxane (4 M, 10 eq) was added to a solution of N-methyl-N-[2-[2-[5-(2-oxoindoline-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate (1 eq) in DCM, and the resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under vacuum to give 5-[2-[2-[2-(methylamino)ethoxy]ethyl]pyrazol-3-yl]indoline-2-one hydrochloride.

[0814] Step 2. Add 1-methylimidazolium (3 eq) and [chloro(dimethylamino)methylene]dimethylammonium hexafluorophosphate (1.5 eq) to a solution of 5-[2-[2-[5-(2-oxoindoline-5-yl)pyrazol-1-yl]ethoxy]ethyl]-1H-pyrrole-3-carboxamide (N-1) in acetonitrile, and stir the mixture at 25 °C for 0.5 h. Concentrate the reaction mixture under vacuum and purify by silica gel column chromatography. Wet mill the crude product with MeOH at 25 °C for 10 min, then filter to give 2-formyl-N,5-dimethyl-N-[2-[2-[5-(2-oxoindoline-5-yl)pyrazol-1-yl]ethoxy]ethyl]-1H-pyrrole-3-carboxamide (N-1).

[0815] General Method O

[0817] Piperidine (2 eq) was added to a solution of N-1 (1 eq) in EtOH. The mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled and concentrated under vacuum. The crude product was wet-milled with MeOH at 25 °C for 10 minutes to give the title compound (41).

[0818] Example 1

[0819] Methyl 2-[(Z)-(5-chloro-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene)methyl]-1H-pyrrole-3-carboxylate (A-27) was prepared according to general method A.

[0821] A mixture of 5-chloro-1,3-dihydropyrrolo[2,3-c]pyridin-2-one (1.0 g, 5.93 mmol, 1 eq), methyl 2-formyl-1H-pyrrole-3-carboxylate (908 mg, 5.93 mmol, 1 eq), and piperidine (1.01 g, 11.86 mmol, 1.17 mL, 2.0 eq) in EtOH (100 mL) was stirred at 80 °C for 1 hour. After stirring, the mixture was cooled to ambient temperature and the product precipitated. The solid was filtered, washed with EtOH (30 mL), and dried under vacuum to give methyl 2-[(Z)-(5-chloro-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene)methyl]-1H-pyrrole-3-carboxylate (1.6 g, 4.21 mmol, 71% yield) as a yellow powder. 1 H NMR (400MHz, DMSO-d6) δ (ppm).

[0822] A-28 to A31 were prepared following a similar procedure to A-27.

[0824] Example 2

[0825] 3-[3-(tert-Butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazole-1-carboxylic acid tert-butyl ester (BI-2) was prepared according to the general method BI.

[0827] Step 1: At 25°C, (Boc)₂O (14.28 g, 65.4 mmol, 15.0 mL, 1.1 eq) was added to a solution of 1,2-dihydropyrazole-3-one (5.0 g, 59.5 mmol, 1 eq) and TEA (7.82 g, 77.3 mmol, 10.7 mL, 1.3 eq) in DCM (200 mL). The mixture was stirred at 25°C for 4 hours. After stirring, the mixture was diluted with DCM (200 mL) and washed with brine (100 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to give tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (9.0 g, 47.4 mmol, 79.7% yield, 97% purity) as a pale yellow powder. 1H NMR (400MHz, CDCl3) δ (ppm) 7.81 (d, J=3.2Hz, 1H), 5.90 (d, J=3.2Hz, 1H), 1.63 (s, 9H).

[0828] Step 2. K₂CO₃ (7.88 g, 57.0 mmol, 1 eq) was added to a solution of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (7.0 g, 38.0 mmol, 1 eq) and tert-butyl N-(3-bromopropyl)carbamate (9.95 g, 41.80 mmol, 1.1 eq) in DMF (21 mL). The mixture was stirred at 80 °C for 16 hours. After completion, the mixture was diluted with EtOAc (100 mL) and washed with brine (2 × 40 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by combi-flash (40 g silica gel column, 0-40 EtOAc / PE, elution of approximately 10%) to give tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]pyrazole-1-carboxylate (8.2 g, 22.8 mmol, 60% yield, 95% purity) as a white oil. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.08 (d, J = 3.2Hz, 1H), 6.93-6.83 (m, 1H), 6.08 (d, J = 3.2Hz, 1 H), 4.16 (t, J=6.3Hz, 2H), 3.10-2.99 (m, 2H), 2.53-2.50 (m, 2H), 1.55 (s, 9H), 1.37 (s, 9H).

[0829] Step 3. Under a nitrogen atmosphere, add (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (291.2 mg, 439 μmol, 0.1 eq) and 4-tert-butyl-2-(4-tert-butyl-2-pyridinyl)pyridine (235 mg, 878 μmol, 0.2 eq) to a solution of 3-[3-(tert-butyloxycarbonylamino)propoxy]pyrazole-1-carboxylate (1.50 g, 4.39 mmol, 1 eq) and Pin2B2 (2.23 g, 8.7 mmol, 2.0 eq) in THF (30 mL). Stir the mixture at 70 °C for 16 hours. After completion, dilute the mixture with EtOAc (50 mL) and wash with brine (2 × 20 mL). The organic layer was dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (40 g, 0-100% EA / PE, elution approximately 35%) to give tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazole-1-carboxylate (BI-2, 2.3 g, 2.9 mmol, 67.2% yield) as a white oil. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.10 (s, 1H), 6.81 (t, J = 5.2Hz, 1H), 3.80-3.76 (m, 2H) , 3.06 (q, J=6.4Hz, 2H), 1.84-1.82 (m, 1H), 1.55 (s, 9H), 1.37 (s, 9H), 1.25 (s, 12H).

[0830] Example 3

[0831] N-[3-[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazol-3-yl]oxypropyl]tert-butyl carbamate (BI-5) was prepared according to the general method BI.

[0833] Step 1. K₂CO₃ (14.79 g, 107.03 mmol, 1.5 eq) was added to a solution of 2-methyl-1H-pyrazole-5-one (7 g, 71.35 mmol, 1 eq) and N-(3-bromopropyl)carbamate tert-butyl ester (22.09 g, 92.76 mmol, 1.3 eq) in DMF (70 mL). The mixture was stirred at 80 °C for 16 hours. After completion, the mixture was cooled to 25 °C, diluted with water (100 mL), and extracted with EA (3 × 60 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 30:1 to 3:1) to give colorless gel-like N-[3-(1-methylpyrazol-3-yl)oxypropyl]carbamate tert-butyl ester (15 g, 58.75 mmol, 82.3% yield). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.10 (d, J = 2.4Hz, 1H), 5.58 (d, J = 2.4Hz, 1H), 4.95-4.92 (m, 1H), 4.18-4.15(m, 2H), 3.71(s, 3H), 3.30-3.25(m, 2H), 1.94-1.90(m, 2H), 1.43(s, 9H).

[0834] Step 2. At 25°C, NBS (5.03 g, 28.24 mmol, 1.03 eq) was added to a solution of N-[3-(1-methylpyrazol-3-yl)oxypropyl]carbamate tert-butyl ester (7 g, 27.42 mmol, 1 eq) in ACN (40 mL). The mixture was stirred at 25°C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 25:1 to 2:1) to give N-[3-(4-bromo-1-methylpyrazol-3-yl)oxypropyl]carbamate tert-butyl ester (7.3 g, 21.84 mmol, 79.6% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.18 (s, 1H), 5.04-5.02 (m, 1H), 4.28-4.25 (m, 2H), 3.72 (s, 3H), 3.32-3.27 (m, 2H), 1.97-1.94 (m, 2H), 1.44 (s, 9H).

[0835] Step 3. Under nitrogen atmosphere, Xphos-Pd-G2 (706 mg, 897 μmol, 0.1 eq) was added to a mixture of N-[3-(4-bromo-1-methylpyrazol-3-yl)oxypropyl]carbamate tert-butyl ester (3.0 g, 8.98 mmol, 1 eq), AcOK (2.64 g, 26.93 mmol, 3.0 eq), and Pin2B2 (10.26 g, 40.39 mmol, 4.5 eq) in dioxane (50 mL). The mixture was stirred at 60 °C under nitrogen atmosphere for 16 hours. After completion, the mixture was cooled to ambient temperature, diluted with PE (200 mL), and filtered. The organic layer was concentrated under vacuum to obtain a grass-green oily substance. The crude material was purified by silica gel column chromatography (20 g, 0-100% EtOAc / PE, 15 min, approximately 60% elution) to obtain a brown, gel-like N-[3-[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazol-3-yl]oxypropyl] tert-butyl carbamate (BI-5, 2.9 g, 6.08 mmol, 68% yield). LCMS: m / z 381.9 (M+1) + .

[0836] Example 4

[0837] N-[3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenoxy]propyl]tert-butyl carbamate (B-II-1) was prepared according to the general method B-II.

[0839] N-(3-bromopropyl)carbamate tert-butyl ester (11.9 g, 50.0 mmol, 1 eq) was added to a mixture of 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenol (10 g, 45.4 mmol, 1 eq), K₂CO₃ (18.8 g, 136 mmol, 3.0 eq), and KI (754 mg, 4.54 mmol, 0.1 eq) in DMF (50 mL). The mixture was stirred at 80 °C for 16 hours. After stirring, the mixture was cooled, diluted with ethyl acetate (200 mL), washed with brine (2 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, 0-100% EtOAc / PE, elution approximately 25%) to obtain N-[3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenoxy]propyl]carbamate tert-butyl ester (B-II-1, 10 g, 22.5 mmol, 49.5% yield, 85% purity) as a colorless gel. 1H NMR (400MHz, CDCl3) δ (ppm) 7.70-7.76 (m, 1H), 7.37-7.44 (m, 1H), 6.95-7.01 (m, 1H), 6.86-6.92 (m, 1H), 5.46-5.62 (m, 1H), 4.05-4.12 (m, 2H), 3.36-3.49 (m, 2H), 1.96-2.05 (m, 2H), 1.44 (s, 10H), 1.37 (s, 12H).

[0840] Example 5

[0841] N-[3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenoxy]ethyl]tert-butyl carbamate (B-II-2) was prepared according to the general method B-II.

[0842] B-II-2 was prepared using a procedure similar to that used for B-II-1.

[0843] Example 6

[0844] [2-[2-[2-(tert-Butoxycarbonylamino)ethoxy]ethyl]pyrazol-3-yl]boronic acid (B-III-7) was prepared according to the general method B-III.

[0846] MsCl (16.7 g, 146 mmol, 11.3 mL, 1.5 eq) was added to a mixture of N-[2-(2-hydroxyethoxy)ethyl]carbamate tert-butyl ester (20.0 g, 97.4 mmol, 1 eq) and TEA (29.6 g, 292 mmol, 40.7 mL, 3.0 eq) in DCM (500 mL) in an ice bath. The mixture was stirred at 25 °C for 2 hours. After stirring, the mixture was quenched with water (300 mL), and the combined organic layer was washed with saturated NaHCO3 (80 mL) and brine (300 mL), dried over sodium sulfate, and concentrated under vacuum to give 2-[2-(tert-butyloxycarbonylamino)ethoxy]ethyl methanesulfonic acid (25.0 g, 75.0 mmol, 76.9% yield) as a pale yellow gel. 1 H NMR (400MHz, DMSO-d6) δ = 6.79 (s, 1H), 4.30 (t, J = 4.8Hz, 2H), 3.64 (t, J = 4.8Hz , 2H), 3.42 (t, J=6.0Hz, 2H), 3.18 (s, 3H), 3.09 (t, J=6.0Hz, 2H), 1.38 (s, 9H).

[0847] Step 2. Add 1H-pyrazole (3.84 g, 56.5 mmol, 1.0 eq) and Cs₂CO₃ (36.8 g, 112 mmol, 2 eq) to a solution of 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl methanesulfonic acid (16.0 g, 56.5 mmol, 1 eq) in DMF (80 mL). Stir the mixture at 50 °C for 2 hours. After completion, quench the mixture with water (200 mL) and dilute with EA (3 × 100 mL). Wash the combined organic layers with brine (200 mL), dry to Na₂SO₄, and concentrate under vacuum to obtain the crude substance. Purify the residue by column chromatography (SiO₂, DCM:MeOH = 20:1) to obtain N-[2-(2-pyrazole-1-ylethoxy)ethyl]carbamate tert-butyl ester (13.0 g, 48.3 mmol, 85.6% yield) as a colorless oil. LCMS: m / z 256.0 (M+1) + .

[0848] Step 3. At -70°C, n-BuLi (2.5M, 9.40mL, 3eq) was added dropwise to a solution of N-[2-(2-pyrazol-1-ylethoxy)ethyl]carbamate tert-butyl (2.00g, 7.83mmol, 1eq) in 2-MeTHF (150mL). The mixture was stirred at 25°C for 0.5 hours, followed by the addition of 2-MeTHF (150mL) containing triisopropyl borate (2.21g, 11.7mmol, 2.70mL, 1.5eq) at -70°C. The mixture was stirred at 25°C for 1.5 hours. Upon completion, the mixture was quenched with MeOH (50 mL), concentrated under vacuum, and purified by reverse-phase HPLC to obtain [2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl]pyrazol-3-yl]boronic acid (B-III-7, 500 mg, 18.1% yield) as a white powder. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.36 (m, 2H), 7.39 (s, 1H), 6.71 (s, 2H), 4.50 (t, J = 4.8Hz, 2H,), 3.68 (t, J=4.8Hz, 2H), 3.33 (t, J=6.0Hz, 2H), 3.01 (t, J=6.0Hz, 2H), 1.37 (s, 9H). LCMS: m / z 300(M+1) + .

[0849] Example 7

[0850] [2-[2-[2-[2-[tert-Butoxycarbonyl(methyl)amino]ethoxy]ethyl]pyrazol-3-yl]boronic acid (B-III-8) was prepared according to the general method B-III.

[0851] B-III-8 was prepared using a similar procedure to that used for B-III-7. LCMS: m / z 314.1 (M+1) + .

[0852] Preparation of [2-[2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino]ethyl]pyrazol-3-yl]boronic acid (B-III-9)

[0854] Step 1. MsCl (852 mg, 7.44 mmol, 1.2 eq.) was added to a mixture of N-(2-hydroxyethyl)carbamate tert-butyl ester (1.00 g, 6.20 mmol, 1 eq.) and TEA (941 mg, 9.31 mmol, 1.5 eq.) in DCM (30 mL) in an ice bath. The mixture was stirred at 25 °C for 3 hours. After stirring, the mixture was quenched with water (10 mL) and diluted with DCM (20 mL). The organic layer was washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over sodium sulfate and concentrated under vacuum to give a pale yellow oily product of methanesulfonic acid (2-(tert-butyloxycarbonylamino)ethyl ester (1.20 g, 4.51 mmol, 72% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δ=4.90 (s, 1H), 4.21 (t, J=5.2Hz, 2H), 3.41 (dd, J=10.8, 5.6Hz, 2H), 2.97 (s, 3H), 1.38 (s, 9H).

[0855] Step 2. 2-(tert-Butoxycarbonylamino)ethyl methanesulfonate (9.00 g, 37.0 mmol, 1.0 eq.) and 2-aminoethanol (22.9 g, 376 mmol, 10 eq.) were heated to 80 °C and maintained for 16 hours. The mixture was quenched with water (200 mL) and diluted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated under vacuum to give tert-butyl N-[2-(2-hydroxyethylamino)ethyl]carbamate (10.0 g, 36.7 mmol, 97.6% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 6.77-6.65 (m, 1H), 4.52-4.34 (m, 1H), 3.42 (t, J = 5.7 Hz, 2H), 3.04-2.93 (m, 2H), 2.57-2.52 (m, 4H), 2.52-2.50 (m, 2H), 1.38 (s, 9H).

[0856] Step 3. Add NaHCO3 (3.70 g, 44.0 mmol, 3 eq.) and Cb2Cl (3.26 g, 19.0 mmol, 1.3 eq.) to a solution of N-[2-(2-hydroxyethylamino)ethyl]carbamate tert-butyl ester (3.00 g, 14.6 mmol, 1 eq.) in THF (50 mL) and H2O (12 mL). Stir the mixture at 20 °C for 16 hours. After completion, quench the mixture with water (150 mL) and extract with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, concentrated under vacuum, and the residue was purified by rapid chromatography (40 g silica gel column, 0% to 100% EtOAc / PE) to give N-[2-(tert-butoxycarbonylamino)ethyl]-N-(2-hydroxyethyl)carbamate (3.40 g, 9.54 mmol, 64.9% yield) as a colorless gel. 1 H NMR (400MHz, DMSO-d6) δ=7.44-7.27(m, 5H), 6.94-6.80(m, 1H), 5.07(s, 2H), 4.78-4.68(m, 1H), 3.48 (d, J=3.5Hz, 2H), 3.31-3.24 (m, 4H), 3.07 (d, J=6.3Hz, 2H), 1.37 (s, 9H); LCMS: m / z 239.1(M+1-100) + .

[0857] Step 4. In an ice bath, add MsCl (1.73 g, 15.0 mmol, 1.17 mL, 1.5 eq.) to a solution of N-[2-(tert-butoxycarbonylamino)ethyl]-N-(2-hydroxyethyl)carbamate (3.40 g, 10.0 mmol, 1 eq.) and TEA (3.05 g, 30.1 mmol, 3.0 eq.) in DCM (100 mL). Stir the mixture at 25 °C for 3 hours. After completion, quench the mixture with water (150 mL) and dilute with DCM (3 × 150 mL). The combined organic layers were washed with saturated NaHCO3 (100 mL) and brine (80 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a pale yellow, gelatinous crude substance (2-[benzyloxycarbonyl-[2-(tert-butyloxycarbonylamino)ethyl]amino]ethyl methanesulfonic acid, 4.00 g, 9.60 mmol, 95% yield). LCMS: m / z 317.1 (M+1-100) + .

[0858] Step 5. Add 1H-pyrazole (721 mg, 10.6 mmol, 1 eq.) and Cs₂CO₃ (6.91 g, 21.2 mmol, 2 eq.) to a solution of 2-[benzyloxycarbonyl-[2-(tert-butyloxycarbonylamino)ethyl]amino]ethyl methanesulfonic acid (5.30 g, 12.7 mmol, 1.2 eq.) in DMF (40 mL). Stir the mixture at 50 °C for 3 hours. After completion, quench the mixture with water (50 mL) and extract with EtOAc (3 × 50 mL). Wash the combined organic layers with brine (50 mL), dry over sodium sulfate, and concentrate under vacuum. The residue was purified by rapid chromatography (12 g silica column, EtOAc / PE 0% to 100%) to obtain N-[2-(tert-butoxycarbonylamino)ethyl]-N-(2-pyrazol-1-ylethyl)carbamate (3.60 g, 7.88 mmol, 74.2% yield), a pale yellow gel. LCMS: m / z 389.4 (M+1) + .

[0859] Step 6. At -70°C and under a N2 atmosphere, LDA (2M, 6.18mL, 3eq.) was added dropwise to a mixture of N-[2-(tert-butoxycarbonylamino)ethyl]-N-(2-pyrazol-1-ylethyl)carbamate (1.60g, 4.12mmol, 1eq.) and 2-MeTHF (70mL). The mixture was stirred at -70°C for 0.5 hours, followed by the addition of triisopropyl borate (1.55g, 8.24mmol, 2eq.). The resulting mixture was stirred at -70°C under a N2 atmosphere for 1.5 hours. After completion, the mixture was quenched with MeOH (10mL) and extracted with EtOAc (3×60mL). The combined organic layers were washed with pure water (70mL) and the aqueous phase was lyophilized. The residue was purified by reverse-phase preparative HPLC (0.5% FA as additive) to obtain [2-[2-[benzyloxycarbonyl-[2-(tert-butyloxycarbonylamino)ethyl]amino]ethyl]pyrazol-3-yl]boronic acid (B-III-9, 500 mg, 0.925 mmol, 22.4% yield) as a white solid. LCMS: m / z 433.4 (M+1) + .

[0860] Example 8

[0861] Preparation of N-[2-[(4-bromo-2-methyl-pyrazole-3-yl)methoxy]ethyl]tert-butyl carbamate (BV-1) and N-[2-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazole-3-yl]methoxy]ethyl]tert-butyl carbamate (B-VI-1)

[0863] Step 1. LiAlH4 (1.65 g, 43.4 mmol, 1 eq) was added to a solution of methyl 4-bromo-2-methylpyrazol-3-carboxylate (9.5 g, 43.4 mmol, 1 eq) in THF (100 mL). The mixture was stirred at 0 °C for 15 min, and then slowly quenched with water (0.086 mL), followed by the addition of saturated sodium hydroxide (1.65 mL) and water (4.8 mL). The reaction mixture was filtered and concentrated under reduced pressure to give (7.75 g, 40.6 mmol, 93.5% yield) of (4-bromo-2-methylpyrazol-3-yl)methanol as a colorless oil. LCMS: 190.9 (M+1) + .

[0864] Step 2. At 0 °C, CBr4 (16.2 g, 48.7 mmol, 1.2 eq) was added to a solution of (4-bromo-2-methylpyrazol-3-yl)methanol (7.75 g, 40.6 mmol, 1 eq) in DCM (70 mL), followed by dropwise addition of PPh3 (12.8 g, 48.7 mmol, 1.2 eq) in DCM (2 mL). The mixture was stirred at 0 °C for 0.5 h. The mixture was slowly quenched with water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 25:1 to 3:1) to give 4-bromo-5-(bromomethyl)-1-methylpyrazol (7.60 g, 29.9 mmol, 73.8% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.56 (s, 1H), 4.75 (s, 2H), 3.87 (s, 3H).

[0865] Step 3. To a solution of 4-bromo-5-(bromomethyl)-1-methylpyrazole (1.00 g, 3.94 mmol, 1 eq) in THF (2 mL), add N-(2-hydroxyethyl)carbamate tert-butyl ester (952 mg, 5.91 mmol, 0.915 mL, 1.5 eq), tetrabutylammonium iodide (145 mg, 0.394 mmol, 0.1 eq), and KOH (663 mg, 11.8 mmol, 3 eq). Stir the mixture at 25 °C under N2 for 16 hours. Quench the reaction mixture with water (30 mL) and extract with EtOAc (3 × 20 mL). Wash the combined organic layers with brine (2 × 10 mL), dry to Na2SO4, filter, and concentrate under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]carbamate tert-butyl ester (BV-1, 1.2 g, 3.12 mmol, 79.3% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ=7.42 (s, 1H), 4.80 (s, 1H), 4.55 (s, 2H), 3.91 (s, 3H), 3.52-3.48 (m, 2H), 3.32 (d, J=5.2Hz, 2H), 1.44 (s, 9H).

[0866] Step 4. At 25°C and under nitrogen, [2-(2-aminophenyl)phenyl]chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphine (235 mg, 0.299 mmol, 0.1 eq) was added to a solution of N-[2-[(4-bromo-2-methylpyrazol-3-yl)methoxy]ethyl]carbamate (1.00 g, 2.99 mmol, 1 eq), KOAc (880 mg, 8.98 mmol, 3 eq), and Pin2B2 (11.4 g, 44.9 mmol, 15 eq) in dioxane (10 mL). The mixture was stirred at 60°C under N2 for 12 hours. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 25:1 to 3:1) to give N-[2-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazol-3-yl]methoxy]ethyl]tert-butyl carbamate (B-VI-1, 1.55 g, 2.64 mmol, 88.3% yield) as a yellow oil. 1H NMR (400MHz, CDCl3) δ=7.70 (s, 1H), 4.73 (s, 2H), 3.90 (s, 3H), 3.50 (d, J=4.8Hz, 2H), 3.32 (d, J=4.8Hz, 2H), 1.44 (s, 9H), 1.31 (s, 12H).

[0867] Example 9

[0868] Preparation of N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate tert-butyl ester (BV-2)

[0870] At 0 °C, NaH (191 mg, 4.79 mmol, 60%, 2.5 eq) was added to a solution of N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]carbamate tert-butyl ester (640 mg, 1.91 mmol, 1 eq) in 2-MeTHF (30 mL). The mixture was stirred at 0 °C for 0.5 h, followed by the addition of CH3I (407.71 mg, 2.87 mmol, 1.5 eq). The mixture was stirred at ambient temperature for 1.5 h. After completion, the mixture was poured into ice water (40 mL), extracted with EtOAc (80 mL), and washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 100:0 to 100:35) to give N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate tert-butyl ester (630 mg, 1.81 mmol, 94% yield) as a colorless oil. LCMS: m / z 370.2 (M+Na) + .

[0871] Example 10

[0872] Preparation of N-[2-[benzyloxycarbonyl-[(4-bromo-2-methyl-pyrazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate tert-butyl ester (BV-3)

[0874] Step 1. Add AcOH (1.45 g, 24.1 mmol, 1 eq) to a solution of 4-bromo-2-methylpyrazole-3-carboxaldehyde (4.55 g, 24.1 mmol, 1 eq) and N-(2-aminoethyl)-N-methyl-tert-butyl carbamate (8.39 g, 48.2 mmol, 8.61 mL, 2 eq) in MeOH (90 mL). Stir the reaction mixture at 25 °C for 0.5 h, cool to 0 °C, and treat with NaBH(OAc)3 (7.66 g, 36.1 mmol, 1.5 eq). Stir the mixture at 25 °C for 13 h, quench with water (100 mL), and extract with ethyl acetate (3 × 40 mL). Dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 10:1) to give N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methylamino]ethyl]-N-methyl-carbamate tert-butyl ester (3.40 g, 8.52 mmol, 35.3% yield) as a yellow oil. LCMS: m / z 348.9 (M+1) + .

[0875] Step 2. Add Cb2Cl (1.75 g, 10.3 mmol, 1.46 mL, 1.3 eq) to a mixture containing 80 mL of THF (2.74 g, 7.89 mmol, 1 eq) of N-[2-[(4-bromo-2-methylpyrazol-3-yl)methylamino]ethyl]-N-methyl-carbamate tert-butyl ester (2.74 g, 7.89 mmol, 1 eq) of NaHCO3 (1.99 g, 23.7 mmol, 3 eq) of H2O (20 mL). Stir the mixture at 20 °C for 16 hours, quench with water (80 mL), and extract with ethyl acetate (50 mL × 3). Dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 4:1) to give N-[2-[benzyloxycarbonyl-[(4-bromo-2-methyl-pyrazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate tert-butyl ester (BV-3, 2.89 g, 5.83 mmol, 73.9% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.42 (s, 1H), 7.36 (s, 5H), 5.18 (s, 2H), 4.67 (s, 2H), 3.84 (s, 2H), 3.70-3.23 (m, 6H), 2.79-2.67 (m, 2H), 1.45 (s, 9H).

[0876] Example 11

[0877] N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl ester (BV-4) and N-methyl-N-[2-[methyl-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazol-3-yl]methyl]amino]ethyl]carbamate tert-butyl ester (B-IV-4) were prepared.

[0879] NaBH3CN (716 mg, 11.4 mmol, 1.2 eq) was added to a solution of N-[2-[(4-bromo-2-methylpyrazol-3-yl)methylamino]ethyl]-N-methyl-carbamate tert-butyl ester (3.30 g, 9.50 mmol, 1 eq), (CH2O)n (1.70 g, 18.9 mmol, 1.99 eq), and AcOH (2.10 g, 34.9 mmol, 2 mL, 3.68 eq) in MeOH (80 mL). The mixture was stirred at 20 °C for 16 hours. After completion, the mixture was quenched with saturated NH4Cl (10 mL), concentrated under vacuum, diluted with EtOAc (100 mL), and washed with brine (2 × 70 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 100:40) to give colorless gel-like N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl ester (BV-4, 3 g, 8.30 mmol, 87% yield). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.37 (s, 1H), 3.87 (s, 3H), 3.51 (s, 2H), 3.39-3.21 (m, 2H), 2.73 (s, 3H), 2.54-2.43 (m, 2H), 2.24 (s, 3H), 1.42 (s, 9H).

[0881] At -70 °C, n-BuLi (2.5 M, 3.04 mL, 2.5 eq) was added to a solution of N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl ester (1.10 g, 3.04 mmol, 1.0 eq) in 2-MeTHF (45.0 mL). The mixture was stirred at -70 °C for 0.5 h, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoboronyl cyclopentane (849 mg, 4.57 mmol, 931 μL, 1.5 eq) at this temperature, and stirred at -70 °C for 1.5 h. After completion, the mixture was quenched with saturated NH4Cl (50.0 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (2 × 25.0 mL), dried over sodium sulfate, and concentrated under vacuum to give N-methyl-N-[2-[methyl-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazol-3-yl]methyl]amino]ethyl]carbamate tert-butyl ester (1.6 g, 2.35 mmol, 77.2% yield).

[0882] Preparation of N-[2-[benzyloxycarbonyl-[(4-bromo-3-methyl-1H-pyrazol-5-yl)methyl]amino]ethyl]-N-methyl-carbamate tert-butyl ester (BV-5)

[0884] BV-5 was prepared using a procedure similar to that used for BV-3. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.05 (s, 1H), 7.40-7.27 (m, 5H), 5.08 (s, 2H), 4 .41(s, 2H), 3.31(s, 2H), 3.26(s, 2H), 2.76(s, 3H), 2.15(s, 3H), 1.36(s, 9H). LCMS: m / z 483.3(M+1) + .

[0885] Preparation of N-[2-[(4-bromo-5-methyl-isoxazol-3-yl)methoxy]ethyl]-N-methyl-carbamate tert-butyl ester (BV-6)

[0887] BV-6 was prepared using a similar procedure to that used for BV-2, starting with (5-methylisoxazol-3-yl)methanol. 1H NMR (400MHz, CDCl3) δ=4.55 (s, 2H), 3.62 (t, J=5.6Hz, 2H), 3.41 (d, J=5.6Hz, 2H), 2.91 (s, 3H), 2.42 (s, 3H), 1.44 (s, 9H).

[0888] Preparation of N-[2-[benzoxycarbonyl-[(4-bromo-5-methyl-isoxazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate tert-butyl ester (BV-7)

[0890] Step 1. Add MnO2 (38.4 g, 442 mmol, 5 eq.) to a solution of (5-methylisoxazole-3-yl)methanol (10.0 g, 88.0 mmol, 1 eq.) in DCM (100 mL). Stir the mixture at 25 °C for 16 hours and filter. Concentrate the filtrate under vacuum to give 5-methylisoxazole-3-carboxaldehyde (6.50 g, 35.0 mmol, 39.71% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ = 10.12 (s, 1H), 6.40 (s, 1H) 2.53 (s, 3H).

[0891] Step 2. Add AcOH (3.50 g, 58.0 mmol, 1 eq.) and NaBH(OAc)3 (24.8 g, 117 mmol, 2 eq.) to a solution of 5-methylisoxazole-3-carboxaldehyde (6.50 g, 58.0 mmol, 1 eq.) in DCE (50 mL). Stir the mixture at 25 °C for 16 hours. Upon completion, add 50 mL of water and extract the reaction mixture with EtOAc (3 × 50 mL). Concentrate the combined extracts under vacuum. The residue was purified by column chromatography (SiO2, DCM / MeOH, 100:0 to 100:10) to give N-methyl-N-[2-[(5-methylisoxazol-3-yl)methylamino]ethyl]carbamate tert-butyl ester (1.30 g, 4.20 mmol, 7.18% yield) as a colorless oil. LC-MS: m / z 270.2 (M+1) + .

[0892] Step 3. Add NaHCO3 (1.10 g, 13.4 mmol, 3 eq.) to a solution of N-methyl-N-[2-[(5-methylisoxazol-3-yl)methylamino]ethyl]carbamate (1.20 g, 4.50 mmol, 1 eq.) and benzoyl chloroformate (912 mg, 5.30 mmol, 1.2 eq.) in THF (10 mL) and H2O (10 mL). Stir the mixture at 25 °C for 16 hours. Upon completion, extract the reaction mixture with EtOAe (3 × 10 mL) and then concentrate under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc, 100:1 to 100:25) to give N-[2-[benzoxycarbonyl-[(5-methylisoxazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate tert-butyl ester (1.20 g, 2.60 mmol, 58% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ = 7.28 (s, 5H), 5.91 (s, 1H), 5.09 (s, 2H), 4.47-4.41 (m , 2H), 3.38-3.22(m, 4H), 2.80(s, 3H), 2.32(s, 3H), 1.36(s, 9H); LC-MS: m / z 304.5(M+1) + .

[0893] Step 4. Add NBS (462 mg, 2.60 mmol, 1.5 eq.) to a solution of N-[2-[benzyloxycarbonyl-[(5-methylisoxazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate tert-butyl ester (700 mg, 1.70 mmol, 1 eq.) in DMF (25 mL). Stir the mixture at 60 °C for 20 hours. Dilute the mixture with EtOAc (100 mL) and wash with brine (4 × 40 mL). The organic layer was dried with Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether: EtOAc, 100:0 to 100:30) to obtain N-[2-[benzyloxycarbonyl-[(4-bromo-5-methyl-isoxazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate tert-butyl ester (BV-7, 320 mg, 630 μmol, 36.4% yield) as a colorless gel. 1 H NMR (400MHz, CDCl3) δ = 7.38-7.33 (m, 5H), 5.18 (s, 2H), 4.61-4.50 (m, 2H), 3.60-3.28 (m, 4H), 2.77-2.66 (m, 3H), 2.40 (s, 3H), 1.44 (s, 9H); LC-MS: m / z 384.3(M-99) + .

[0894] Preparation of N-[2-[(4-bromo-2,5-dimethyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl ester (BV-8)

[0896] Step 1. Add AcOH (967 mg, 16.1 mmol, 1 eq) to a mixture of 2,5-dimethylpyrazole-3-carboxaldehyde (2.00 g, 16.1 mmol, 1 eq) and N-methyl-N-[2-(methylamino)ethyl]carbamate tert-butyl ester (4.55 g, 24.2 mmol, 1.5 eq) in DCE (2 mL). After 0.5 h at 25 °C, add NaBH(OAc)3 (10.2 g, 48.3 mmol, 3 eq) at 0 °C. Stir the mixture at 25 °C for 16 h. Quench the mixture by pouring it into water, then extract with EtOAc (3 × 50 mL). Wash the combined organic layers with brine (2 × 30 mL), dry with Na2SO4, filter, and concentrate under vacuum. The residue was purified by rapid silica gel chromatography (DCM:MeOH = 25:1 to 10:1) to give N-[2-[(2,5-dimethylpyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl ester (1.80 g, 5.82 mmol, 36% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ = 9.93 (s, 1H), 5.92 (s, 1H), 3.80 (s, 3H), 3.60-3.48 (m, 2H), 3.40-3.2 8(m, 2H), 2.80(s, 3H), 2.62-2.52(m, 2H), 2.27(s, 3H), 2.24(s, 3H), 1.43(s, 9H); LC-MS: m / z 297.2(M+1) + .

[0897] Step 2. At 25°C, NBS (1.22 g, 6.88 mmol, 1.2 eq) was added to a solution of N-[2-[(2,5-dimethylpyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl ester (1.7 g, 5.74 mmol, 1 eq) in DMF (2 mL). The mixture was stirred at 60°C under N2 for 16 hours. The reaction mixture was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (DCM:MeOH = 25:1 to 10:1) to give N-[2-[(4-bromo-2,5-dimethylpyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl ester (MV-8, 1.3 g, 3.38 mmol, 58.9% yield, 97.5% purity) as a yellow oil.1 H NMR (400MHz, CDCl3) δ=3.80 (s, 3H), 3.46 (s, 2H), 3.36-3.21 (m, 2H), 2.85-2.84 (m, 3H), 2.74 (s, 2H), 2.17 (s, 3H), 2.01 (s, 3H), 1.40 (s, 9H).

[0898] Preparation of N-[2-[(2-bromophenyl)methyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl ester (BV-9)

[0900] To a solution of N-methyl-N-[2-(methylamino)ethyl]carbamate tert-butyl ester (2.65 g, 14.0 mmol, 1.3 eq) and 2-bromobenzaldehyde (2.00 g, 10.8 mmol, 1.25 mL, 1 eq) in DCE (10 mL), NaBH(OAc)3 (3.44 g, 16.2 mmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 16 hours. After completion, the mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, concentrated under vacuum, and purified by rapid silica gel chromatography (40 g silica gel column, DCM / MeOH, 0% to 100%) to give N-[2-[(2-bromophenyl)methyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl ester (MV-9, 3.50 g, 8.82 mmol, 81.5% yield) as a colorless gel. LC-MS: m / z 357.9 (M+1) + .

[0901] Preparation of N-[3-(4-bromo-2,5-dimethylpyrazol-3-yl)oxypropyl]-N-methyl-carbamate tert-butyl ester (BV-10)

[0903] Step 1. K₂CO₃ (9.24 g, 66.8 mmol, 1.50 eq) was added to a solution of 2,5-dimethylpyrazole-3-ol (5 g, 44.59 mmol, 1 eq) and N-(3-bromopropyl)carbamate tert-butyl ester (12.74 g, 53.51 mmol, 1.2 eq) in DMF (180 mL). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove DMF. 1,4-Dioxane (300 mL) was added to the residue, and the mixture was filtered and washed with petroleum ether (30 mL × 3). The filtrate was washed with brine (15 mL × 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give N-(3-chlorophenyl)-N-methyl-tert-butyl carbamate (24.5 g, crude product).1 H NMR (400MHz, DMSO-d6) δ = 6.89 (s, 1H), 5.40 (s, 1H), 4.02-3.95 (m, 2H), 3.4 3(s, 3H), 3.08-3.03(m, 2H), 2.02(s, 3H), 1.88-1.76(m, 2H), 1.37(s, 9H).

[0904] Step 2. At 0°C, NaH (1.11 g, 27.8 mmol, 60% purity, 1.5 eq) was added to a solution of N-[3-(2,5-dimethylpyrazol-3-yl)oxypropyl]carbamate tert-butyl ester (5 g, 18.6 mmol, 1 eq) in THF (50 mL). The mixture was stirred at 0°C for 0.5 h, followed by the addition of MeI (3.95 g, 27.8 mmol, 1.5 eq). The mixture was stirred at 25°C for 1 h, quenched by slow addition of water, and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give N-[3-(2,5-dimethylpyrazol-3-yl)oxypropyl]-N-methyl-carbamate tert-butyl ester (10 g, 31.7 mmol, 85.5% yield), which was a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ = 5.39 (s, 1H), 4.00-3.96 (m, 2H), 3.44 (s, 3H), 3.3 3-3.29 (m, 2H), 2.77 (s, 3H), 2.02 (s, 3H), 1.93-1.85 (m, 2H), 1.33 (s, 9H).

[0905] Step 3. At 25°C, NBS (3.77 g, 21.2 mmol, 1 eq) was added to a solution of N-[3-(2,5-dimethylpyrazol-3-yl)oxypropyl]-N-methyl-carbamate tert-butyl ester (6 g, 21.2 mmol, 1 eq) in ACN (30 mL), and the mixture was stirred under N2 for 16 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 25:1 to 2:1) to give N-[3-(4-bromo-2,5-dimethylpyrazol-3-yl)oxypropyl]-N-methyl-carbamate tert-butyl ester (BV-10, 6.8 g, 18.2 mmol, 86% yield) as a yellow oil. 1H NMR (400MHz, CDCl3) δ=4.20 (s, 2H), 3.56 (s, 3H), 3.33 (s, 2H), 2.82 (s, 3H), 2.03 (s, 3H), 1.97-1.88 (m, 2H), 1.38 (s, 9H). LCMS: m / z 384.1(M+Na) + .

[0906] Preparation of N-[2-[(4-bromo-2,5-dimethyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate tert-butyl ester (BV-11)

[0908] Step 1. Add NBS (12.7 g, 71.3 mmol, 1.2 eq) to a solution of ethyl 2,5-dimethylpyrazole-3-carboxylate (10 g, 59.4 mmol, 1 eq) in DCE (200 mL). Stir the mixture at 80 °C for 16 hours. Concentrate the reaction mixture under vacuum. Purify the residue by silica gel column chromatography (PE:EA = 25:1 to 2:1) to give ethyl 4-bromo-2,5-dimethylpyrazole-3-carboxylate (12 g, 45.2 mmol, 75.9% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ = 4.35-4.29 (m, 2H), 4.02 (s, 3H), 2.17 (s, 3H), 1.34-1.32 (m, 3H).

[0909] Step 2. LiAlH4 (1.60 g, 42.1 mmol, 1.1 eq) was added to a solution of ethyl 4-bromo-2,5-dimethylpyrazol-3-carboxylate (9.46 g, 38.3 mmol, 1 eq) in THF (100 mL). The mixture was stirred at 0 °C for 0.5 h and quenched by the slow addition of ice water (0.086 mL), sodium hydroxide aqueous solution (15%, 1.65 mL), and water (4.8 mL). The reaction mixture was filtered and concentrated under reduced pressure to give (4-bromo-2,5-dimethylpyrazol-3-yl)methanol (6.5 g, 31.7 mmol, 82.8% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ = 5.31 (s, 1H), 4.44-4.40 (m, 2H), 3.79 (s, 3H), 2.22 (s, 3H).

[0910] Step 3. PBr3 (8.18 g, 30.2 mmol, 1 eq) was added dropwise to a solution of (4-bromo-2,5-dimethylpyrazol-3-yl)methanol (6.2 g, 30.24 mmol, 1 eq) in DCM (120 mL) at 0–25 °C. The mixture was stirred at 25 °C for 4 hours, quenched by slow addition of water, and extracted with EtOA (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 25:1 to 3:1) to give 4-bromo-5-(bromomethyl)-1,3-dimethylpyrazol (6.2 g, 22.4 mmol, 74.2% yield) as a white solid. LCMS: m / z 269.0 (M+1) + .

[0911] Step 4. To a solution of 4-bromo-5-(bromomethyl)-1,3-dimethylpyrazole (4 g, 14.9 mmol, 1 eq) in THF (80 mL), add N-(2-hydroxyethyl)-N-methylcarbamate tert-butyl ester (2.88 g, 16.4 mmol, 1.1 eq), TBAI (551.40 mg, 1.49 mmol, 0.1 eq), and KOH (2.51 g, 44.8 mmol, 3 eq). Stir the mixture at 25 °C under N2 for 16 hours. After completion, concentrate the reaction mixture under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give N-[2-[(4-bromo-2,5-dimethyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate tert-butyl ester (BV-11, 5.5 g, 14.6 mmol, 97.6% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ = 4.50-4.46 (m, 2H), 3.83 (s, 3H), 3.63-3.31 (m, 4H), 2.87 (s, 3H), 2.22 (s, 3H), 1.44 (s, 9H).

[0912] Preparation of N-[2-[(4-bromo-5-cyclopropyl-isoxazol-3-yl)methoxy]ethyl]-N-methyl-carbamate tert-butyl ester (BV-12)

[0914] BV-12 was prepared using a procedure similar to that used for BV-1, starting with 5-cyclopropylisoxazol-3-carboxylic acid. The bromination procedure was similar to that used for BV-7. 1H NMR (400MHz, CDCl3) δ = 4.53 (s, 2H), 3.60 (s, 2H), 3.40 (s, 2H), 2.91 (s, 3H), 2.10-2.07 (m, 1H), 1.17 (s, 9H), 1.16-1.12 (m, 2H), 1.11-1.10 (m, 2H). LCMS: m / z 277.1(M-Boc) + .

[0915] Preparation of N-[2-[(4-bromo-5-isopropyl-isoxazol-3-yl)methoxy]ethyl]-N-methyl-carbamate tert-butyl ester (BV-13)

[0917] BV-13 was prepared using a procedure similar to that used for BV-1, starting with ethyl 5-isopropylisoxazole-3-carboxylate. The bromination procedure was similar to that used for BV-7. 1 H NMR (400MHz, CDCl3) δ = 4.55 (s, 2H), 3.63 (s, 2H), 3.41 (s, 2H), 2.91 (s, 3H), 1.45 (s, 9H), 1.34 (d, J = 7.2Hz, 6H). LCMS: m / z277.1(M-Boc) + .

[0918] Preparation of N-[3-(4-bromo-2-methyl-pyrazol-3-yl)oxypropyl]-N-methyl-carbamate tert-butyl ester (BV-14)

[0920] BV-14 was prepared using a similar procedure to that used for BV-10, starting with 2-methylpyrazole-3-ol. 1 H NMR (400MHz, CDCl3) δ=7.20 (s, 1H), 4.25 (s, 2H), 3.61 (s, 3H), 3.43-3.28 (m, 2H), 2.82 (s, 3H), 1.96-1.89 (m, 2H), 1.38 (s, 9H). LCMS: m / z 350.2(M+1) + .

[0921] 3-[3-(tert-butoxycarbonylamino)propoxy]-4-[(3Z)-3-[(3-methoxycarbonyl-1H-pyrrolo-2-yl)methylene]-2-oxo-1H-pyrrolo[2,3-c]pyridin-5-yl]pyrazole-1-carboxylic acid tert-butyl ester (C-6a) was prepared according to general method C.

[0923] Methyl 2-[(Z)-(5-chloro-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene)methyl]-1H-pyrrolo-3-carboxylate (500 mg, 1.65 mmol, 1 eq) and tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazol-1-carboxylate (3.85 g, 8.23 ​​mmol, 5 eq) in dioxane (10 mL) and H₂O (1 mL) were added to a solution of 2-[(Z)-(5-chloro-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene)carboxylate (3.85 g, 8.23 ​​mmol, 5 eq) and 3-[(tert-butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazol-1-carboxylate (1.61 g, 4.94 mmol, 3 eq) and 3-[(tert-butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazol-1-carboxylate (1.15 mg, 0.165 mmol, 0.1 eq). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 14 hours. After completion, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (DCM:MeOH = 100:1 to 20:1) to give C-6a as a white solid (251 mg, 0.412 mmol, 25% yield).

[0924] C-67 to C73 are prepared following a similar procedure to C-6a.

[0927] The preparation of 3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(nitromethyl)pyrazolo[4,3-n]dipyrrolo[3,2-g:3′,4′-j][1,5]oxazonide-pentadecanyne-3,8(2H,5H)-dione (6) was carried out according to the general method J.

[0929] Step 1. LiOH·H₂O (206 mg, 4.93 mmol, 15 eq) was added to a solution of tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-[(3Z)-3-[(3-methoxycarbonyl-1H-pyrrolo-2-yl)methylene]-2-oxo-1H-pyrrolo[2,3-c]pyridin-5-yl]pyrazole-1-carboxylic acid (200 mg, 0.329 mmol, 1 eq) in MeOH (4 mL) and H₂O (0.4 mL). The mixture was stirred at 50 °C for 15 hours. After stirring, the mixture was concentrated under vacuum and dissolved in water (300 mL). The aqueous phase was adjusted to pH 5-6 with 1 M HCl aqueous solution to precipitate the product. The solid was filtered and wet-milled with MeOH (15 mL) at 25 °C for 5 minutes to give 2-[(Z)-[5-[3-[3-(tert-butoxycarbonylamino)propoxy]-1H-pyrazol-4-yl]-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene]methyl]-1H-pyrrolo-3-carboxylic acid (154 mg, 0.311 mmol, 95% yield) as an orange solid. LCMS m / z 495.2 (M+1) + .

[0930] Step 2. A mixture of 2-[(Z)-[5-[3-[3-(tert-butoxycarbonylamino)propoxy]-1H-pyrazol-4-yl]-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene]methyl]-1H-pyrrolo-3-carboxylic acid (154 mg, 0.311 mmol, 1 eq) and HCl / dioxane (4 M, 0.778 mL, 10 eq) in DCM (2 mL) was stirred at 25 °C for 2 hours. After completion, the mixture was concentrated under vacuum to obtain 2-[(Z)-[5-[3-(3-aminopropoxy)-1H-pyrazol-4-yl]-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene]methyl]-1H-pyrrolo-3-carboxylic acid salt (130 mg) as a red solid. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.99-13.83 (m, 1H), 12.92-12.66 (m, 1H), 11.87-11.72 (m, 1H), 8.93-8.81 (m, 1H), 8.68-8.53 (m, 1H) ), 8.16 (s, 2H), 7.97-7.80 (m, 3H), 7.70-7.65 (m, 1H), 6.97-6.91 (m, 1H), 4.48-4.42 (m, 2H), 3.19-3.14 (m, 2H), 2.23-2.16 (m, 2H).

[0931] Step 3. Add DIPEA (114 mg, 0.887 mmol, 0.154 mL, 5 eq) and FDPP (136 mg, 0.355 mmol, 2 eq) to a solution of 2-[(Z)-[5-[3-(3-aminopropoxy)-1H-pyrazol-4-yl]-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene]methyl]-1Hpyrrolo-3-carboxylic acid (70 mg, HCl) in DMF (3.5 mL). Stir the mixture at 20 °C for 0.5 h. Upon completion, quench the reactants with H2O (30 mL) and filter. Concentrate the filter cake under vacuum to obtain a crude product, which is then wet-milled with MeOH (2 mL), filtered, and vacuum-dried to give 6 (23.4 mg, 32.5% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.58 (s, 1H), 12.15 (s, 1H), 11.12 (s, 1H), 8.94 (s, 1H), 8.54-8.47 (m, 1H), 8.11 (s, 2 LCMS m / z 377.4(M+1) + .

[0932] Examples 7, 11, 14, 22, 24, 39, and 123 were prepared following a procedure similar to that of example 6.

[0935] N-methyl-N-[2-[2-[5-(2-oxoindoline-5-yl)pyrazol-1-yl]ethoxy]ethyl]tert-butyl carbamate (K-1) was prepared according to general method K.

[0937] Under nitrogen atmosphere, Pd(PPh3)2Cl2 (131 mg, 0.187 mmol, 0.1 eq) was added to a mixture of [2-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]ethyl]pyrazol-3-yl]boronic acid (588 mg, 1.88 mmol, 1 eq), 5-bromoindoline-2-one (517 mg, 2.44 mmol, 1.3 eq), and Cs2CO3 (1.84 g, 5.63 mmol, 3 eq) in dioxane (10 mL) and H2O (2 mL). The mixture was stirred at 100 °C under N2 for 16 hours, then cooled and concentrated under vacuum. The residue was purified by column chromatography (SiO2, DCM / MeOH = 30 / 1 to 10 / 1) to give N-methyl-N-[2-[2-[5-(2-oxoindoline-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate tert-butyl ester (K-1, 150 mg, 17% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ (ppm) 8.17 (s, 1H), 7.58 (d, J = 6.8Hz, 1H), 7.41-7.35 (m, 2H), 6.96 (d, J = 2.4Hz, 1H), 6.25 (d, J = 1.6Hz, 1 H), 4.27 (t, J=5.6Hz, 2H), 3.92 (t, J=5.6Hz, 2H), 3.61 (s, 2H), 3.48 (s, 2H), 3.30 (d, J=5.6Hz, 2H), 2.78 (s, 3H), 1.42 (s, 9H). LCMS: m / z 401.0(M+1) + .

[0938] K-2 was prepared following a similar procedure to K-1.

[0940] N-methyl-N-[2-[[2-methyl-4-(2-oxoindoline-5-yl)pyrazol-3-yl]methoxy]ethyl]tert-butyl carbamate (L-1) was prepared according to the general method L.

[0942] Under nitrogen atmosphere, Pd(dppf)Cl2 (125 mg, 0.172 mmol, 0.1 eq) and an aqueous solution of Na2CO3 (2 M, 2.58 mL, 3.0 eq) were added to a solution of N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate tert-butyl ester (600 mg, 1.72 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indoline-2-one (668 mg, 2.58 mmol, 1.5 eq) in dioxane (17 mL). The mixture was stirred at 100 °C under nitrogen atmosphere for 2 hours. After completion, the mixture was concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 100:5) to give a light brown gel-like N-methyl-N-[2-[[2-methyl-4-(2-oxoindololin-5-yl)pyrazol-3-yl]methoxy]ethyl]carbamate tert-butyl ester (L-1, 600 mg, 1.50 mmol, 87% yield). LCMS: m / z 401.2 (M+1) + .

[0943] L-2 to L-13 were prepared following a similar procedure to L-1.

[0947] Preparation of N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate tert-butyl ester (M1)

[0949] Step 1. A solution of ethyl 2-diazocarbamate (9.77, 85.6 mmol, 3 eq) in DCM (50 mL) was added dropwise to a mixture of N-(2-hydroxyethyl)-N-methyl-carbamate tert-butyl ester (5.0 g, 28.5 mmol, 1 eq) and Rh(OAc)2 (315 mg, 1.43 mmol, 0.05 eq) in DCM (80 mL). The mixture was stirred at 25 °C for 16 hours and partitioned by adding H2O (5 mL). The organic phase was separated, washed with H2O (10 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give ethyl 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]acetate (13.0 g, crude substance) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ=4.23 (d, J=2.4Hz, 2H), 4.09-4.05 (m, 2H), 3.66 (br s, 2H), 3.49-3.41 (m, 2H), 2.93 (s, 3H), 1.45 (s, 9H), 1.30-1.27 (m, 3H).

[0950] Step 2. At 0°C and under N2, LiAlH4 (1.31 g, 34.4 mmol, 1.5 eq) was added to a solution of ethyl 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]acetate (6.00 g, 22.9 mmol, 1 eq) in THF (60 mL). The mixture was stirred at 25°C for 2 hours. After completion, the mixture was quenched with water (1 mL), followed by the addition of NaOH aqueous solution (15%, 3 mL) and H2O (3 mL). Na2SO4 was added to the combined mixture, followed by stirring for 10 minutes. The mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1 to 4 / 1) to give N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate tert-butyl ester (3.00 g, 13.7 mmol, 60% yield) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ = 3.73-3.68 (m, 2H), 3.63-3.55 (m, 4H), 3.41 (d, J = 5.2Hz, 2H), 2.90 (s, 3H), 2.31 (s, 1H), 1.45 (s, 9H)

[0951] Preparation of N-[2-[(2R)-2-hydroxypropoxy]ethyl]-N-methyl-carbamate tert-butyl ester (M5)

[0953] Step 1. At 0 °C, trifluoromethanesulfonic acid (1.11 mL) was added dropwise to a mixture of (2R)-2-hydroxypropionate methyl ester (20.0 g, 192 mmol, 1 eq.) and 2,2,2-trichloroethaneimine benzyl ester (51.0 g, 202 mmol, 1.05 eq.) in DCM (66.5 mL) and hexane (133 mL). The mixture was stirred at 20 °C for 50 hours and then filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc, 100:1 to 100:3) to give (2S)-2-phenylmethoxypropionate methyl ester (8.00 g, 37.0 mmol, 19% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ=7.32-7.17 (m, 5H), 4.61 (d, J=11.6Hz, 1H), 4.37 (d, J=11.6Hz, 1H), 3.99 (m, 1H), 3.67 (s, 3H), 1.36 (d, J=6.8Hz, 3H).

[0954] Step 2. At 0 °C, LAH (2.30 g, 62.0 mmol, 1.5 eq) was slowly added to a mixture of methyl (2R)-2-benzoxypropionate (8.00 g, 41.0 mmol, 1.0 eq) and 2-MeTHF (100 mL). The mixture was stirred at 20 °C for 2 hours. After stirring, the mixture was slowly quenched at 0 °C with water (2.3 mL), followed by quenching with 15% NaOH aqueous solution (2.3 mL) and water (7.0 mL). After filtration, the filtrate was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether: EtOAc, 100:0 to 100:40) to give (2R)-2-benzoxyprop-1-ol (7.00 g, 34.0 mmol, 81.79% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ=7.41-7.29 (m, 5H), 4.67 (d, J=11.6Hz, 1H), 4.52 (d, J=11.6Hz, 1H), 3.74-3.67(m, 1H), 3.66-3.60(m, 1H), 3.58-3.51(m, 1H), 1.21(d, J=6.0Hz, 3H).

[0955] Step 3. Add t-BuOK (14.2 g, 126 mmol, 3.0 eq.) to a mixture of (2R)-2-benzoxypropoxy-1-ol (7.00 g, 42 mmol, 1.0 eq.) and 2-chloro-N-methylacetamide (6.80 g, 63.0 mmol, 1.5 eq.) in t-BuOH (100 mL). Stir the mixture at 25 °C for 16 hours. After completion, dilute the mixture with EtOAe (80 mL) and wash with water (30 mL), saturated NH4Cl (30 mL), and brine (30 mL). Dry the organic layer with sodium sulfate, concentrate under vacuum, and purify by silica gel column chromatography (DCM:MeOH, 100:0 to 100:2) to give 2-[(2R)-2-benzoxypropoxy]-N-methylacetamide (4.50 g, 17.0 mmol, 40.5% yield) as a colorless oil.

[0956] 1H NMR (400MHz, CDCl3) δ=7.32-7.19 (m, 5H), 7.02 (s, 1H), 4.59 (d, J=11.2Hz, 1H), 4.39 (d, J=11.2Hz, 1H), 3.92 (d, J=16.0Hz, 1H), 3.83 (d, J=16.0Hz , 1H), 3.70 (t, J=6.4, 3.2Hz, 1H), 3.50 (dd, J=10.0, 3.2, 1H), 3.36 (dd, J=10.4, 6.8Hz, 1H), 2.49 (d, J=4.8Hz, 3H), 1.14 (d, J=6.4Hz, 3H); LCMS: m / z 238.4(M+1) + .

[0957] Step 4. At 0 °C, LAH (959 mg, 25.3 mmol, 1.5 eq.) was slowly added to a mixture of 2-[(2R)-2-benzoxypropoxy]-N-methylacetamide (4.00 g, 16.7 mmol, 1.0 eq.) and 2-MeTHF (100 mL). The mixture was stirred at 60 °C for 2 hours. Upon completion, water (1 mL) was slowly added to the mixture at 0 °C, followed by 1 mL of 15% NaOH aqueous solution and water (3 mL). The mixture was filtered, and the filtrate was concentrated under vacuum to give 2-[(2R)-2-benzoxypropoxy]-N-methylethylamine (4.00 g, 11.6 mmol, 69.1% yield).

[0958] Step 5. A mixture of 2-[(2R)-2-benzoxypropoxy]-N-methyl-ethylamine (3.77 g, 16.9 mmol, 1.0 eq.), DMAP (206 mg, 1.69 mmol, 0.1 eq.), (Boc)₂O (4.42 g, 20.3 mmol, 1.2 eq.), and TEA (2.56 g, 25.3 mmol, 1.5 eq.) in DCM (50 mL) was stirred at 20 °C for 16 hours. The mixture was concentrated under vacuum to obtain a crude substance, which was purified by silica gel column chromatography (petroleum ether: EtOAc, 100:0 to 100:10) to give N-[2-[(2R)-2-benzoxypropoxy]ethyl]-N-methyl-carbamate tert-butyl ester (4.00 g, 10.51 mmol, 62.28% yield) as a colorless oil. LCMS: m / z 234.3(M+1) + .

[0959] Step 6. Under a nitrogen atmosphere, Pd(OH)₂ (825 mg, 1.17 mmol, 20% purity, 0.1 eq.) was added to a mixture of N-[2-[(2R)-2-phenylmethoxypropoxy]ethyl]-N-methyl-carbamate tert-butyl ester (3.80 g, 11.7 mmol, 1.0 eq.) and MeOH (40 mL). The mixture was stirred at 25 °C under 50 Psi H₂ for 16 hours. After completion, the mixture was filtered, and the filtrate was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether: EtOAc, 100:0 to 100:30) to give N-[2-[(2R)-2-hydroxypropoxy]ethyl]-N-methyl-carbamate tert-butyl ester (M5, 2.10 g, 9.00 mmol, 76.6% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ = 4.53 (d, J = 4.0Hz, 1H), 3.70 (t, J = 5.6Hz, 1H), 3.52-3.43 (m, 2H), 3.3 1-3.25 (m, 3H), 3.21-3.14 (m, 1H), 2.80 (d, J=7.2Hz, 3H), 1.38 (s, 9H), 1.02 (d, J=6.4Hz, 3H).

[0960] Preparation of methyl (2R)-3-[tert-butoxycarbonyl(methyl)amino]-2-(2-hydroxyethoxy)propionate (M6)

[0962] Step 1. A solution of (2R)-ethylene oxide-2-carboxylate (7.00 g, 68.4 mmol, 1 eq.) and N-methyl-1-phenyl-methylamine (8.48 g, 69.9 mmol, 2.26 mL, 1.02 eq.) in MeOH (25 mL) was stirred at 70 °C for 16 h. LC-MS showed the desired peak in the main phase. The mixture was concentrated under vacuum and the residue was purified by rapid chromatography (220 g silica gel column, EtOAc / PE, 0% to 100%) to give methyl (2R)-3-[benzyl(methyl)amino]-2-hydroxypropionate (15.3 g, 68.5 mmol, 99.9% yield) as a brown oil. 1 H NMR (400MHz, CDCl3) δ = 7.40-7.19 (m, 5H), 4.27 (t, J = 6.0Hz, 1H), 3.74 (s, 3H), 3.65 (d, J=13.2Hz, 1H), 3.52 (d, J=13.2Hz, 1H), 2.78 (d, J=5.6Hz, 2H), 2.25 (s, 3H); LC-MS: m / z 224.1(M+1) + .

[0963] Step 2. To a solution of (2R)-3-[benzyl(methyl)amino]-2-hydroxypropionate (19.0 g, 85.1 mmol, 1 eq.) and Rh(OAc)2 (940 mg, 4.25 mmol, 0.05 eq.) in DCM (200 mL), tert-butyl 2-diazoacetate (24.2 g, 170 mmol, 2 eq.) in DCM (50 mL) was added dropwise. The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under vacuum and the residue was purified by rapid chromatography (330 g silica gel column, EtOAc / PE, 0% to 100%) to give methyl (2R)-3-[benzyl(methyl)amino]-2-(2-tert-butoxy-2-oxo-ethoxy)propionate (9.80 g, 29.0 mmol, 34.1% yield) as a brown oil. 1 H NMR (400MHz, CDCl3) δ = 7.32-7.23 (m, 5H), 4.28 (t, J = 5.2Hz, 1H), 4.20 (d, J = 16.4Hz, 1H), 3.95 (d, J = 16.4Hz, 1H), 3. 75 (s, 3H), 3.66 (d, J=13.2Hz, 1H), 3.58 (d, J=13.2Hz, 1H), 2.90-2.88 (m, 2H), 2.30 (s, 3H), 1.49 (s, 9H); LC-MS: m / z 338.2(M+1) + .

[0964] Step 3. Add TFA (77.0 g, 675 mmol, 50 mL, 23.2 eq.) to a solution of (2R)-3-[benzyl(methyl)amino]-2-(2-tert-butoxy-2-oxo-ethoxy)propionate (9.80 g, 29.0 mmol, 1 eq.) in DCM (50 mL). Stir the mixture at 25 °C for 16 hours. Concentrate the mixture under vacuum and purify the residue by a combi flash (120 g silica gel column, MeOH / DCM 0% to 30%) to give 2-[(1R)-1-[[benzyl(methyl)amino]methyl]-2-methoxy-2-oxo-ethoxy]acetic acid (8.30 g) as a brown oil. 1H NMR (400MHz, CDCl3) δ=7.57-7.55 (m, 2H), 7.49-7.47 (m, 3H), 4.28 (t, J=5.2Hz, 1H), 4.20 (d, J=16.4Hz, 1H), 3.95 (d, J=16.4H z, 1H), 3.75 (s, 3H), 3.66 (d, J=13.2Hz, 1H), 3.58 (d, J=13.2Hz, 1H), 2.90-2.88 (m, 2H), 2.30 (s, 3H), 1.49 (s, 9H); LC-MS: m / z 282.4(M+1) + .

[0965] Step 4. BH3-Me2S (10M, 8.85mL, 3eq.) was added to a solution of 2-[(1R)-1-[[benzyl(methyl)amino]methyl]-2-methoxy-2-oxo-ethoxy]acetic acid (8.30 g, 29.5 mmol, 1 eq.) in THF (80 mL) at 0 °C. The mixture was stirred at 15 °C for 16 h. The mixture was quenched with MeOH (3 mL) and concentrated under vacuum. The residue was purified by combi flash (80 g silica gel column, EtOAc / PE 0% to 100%, MeOH / EtOAc 0% to 100%) to give methyl (2R)-3-[benzyl(methyl)amino]-2-(2-hydroxyethoxy)propionate (4.60 g, 10.8 mmol, 36.7% yield) as a brown oil. LC-MS: m / z 238.1 (M+1) + .

[0966] Step 5. Pd / C (400 mg, 10% purity) was added to a mixture of (2R)-3-[benzyl(methyl)amino]-2-(2-hydroxyethoxy)propionate (2.60 g, 9.73 mmol, 1 eq.) and MeOH (30 mL). The mixture was stirred at 15 °C under H2 (15 Psi) for 3 hours. The mixture was filtered and the filtrate was concentrated under vacuum to give methyl (2R)-2-(2-hydroxyethoxy)-3-(methylamino)propionate (1.3 g) as a colorless oil. LC-MS: m / z 178.1 (M+1) + .

[0967] Step 6. Add DMAP (186 mg, 1.52 mmol, 0.1 eq.) and Boc2O (4.99 g, 22.8 mmol, 5.25 mL, 1.5 eq.) to a solution of (2R)-2-(2-hydroxyethoxy)-3-(methylamino)propionate (2.70 g, 15.2 mmol, 1 eq.) and Et3N (3.08 g, 30.5 mmol, 4.24 mL, 2 eq.) in DCM (30 mL). Stir the mixture at 15 °C for 16 hours. Concentrate the mixture under vacuum and purify the residue by a combi flash (20 g silica gel column, EtOAc / PE 0% to 100%) to give methyl (2R)-3-[tert-butoxycarbonyl(methyl)amino]-2-(2-hydroxyethoxy)propionate (1.15 g, 4.15 mmol, 27.22% yield) as a colorless oil. LC-MS: m / z 278.1 (M+1) + .

[0968] Preparation of N-[2-(2-hydroxyethylthio)ethyl]-N-methyl-carbamate tert-butyl ester (M8)

[0970] Step 1. K₂CO₃ (5.77 g, 41.75 mmol, 2 eq) was added to a solution of N-(2-thioethyl)carbamate (3.7 g, 20.9 mmol, 1 eq) and 2-bromoethoxy-tert-butyl-dimethyl-silane (5.2 g, 21.7 mmol, 1.04 eq) in DMF (10 mL). The mixture was stirred at 25 °C for 10 hours. After stirring, the mixture was quenched with water (5 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 30 / 1 to 20 / 1) to give N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylthio]ethyl]carbamate (5.5 g, 16.39 mmol, 78.5% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 6.84 (t, J = 5.6Hz, 1H), 3.66 (t, J = 6.8Hz, 2H), 3.06-2.97 (m, 2H), 2 .55(t, J=6.8Hz, 2H), 2.51-2.47(m, 2H), 1.32(s, 9H), 0.82(s, 9H), 0.00(s, 6H); LC-MS: m / z 236.1(M-99) + .

[0971] Step 2. At 0°C, NaH (983 mg, 24.6 mmol, 60% purity, 1.5 eq) was added to a mixture of N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylthio]ethyl]carbamate tert-butyl ester (5.5 g, 16.4 mmol, 1 eq) in THF (90 mL). The reaction mixture was stirred at 0°C under N2 for 15 min, followed by dropwise addition of CH3I (3.49 g, 24.6 mmol, 1.5 eq). The reaction mixture was stirred at 25°C under N2 for 6 h. After completion, the mixture was quenched with water (10 mL), then diluted with H2O (90 mL) and extracted with 90 mL EtOAc (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylthio]ethyl]-N-methyl-carbamate tert-butyl ester (4 g, 11.1 mmol, 67.7% yield, 97% purity) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 3.67 (t, J = 6.8Hz, 2H), 3.27-3.23 (m, 2H), 2.72 (s, 3H), 2.62-2.54 (m, 4H), 1.34 (s, 9H), 0.81 (s, 9H), 0.00 (s, 6H).

[0972] Step 3. Add TBAF (1M, 34.3mL, 3eq) to a solution of N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylthio]ethyl]-N-methyl-carbamate tert-butyl ester (4 g, 11.4 mmol, 1 eq) in THF (160 mL). Stir the mixture at 25 °C for 2 hours. After completion, quench the mixture at 0 °C with saturated ammonium chloride aqueous solution (100 mL), and then dilute with H2O (50 mL) and extract with EtOAc (100 mL × 3). Dry the combined organic phases over anhydrous sodium sulfate, filter and concentrate. Purify the residue by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give N-[2-(2-hydroxyethylthio)ethyl]-N-methyl-carbamate tert-butyl ester (M8, 2.6 g, 10.5 mmol, 91.7% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 4.82 (t, J = 5.2Hz, 1H), 3.62-3.54 (m, 2H), 3.34-3.32 ( m, 2H), 2.82 (s, 3H), 2.66 (t, J=7.2Hz, 2H), 2.62 (t, J=7.2Hz, 2H), 1.43 (s, 9H).

[0973] Preparation of N-[2-[benzyloxycarbonyl(2-hydroxyethyl)amino]ethyl]-N-methyl-carbamate tert-butyl ester (M9)

[0975] Step 1. K₂CO₃ (23.8 g, 172 mmol, 3 eq) was added to a solution of N-(2-aminoethyl)-N-methyl-carbamate tert-butyl ester (10.0 g, 57.3 mmol, 10.2 mL, 1 eq) and 2-bromoethoxy-tert-butyl-dimethyl-silane (10.9 g, 45.9 mmol, 0.8 eq) in ACN (150 mL). The mixture was stirred at 80 °C for 16 hours. After completion, the mixture was quenched with water (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (120 g silica gel column, DCM / MeOH 0% to 100%) to give N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]ethyl]-N-methyl-carbamate tert-butyl ester (7.50 g, 18.0 mmol, 31.4% yield) as a colorless gel. LC-MS: m / z 333.8 (M+1) + .

[0976] Step 2. Add Cb2Cl (1.80 g, 10.5 mmol, 1.50 mL, 1.3 eq) and NaHCO3 (2.05 g, 24.3 mmol, 947 μL, 3 eq) to a solution of N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]ethyl]-N-methyl-carbamate tert-butyl ester (2.70 g, 8.12 mmol, 1 eq) in THF (80 mL) and H2O (20 mL). Stir the mixture at 25 °C for 16 hours. After completion, dilute the mixture with water (100 mL) and extract with EtOAc (3 × 80 mL). Dry the combined organic phases over Na2SO4, filter, and concentrate. The residue was purified by rapid silica gel chromatography (40.0 g silica gel column, PE / EA 0% to 100%) to give N-[2-[benzyloxycarbonyl-[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]ethyl]-N-methyl-carbamate tert-butyl ester (3.80 g, 7.33 mmol, 90.2% yield) as a colorless gel. 1H NMR (400MHz, DMSO-d6) δ = 7.34-7.30 (m, 5H), 5.05 (s, 2H), 3.72-3.60 (m, 2H), 3.38 (s, 2H), 3.38-3 .31 (m, 4H), 2.80-2.66 (m, 3H), 1.35 (s, 9H), 0.83 (d, J=10.8Hz, 9H), 0.07-0.09 (m, 6H); LC-MS: m / z 367.6(M-99) + .

[0977] Step 3. Add tetrabutylammonium trihydrate (1M, 4.29mL, 2eq) to a solution of N-[2-[benzyloxycarbonyl-[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]ethyl]-N-methyl-carbamate tert-butyl (1.00 g, 2.14 mmol, 1 eq) in THF (20 mL). Stir the mixture at 25 °C for 2 hours. After completion, quench the mixture with NH4Cl (8 mL) and extract with EtOAc (3 × 30 mL). Wash the combined organic layers with brine (50 mL), dry with sodium sulfate, and concentrate under vacuum. The residue was purified by rapid silica gel chromatography (12 g silica gel column, DCM / MeOH 0% to 100%) to give colorless gel-like N-[2-[benzyloxycarbonyl(2-hydroxyethyl)amino]ethyl]-N-methyl-carbamate tert-butyl ester (M9, 500 mg, 1.21 mmol, 56.2% yield). 1 H NMR (400MHz, DMSO-d6) δ = 7.31-7.05 (m, 5H), 4.86 (s, 2H), 4.59-4.48 (m, 1H), 3.29 (s, 2 H), 3.18 (d, J=5.3Hz, 2H), 3.15-3.03 (m, 4H), 2.57 (s, 2H), 1.24-1.10 (m, 9H); LCMS: m / z 253.0(M-99) + .

[0978] Preparation of N-[2-[2-(6-chloro-2-oxo-indoline-5-yl)oxoethyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl ester (M10)

[0980] Step 1. K₂CO₃ (11.0 g, 79.6 mmol, 1 eq) was added to a solution of N-methyl-N-[2-(methylamino)ethyl]carbamate tert-butyl ester (15.0 g, 79.6 mmol, 1 eq) and 2-bromoethoxy-tert-butyl-dimethylsilane (19.0 g, 79.6 mmol, 1 eq) in ACN (300 mL). The mixture was stirred at 80 °C for 16 hours. After completion, the mixture was quenched with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (220 g silica gel column, DCM / MeOH 0% to 100%) to give colorless gel-like N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl ester (16 g, 39.2 mmol, 49.2% yield). 1 H NMR (400MHz, DMSO-d6) δ=3.62 (t, J=6.4Hz, 2H), 3.20 (t, J=6.8Hz, 2H), 2.76 (s, 3H), 2.46 (s, 4H), 2.22 (s, 3H), 1.38 (s, 9H), 0.85 (s, 9H), 0.03 (s, 6H).

[0981] Step 2. Tetrabutylammonium trihydrate (1M, 86.5mL, 2eq) was added to a solution of N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-methyl-amino]ethyl]-N-methyl-carbamate (15.0 g, 43.2 mmol, 1 eq) in THF (400 mL). The mixture was stirred at 25 °C for 16 hours. After completion, the mixture was diluted with water (200 mL) and extracted with DCM (3 × 180 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (180 g silica gel column, DCM / MeOH 0% to 100%) to give N-[2-[2-hydroxyethyl(methyl)amino]ethyl]-N-methyl-carbamate (M10, 9 g, 34.8 mmol, 80.5% yield) as a colorless gel. 1 H NMR (400MHz, DMSO-d6) δ = 4.30 (s, 1H), 3.48-3.40 (m, 2H), 3.20 (t, J = 7.0Hz, 2H), 2.76 (s, 3H), 2.43 (q, J = 6.7Hz, 4H), 2.20 (s, 3H), 1.38 (s, 9H).

[0982] N-methyl-N-[2-[2-(2-oxoindoline-5-yl)oxyethoxy]ethyl]carbamate tert-butyl ester (M-1) was prepared according to general method M.

[0984] In an ice bath, DIAD (1.19 g, 5.90 mmol, 2.2 eq) was added to a solution of 5-hydroxyindoline-2-one (400 mg, 2.68 mmol, 1 eq), PPh3 (1.55 g, 5.90 mmol, 2.2 eq), and N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate tert-butyl ester (1.18 g, 5.36 mmol, 2.0 eq) in 2-MeTHF (20 mL). The mixture was stirred at 50 °C for 16 hours, quenched with MeOH (1 mL), and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 100:3) to give a light brown gel-like N-methyl-N-[2-[2-(2-oxoindoline-5-yl)oxyethoxy]ethyl]carbamate tert-butyl ester (M-1, 400 mg, 0.719 mmol, 26.8% yield). LCMS: m / z 251.3 (M+1) + .

[0985] M-2 to M-10 were prepared following a similar procedure to M-1.

[0989] Preparation of N-methyl-N-[2-[2-(2-oxoindoline-5-yl)thioethoxy]ethyl]carbamate tert-butyl ester (M-1s)

[0991] Step 1. At 0 °C, TosCl (1.30 g, 6.84 mmol, 1.5 eq) was added to a mixture of N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate tert-butyl ester (1.00 g, 4.56 mmol, 1 eq) and TEA (1.38 g, 13.7 mmol, 3 eq) in DCM (10 mL). The mixture was stirred at 25 °C for 12 h and partitioned with H2O (5 mL). The organic phase was separated, washed with H2O (5 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography to give 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]ethyl 4-methylbenzenesulfonic acid (1.70 g, 4.28 mmol, 93.8% yield) as a pale yellow oil. LCMS: m / z 275 (M-Boc) + .

[0992] Step 2. Add K₂CO₃ (303 mg, 2.20 mmol, 1.1 eq) and 2-[2-[tert-Butoxycarbonyl(methyl)amino]ethoxy]ethyl 4-methylbenzenesulfonic acid (597 mg, 1.60 mmol, 0.8 eq) to a solution of 5-thioindoline-2-one (330 mg, 2.00 mmol, 1 eq) in DMF (5 mL). Stir the mixture at 25 °C under a N₂ atmosphere for 2 hours and allow it to partition between H₂O (10 mL) and EtOAc (10 mL). Separate the organic phase, wash with brine (5 mL × 3), dry with Na₂SO₄, filter, and concentrate under reduced pressure. The residue was purified by rapid silica gel chromatography to give N-methyl-N-[2-[2-(2-oxoindoline-5-yl)thioethoxy]ethyl]carbamate tert-butyl ester (M-1s, 450 mg, 1.06 mmol, 52.8% yield) as a yellow oil. LCMS: m / z 267.4 (M-Boc) + .

[0993] Preparation of N-[2-[2-(6-chloro-2-oxo-indoline-5-yl)thioethoxy]ethyl]-N-methyl-carbamate tert-butyl ester (M-2s)

[0995] M-2s was prepared using a similar procedure to that used for M-1s, with 6-chloro-5-thioindoline-2-one. 1 H NMR (400MHz, DMSO-d6) δ = 10.50 (s, 1H), 7.38 (s, 1H), 6.88 (s, 1H), 3.56 (t, J = 6.4Hz, 2H), 3.48 (s, 3H), 3 .46 (s, 1H), 3.31 (s, 1H), 3.29-3.26 (m, 2H), 3.06 (t, J=6.4Hz, 2H), 2.78 (d, J=9.2Hz, 2H), 1.37 (s, 9H). LCMS: m / z 301.0(M-Boc) + .

[0996] 2-Formyl-N,5-dimethyl-N-[2-[2-[5-(2-oxoindoline-5-yl)pyrazol-1-yl]ethoxy]ethyl]-1H-pyrrole-3-carboxamide (N-1) was prepared according to general method N.

[0998] Step 1. To a solution of N-methyl-N-[2-[2-[5-(2-oxoindoline-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate tert-butyl ester (150 mg, 374 μmol, 1 eq) in DCM (5 mL), HCl / dioxane (4 M, 0.94 mL, 10 eq) was added, and the resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under vacuum to give 5-[2-[2-[2-(methylamino)ethoxy]ethyl]pyrazol-3-yl]indoline-2-one hydrochloride (123 mg, 0.34 mmol, 90% yield) as a white solid. LCMS: m / z 301.3 (M+1) + .

[0999] Step 2. To a solution of 5-[2-[2-[2-(methylamino)ethoxy]ethyl]pyrazol-3-yl]indoline-2-one hydrochloride (113 mg, 0.34 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (51.4 mg, 0.34 mmol, 1 eq) in acetonitrile (1 mL), 1-methylimidazolium (82.6 mg, 1.01 mmol, 3 eq) and [chloro(dimethylamino)methylene]-dimethyl-hexafluorophosphate ammonium (141.2 mg, 0.50 mmol, 1.5 eq) were added, and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (DCM:MeOH = 30:1 to 10:1). The crude product was wet-milled with MeOH (5 mL) at 25 °C for 10 minutes and then filtered to give 2-formyl-N,5-dimethyl-N-[2-[2-[5-(2-oxoindoline-5-yl)pyrazol-1-yl]ethoxy]ethyl]-1H-pyrrole-3-carboxamide (N-1, 110 mg, 0.21 mmol, 62% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.06 (s, 1H), 10.50 (s, 1H), 9.43-9.20 (m, 1H), 8.57 (s, 2H), 7.49 (d, J=1.6Hz, 1H), 6.88 (d , J=8.0Hz, 1H), 6.25 (d, J=2.0Hz, 1H), 6.04-5.86 (m, 1H), 4.19 (s, 2H), 3.52-3.48 (s, 5H), 3.44-3.42 (s, 6H), 2.85 (s, 3H). LCMS: m / z 436.3(M+1) + .

[1000] N-2-N-39 is prepared using a similar procedure to N-1, with the corresponding intermediates K-2, L-1 to L-13, M-1 to M-10, M-1s and M-2s and the corresponding pyrrolic aldehyde.

[1009] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethylenedimethyl)pyrazolo[1,5-d]dipyrrolo[3,4-h:2′,3′-k][1,4,14]oxadiazacyclic hexadecyne-4,19(5H,18H)-dione (41) was prepared according to the general method O.

[1011] Piperidine (43.0 mg, 0.50 mmol, 2 eq) was added to a solution of N-1 (110 mg, 0.25 mmol, 1 eq) in EtOH (30 mL). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled and concentrated under vacuum. The crude product was wet-milled with MeOH (5 mL) at 25 °C for 10 minutes to give 41 (42.2 mg, 0.100 mmol, 40% yield) as an orange solid. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.62 (s, 1H), 11.08 (s, 1H), 7.95 (s, 1H), 7.52 (s , 1H), 7.40 (s, 1H), 7.36 (dd, J=8.0, 1.6Hz, 1H), 7.00 (d, J=8.0Hz, 1H), 6.46 (d, J=2.0Hz, 1H), 6.24 (d, J=2.0Hz, 1H), 4.40-4.27 (m, 3H), 4.18-4.16 (m, 1H), 4.0 4-3.91 (m, 2H), 3.70-3.68 (m, 1H), 3.18-3.07 (m, 1H), 2.98 (s, 3H), 2.41 (s, 3H). LCMS: m / z418.2(M+1) + .

[1012] Examples 42, 91, 92, 124-158, and 160-171 were prepared from starting materials N2-N39, respectively, following a similar procedure to 41. For 42, 125, 127, 139, 145, 160, and 163, the Cbz protecting group was removed after the cyclization step described below:

[1014] The mixture of 125-Cbz (65.0 mg, 0.12 mmol, 1 eq) in TFA (4 mL) was stirred at 60 °C for 16 hours. After completion, the mixture was concentrated under vacuum. The residue was dissolved in saturated NaHCO3 (water solution, 30 mL) and lyophilized to give a solid. The solid was suspended in DCM / MeOH (10:1), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 1:0 to 100:7) to give 125 as an orange powder (3.3 mg, 6.4% yield).

[1015] For esters 133-138, an amide is synthesized after the hydrolysis of ester 132, followed by amide coupling with the corresponding amine, and, if necessary, removal of the Boc- protecting group, as shown below:

[1017] Step 1. LiOH·H2O (27.4 mg, 0.652 mmol, 3 eq.) was added to a solution of 132 (100 mg, 0.217 mmol, 1 eq.) in THF (1 mL), MeOH (1 mL), and H2O (0.5 mL). The mixture was stirred at 15 °C for 3 hours. The mixture was concentrated under vacuum to obtain 132-1 (115 mg, crude substance) as a yellow solid. LC-MS: m / z 446.0 (M+1) + .

[1018] Step 2. At 0°C, HATU (51.2 mg, 0.135 mmol, 1.2 eq.) was added to a solution of 132-1 (50.0 mg, 0.112 mmol, 1 eq.) and tert-butyl 3-aminoazacyclobutane-1-carboxylate (23.2 mg, 0.134 mmol, 1.2 eq.) in DMF (10 mL). The mixture was stirred at 15°C for 0.5 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to give 133-1 (19.0 mg, 30% yield) as a yellow solid. LC-MS: m / z 600.5 (M+1) + .

[1019] Step 3. Add TFA (1 mL) to the mixture of 133-1 (19.0 mg, 0.032 mmol, 1 eq.) in DCM (1 mL). Stir the mixture at 15 °C for 3 hours. Concentrate the mixture under vacuum and purify the residue by combi flash (4 g silica gel column, MeOH / DCM 0% to 20%) to give 133 (7.99 mg) as a yellow solid.

[1020] 144 is oxidized to 148 and 149 respectively, as shown below:

[1022] Potassium persulfate (588 mg, 0.957 mmol, 20 eq) was added to a solution of 144 (20 mg, 47.9 μmol, 1 eq) in DMF (2 mL), MeOH (2 mL), and H₂O (2 mL). The mixture was stirred at 25 °C for 16 hours. After stirring, the mixture was filtered, and the solid was wet-milled with H₂O and MeOH and filtered again to give 148 (1.2 mg) as a pale yellow solid. The filtrate was evaporated and purified by preparative HPLC to give 149 (2.3 mg) as a pale yellow solid.

[1023] 125 is converted to 152 or 156 via a reductive amination reaction using acetaldehyde or acetone, as shown below for 152:

[1025] Acetaldehyde (2.60 g, 23.5 mmol, 3.31 mL, 40% purity, 25 eq) and NaBH3CN (296 mg, 4.71 mmol, 5 eq) were added to a solution of 125 (393 mg, 0.942 mmol, 1 eq) in MeOH (15 mL), followed by the addition of TFA (644 mg, 5.66 mmol, 6 eq). The mixture was stirred at 25 °C for 16 hours. After completion, the mixture was concentrated and purified by rapid silica gel chromatography (12 g silica gel column, DCM / MeOH 0% to 100%) to give 152 (5.89 mg, 12.7 μmol, 1.35% yield) as an orange solid.

[1026] Use the method described below to oxidize 154 and 170 to 155 and 171, respectively:

[1028] At 0 °C, m-CPBA (22.0 mg, 0.104 mmol, 85% purity, 2 eq) was added to a mixture of 154 (20 mg, 0.052 mmol, 1 eq) and DCM (3 mL). The mixture was stirred at 25 °C for 1 hour, quenched by adding saturated NaHCO3 (1 mL), and then extracted with DCM (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 100 / 0 to 30 / 1), followed by recrystallization from MeOH (1 mL) to give 155 (8.21 mg, 34.5% yield) as an orange solid.

[1039] Preparation of [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenedimethyl)pyrazolo[4,3-i]pyrrolo[3,4-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione(159)

[1041] Step 1. At 0 °C, MOMCl (18.1 g, 225 mmol, 1.5 eq) was added to a mixture of ethyl 1H-pyrazole-4-carboxylate (20.0 g, 142 mmol, 1.0 eq) and K2CO3 (39.4 g, 285 mmol, 2.0 eq) in MeCN (250 mL). The mixture was heated to 40 °C and stirred for 2 hours. After completion, the mixture was quenched with water (30 mL) and concentrated under vacuum to obtain a mixture (50 mL), which was diluted with brine (100 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was dried over sodium sulfate, concentrated under vacuum to obtain a crude substance, which was purified by silica gel column chromatography (PE:EA = 2:1) to give a colorless oily ethyl 1-(methoxymethyl)pyrazole-4-carboxylate (17.1 g, 83 mmol, 59% yield). 1 H NMR (400MHz, DMSO-d6) δ = 8.51 (s, 1H), 7.94 (s, 1H), 5.42 (s, 2H), 4.22 (q, J = 6.8Hz, 2H), 3.25 (s, 3H), 1.26 (t, J = 6.8Hz, 3H).

[1042] Step 2. At -70°C, n-BuLi (2.5M, 39.09mL, 2.0eq) was added to a solution of DIPA (9.8g, 97mmol, 2.0eq) in 2-MeTHF (90mL). The mixture was stirred at -70°C for 25 minutes. At -70°C, the resulting LDA mixture was transferred to a solution of ethyl 1-(methoxymethyl)pyrazole-4-carboxylate (9.0g, 48.86mmol, 1.0eq) in 2-MeTHF (45mL) and stirred for 5 minutes. Anhydrous DMF (35.72g, 488mmol, 10.0eq) was added to the mixture, and the mixture was stirred at -70°C for another 1 hour. After completion, the mixture was quenched with saturated NH4Cl (300mL) and extracted with EtOAc (300mL). The organic layer was washed with brine (80mL), dried over sodium sulfate, and concentrated under vacuum to obtain the crude substance. The crude substance was purified by silica gel column chromatography (PE:EA = 100:15) to obtain ethyl 5-formyl-1-(methoxymethyl)pyrazole-4-carboxylate (4.0 g, 16.96 mmol, 34.72% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ = 10.33 (s, 1H), 8.10 (s, 1H), 5.69 (s, 2H), 4.32 (q, J = 7.2Hz, 2H), 1.98 (s, 2H), 1.32 (t, J = 7.2Hz, 3H).

[1043] Step 3. To a solution of ethyl 5-formyl-1-(methoxymethyl)pyrazole-4-carboxylate (90 mg, 0.424 mmol, 1.0 eq) in EtOH (22 mL), add 6-chloro-5-[2-[2-(methylamino)ethoxy]ethoxy]indoline-2-one (M-4-deboc, 120.76 mg, 0.424 mmol, 1.0 eq) and piperidine (144 mg, 1.70 mmol, 4.0 eq). Stir the mixture at 80 °C for 16 hours. After completion, concentrate the reaction mixture under vacuum to obtain a crude product. Purify the crude product by silica gel column chromatography (DCM:MeOH = 100:13) to give 159a (150 mg, 0.288 mmol, 66% yield) as a red solid. LCMS: m / z 479.3 (M+1) + .

[1044] Step 4. LiOH·H2O (105 mg, 2.51 mmol, 12.0 eq) was added to a mixture of 159a (100 mg, 0.208 μmol, 1.0 eq) in MeOH (8.0 mL) and H2O (8.0 mL). The mixture was stirred at 20 °C for 16 hours. After completion, the mixture was concentrated under vacuum, dissolved in water (20.0 mL), adjusted to pH 6 to 7 with HCl aqueous solution (1 M), and then lyophilized. The residue was dissolved in DCM / MeOH (10:1), filtered, and concentrated under vacuum to give 159b (120 mg, 0.186 mmol, 89.2% yield) as a red solid. LCMS: m / z 451.2 (M+1) + .

[1045] Step 5. Add FDPP (93.7 mg, 0.244 mmol, 1.1 eq) to a solution of 159b (100 mg, 0.221 mmol, 1.0 eq) and DIEA (86.0 mg, 0.665 mmol, 3.0 eq) in DMF (20.0 mL). Stir the mixture at 20 °C for 1 hour. After completion, dilute the mixture with EtOAc (100 mL) and wash with brine (3 × 30 mL). The organic layer was concentrated under vacuum and purified by silica gel column chromatography (DCM:MeOH = 100:4) to give 159c (30.0 mg, 55.4 μmol, 25.0% yield) as a red solid. LCMS: m / z 433.2 (M+1) + .

[1046] Step 6. The mixture of 159c (20.0 mg, 46.2 μmol, 1.0 eq) in TFA (1 mL) was stirred at 60 °C for 2 hours. After completion, the mixture was concentrated under vacuum, adjusted to neutral pH with saturated NaHCO3, and then lyophilized. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:5) to give 159c (2.05 mg, 5.27 μmol, 11.4% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ = 13.80-13.49 (m, 1H), 10.72-10.45 (m, 1H), 8.43-7.92 (m, 1H), 7.53-7.38 (m, 1H), 7.22-7.18 (m, 1H), 6.84 (d, J = 7.2 Hz, 1H), 4.28-4.10 (m, 1H), 4.00-3.77 (m, 1H), 3.63 (d, J=11.2Hz, 2H), 3.49 (d, J=3.2Hz, 1H), 3.44 (dd, J=5.2, 7.2Hz, 3H), 2.91-2.72 (m, 2H). LCMS: m / z 389.2(M+1) + .

[1047] Preparation of [16a(17)Z]-19-chloro-2,5,8-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]oxadiazacyclic pentadecylyn-4,16(1H,15H)-dione (164)

[1049] Step 1. Add HCl / dioxane (4M, 18.8mL, 20eq) to a solution of N-[2-[2-(6-chloro-2-oxo-indoline-5-yl)oxoethyl-methyl-amino]ethyl]-N-methyl-carbamate tert-butyl (M-10, 1.50 g, 3.77 mmol, 1 eq) in DCM (30 mL). Stir the mixture at 25 °C for 2 hours. After completion, concentrate the mixture to obtain M-10-deboe HCl salt, which is used directly in the next step. LCMS: m / z 298.0 (M+1) + .

[1050] Step 2. Add EDCI (458 mg, 2.39 mmol, 2 eq), DIEA (464 mg, 3.59 mmol, 625 μL, 3 eq), and DMAP (146 mg, 1.20 mmol, 1 eq) to a solution of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (183 mg, 1.20 mmol, 1 eq) in DCM (15 mL). Stir the mixture at 25 °C for 0.5 h. Then add 6-chloro-5-[2-[methyl-[2-(methylamino)ethyl]amino]ethoxy]indoline-2-one (M-10-deboc HCl salt) (400 mg, 1.20 mmol, 1 eq) to the mixture. Stir the mixture at 25 °C for 2 h. After completion, concentrate the mixture to obtain the residue. The residue was purified by rapid silica gel chromatography (12 g silica gel column, DCM / MeOH 0% to 100%) to give 164 (10.7 mg, 2.09% yield) as an orange solid. 1 H NMR (400MHz, DMSO-d6) δ = 11.48 (d, J = 0.8Hz, 1H), 10.61 (s, 1H), 8.41 (s, 1H), 7.39 (s, 1H), 6.83 (s, 1H), 6.22 (d, J = 1 .8Hz, 1H), 4.75-4.62(m, 1H), 4.40-4.28(m, 2H), 3.31(s, 3H), 2.82(s, 4H), 2.67(s, 1H), 2.39(s, 3H), 2.21(s, 3H). LCMS: m / z 415.1(M+1) + .

[1051] Preparation of [16a(17)Z]-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethylenedimethyl)dipyrrolo[3,2-i:3′,4′-l][1,4,7]dioxazonide-19-carboxynitrile (168)

[1053] Step 1. At 0°C, K₂CO₃ (4.28 g, 31.0 mmol, 3.57 mL, 1.2 eq) was added fractionally to a solution of dimethyl malonate (4.11 g, 31.0 mmol, 3.57 mL, 1.2 eq) in DMF (80 mL) and stirred for 1.0 h. Then, 2,4-difluoro-5-nitrobenzene (4.77 g, 25.9 mmol, 1.0 eq) was added fractionally, and the mixture was stirred at 70°C for 16 h. After completion, the mixture was poured into cold water (150 mL) and extracted with EtOAc (250 mL). The organic layer was washed with brine (150 mL), dried over sodium sulfate, and concentrated under vacuum to obtain the crude substance. The crude material was purified by silica gel column chromatography to obtain dimethyl 2-(4-cyano-5-fluoro-2-nitrophenyl)malonate (168-2, 3.65 g, 12.3 mmol, 47.6% yield).

[1054] Step 2. To a solution of N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate tert-butyl ester (3.00 g, 13.7 mmol, 1 eq) in DMF (40 mL), add NaH (1.09 g, 27.4 mmol, 60% purity, 2 eq) and stir the mixture at 0 °C. Then add dimethyl 2-(4-cyano-5-fluoro-2-nitrophenyl)malonate (3.65 g, 12.3 mmol, 0.9 eq). Stir the mixture at 20 °C for 30 min and heat to 80 °C for 2 h. Quench the reaction mixture with H₂O (80 mL) and extract with EtOAc (100 mL × 3). Wash the combined organic layers with brine (40 mL × 3), dry to anhydrous Na₂SO₄, filter, and dry. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give dimethyl 2-[5-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]ethoxy]-4-cyano-2-nitro-phenyl]malonate (168-3, 850 mg, 1.68 mmol, 12.3% yield), a brown oil. LCMS: 518.1 (M+Na) + .

[1055] Step 3. The mixture of 168-3 (150 mg, 0.302 mmol, 1 eq) in TFA (0.50 mL) and DCM (1 mL) was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 168-4 (80 mg, 0.184 mmol, 60.8% yield) as a brown oil. 1H NMR (400MHz, CDCl3) δ = 8.67-8.40 (m, 1H), 8.32 (s, 0.5H), 8.01 (s, 0.5H), 7.19 (s, 1H), 5.48 (s, 1H), 4.72 (s, 4H), 4.39(s, 1H), 3.93-3.77(m, 3H), 3.77-3.74(m, 3H), 3.29-3.17(m, 1H), 3.00-2.86(m, 3H), 2.75(s, 2H). LCMS:396.1(M+H) + .

[1056] Step 4. A mixture of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (85.2 mg, 0.556 mmol, 1 eq), DIEA (287 mg, 2.23 mmol, 4 eq), T3P (265 mg, 0.835 mmol, 1.5 eq), and 168-4 (220 mg, 0.556 mmol, 1 eq) in DMF (2 mL) was stirred at 20 °C for 2 h, quenched by the addition of H2O (10 mL), and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and dried. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1) to give compound 168-5 (140 mg, 0.251 mmol, 45.1% yield) as a yellow oil. LCMS: m / z 531.1(M+1) + .

[1057] Step 5. Add Fe (57.9 mg, 1.04 mmol, 5 eq) to the mixture of 168-5 (110 mg, 0.207 mmol, 1 eq) in AcOH (2 mL). Stir the reaction mixture at 100 °C for 4 hours. Filter the mixture and concentrate under reduced pressure. Purify the residue by preparative TLC (DCM:MeOH = 10:1) to give compound 168 (16.2 mg, 0.0392 mmol, 18.9% yield) as an orange solid.

[1058] 1H NMR (400MHz, DMSO-d6) δ = 11.48 (s, 1H), 10.81 (s, 1H), 8.01 (s, 1H), 7.49 (s, 1H), 7.06 (s, 1H), 6.31 (s, 1H), 4.61 -4.42 (m, 3H), 3.93-3.75 (m, 3H), 3.69 (s, 1H), 3.01 (dd, J=4.8, 14.4Hz, 1H), 2.82 (s, 3H), 2.42 (s, 3H); LCMS: m / z 393.2(M+1) + .

[1059] Preparation of [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethamine)pyrazolo[4,3-m]dipyrrolo[3,2-f:3′,4′-i][1,4]diazacyclic pentadecyne-3,8(2H,5H)-dione (172)

[1062] Step 1. At 0 °C, fractionally add NaH (1.24 g, 31.09 mmol, 60% purity, 1.2 eq) to a solution of dimethyl malonate (4.11 g, 31.0 mmol, 1.2 eq) in THF (80 mL) and stir the mixture for 1.0 h. Then, add 2,4-dichloro-5-nitropyridine (5.0 g, 25.9 mmol, 1.0 eq) fractionally. Stir the mixture at 70 °C for 16 h. After completion, pour the mixture into cold water (150 mL) and extract with EtOAc (250 mL). Wash the organic layer with brine (150 mL), dry over sodium sulfate, and concentrate under vacuum. Purify the residue by silica gel column chromatography (PE:EA = 100:0 to 100:30) to give 172-2 (3.6 g, 11.2 mmol, 43.3% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ=9.08 (s, 1H), 7.52 (s, 1H), 5.37 (s, 1H), 3.82 (s, 6H). LCMS: m / z 289.1(M+1) + .

[1063] Step 2. Pd(dppf)Cl2 (152 mg, 0.207 mmol, 0.1 eq) was added to a mixture of 172-2 (600 mg, 2.08 mmol, 1.0 eq), B-IV-4 (1.41 g, 2.08 mmol, 60% purity, 1.0 eq), and Na2CO3 (2 M, 3.12 mL, 3.0 eq) in dioxane (8.0 mL). The mixture was stirred at 90 °C under a nitrogen atmosphere for 2 hours. After completion, the mixture was concentrated under vacuum and purified by silica gel column chromatography (DCM:MeOH = 100:2) to give 172-3 (800 mg, 1.50 mmol, 71.9% yield) as a reddish-brown gel. LCMS: m / z 535.4 (M+1) + .

[1064] Step 3. Add HCl / dioxane (4M, 1.64mL, 10eq) to a solution of 172-3 (350mg, 654μmol, 1.0eq) in DCM (10mL). Stir the mixture at 20°C for 1 hour. After completion, concentrate the mixture under vacuum to give 172-4 (300mg, 0.621mmol, 94.9% yield) as a grayish-white solid. LCMS: m / z 435.3 (M+1) + .

[1065] Step 4. At 20°C, EDCI (191 mg, 1.00 mmol, 1.5 eq) was added to a solution of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (102 mg, 0.667 mmol, 1.0 eq), DIEA (258 mg, 2.00 mmol, 3.0 eq), and DMAP (8.15 mg, 0.0667 mmol, 0.1 eq) in 10 mL of DCM, and the mixture was stirred for 0.5 h. Then, 172-4 (290 mg, 0.667 mmol, 1.0 eq) was added. The mixture was stirred for 0.5 h. After completion, the mixture was concentrated under vacuum and purified on a silica gel column (DCM:MeOH = 30:1) to give 172-5 (300 mg, 0.474 mmol, 71.0% yield).

[1066] LCMS: m / z 570.7 (M+1) + .

[1067] Step 5. LiCl (55.8 mg, 1.32 mmol, 3.0 eq) was added to a solution of 172-5 (250 mg, 0.438 mmol, 1.0 eq) in DMSO (5.0 mL) and H2O (1.0 mL). The mixture was stirred at 100 °C for 7 hours. After completion, the mixture was diluted with EtOAc (100 mL) and washed with brine (2 × 40 mL). The organic layer was dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 172-6 (180 mg, 0.334 mmol, 76.1% yield) as a brown gel. LCMS: m / z 512.1 (M+1) + .

[1068] Step 6. Add Fe (163 mg, 2.93 mmol, 10.0 eq) to a solution of 172-6 (150 mg, 0.293 mmol, 1.0 eq) in AcOH (40.0 mL). Stir the mixture at 90 °C for 1 hour. Filter the mixture and concentrate the filtrate under vacuum. Redissolve the residue in MeOH (20.0 mL) and add saturated NaHCO3 (20.0 mL) dropwise while stirring at 20 °C for 2 hours. Concentrate the mixture under vacuum to obtain a gel. Redissolve the gel in DCM / MeOH (ratio = 10:1, 100 mL), filter, and concentrate the filtrate under vacuum to obtain the crude substance. Purify the crude substance by silica gel column chromatography (DCM:MeOH = 100:5) to obtain 172 (7.78 mg, 0.165 mmol, 5.66% yield) as an orange powder.

[1069] 173 and 174 were prepared using a similar procedure to 172, with 2,6-dichloro-3-nitropyridine as the starting material.

[1072] Screening assay

[1073] Biochemical assay

[1074] Kinase binding assays were performed on Eurofins / DiscoveRx using the standard KINOMEscan protocol (Fabian, MA et al., “A small molecule-kinase interaction map for clinical kinase inhibitors,” *Nature Biotechnol.*, 2005, 23(3): 329-36). For most assays, kinase-labeled T7 phage strains were prepared in *E. coli* hosts derived from strain BL21. *E. coli* were grown to the logarithmic phase and infected with T7 phage, and incubated at 32°C with shaking until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were generated in HEK-293 cells and subsequently labeled with DNA for qPCR detection. Magnetic beads coated with streptavidin were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. Ligand-treated beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligands and reduce nonspecific binding. Binding reactions were assembled by combining the kinase, ligand-treated affinity beads, and test compound in 1× binding buffer (20% SeaBlock, 0.17×PBS, 0.05% Tween 20, 6 mM DTT). All reactions were performed in 96-well polystyrene plates with a final volume of 0.135 mL. The plates were incubated with shaking at room temperature for 1 hour, and the affinity beads were washed with washing buffer (1×PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μM non-biotin-labeled affinity ligand) and incubated with shaking at room temperature for 30 minutes. The concentration of kinases in the eluent was measured by qPCR. In this assay, the results of compounds tested at a given concentration are reported as “%Ctrl,” where lower numbers indicate stronger binding in the matrix.

[1075] %Ctrl calculates:

[1076] (Test compound signal - Positive control signal) / (Negative control signal - Positive control signal) × 100

[1077] Table 1

[1080] Table 2

[1083] Table 3

[1087] Table 4

[1090] Table 5

[1094] Table 6

[1097] Table 7

[1101] Table 8

[1104] Cell assay

[1105] The inhibition of cellular activity of wild-type and mutant EGFR will be evaluated using ProQinase GmbH's (www.proqinase.com) cellular phosphorylation assays, designed to measure the activity of compounds against physiological substrates in a physiological environment. The cellular kinase assays include wild-type EGFR, EGFR L858R mutant, EGFR T790M mutant, EGFR G719S mutant, EGFR L861Q mutant, EGFRΔ752-759 mutant, EGFR L858R / T790M mutant, EGFRΔ746-750 / T790M mutant, EGFRΔ746-750 / C797S mutant, EGFR T790M / C797S / L858R mutant, EGFRΔ746-750 / T790M / C797S mutant, and EGFRΔ747-749 / A750P mutant. Detailed experimental protocols are available on the ProQuinry website.

Claims

1. A compound of formula IV or a pharmaceutically acceptable salt thereof, IV in A is a 5-membered heteroaryl group; Each L is independently -C(R) 3 (R) 4 -, -C(O)-, -O-, -N(R) 5 -, -S-, -S(O)- or -S(O)2-, with the constraint that (L) n Excluding -OO-, -OS-, or -ON(R) 5 )-key; X is C(R) 6 ); X 1 Is it N or C(R)? 7 ); X 3 Is it N or C(R)? 9 ); X 4 Is it N or C(R)? 10 ); Y and Y 1 Each is O; Y 2 It is -N(R) 11 )-; Z is a 3- to 7-membered heterocyclic alkylene group, C3-C6 heterocyclic alkylene group, C6-C6 heterocyclic alkylene group. 10 aryl, 5- to 10-membered heteroaryl, -C(R) 12 (R) 13 -, -C(O)-, -O-, -N(R) 14 -, -S-, -S(O)- or -S(O)2-, wherein the 3 to 7-membered heterocyclic alkylene, C3-C6 heterocyclic alkylene, C6-C 10 Each hydrogen atom in the arylene and 5- to 10-membered heteroarylene groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f 、 -P(O)R e R f 、 -P(O)₂R e R f 、 -P(O)NR e R f 、 -P(O)₂NR e R f 、 -P(O)OR e 、 -P(O)₂OR e 、 -CN or -NO₂; Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; R 2 R 5 R 11 Or R 14 Each of the following is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f ,-P(O)2NR e R f ,-P(O)OR e ,-P(O)2OR e' ,-CN or -NO2; Each R 3 R 4 R 12 and R 13 Independently, it is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d ,,-NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN, -NO2, or R 3 R 4 R 12 and R 13 Both of these, together with one or more carbons attached to them, form C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocyclic alkyl group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2; R 6 It is H or deuterium; R 7 It is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; R 9 and R 10 Each of the following is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or R 9 and R 10 Together with the carbon it is attached to, it forms C4-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-C 10 aryl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocyclic alkyl group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f 、 -P(O)R e R f 、 -P(O)₂R e R f 、 -P(O)NR e R f 、 -P(O)₂NR e R f 、 -P(O)OR e 、 -P(O)₂OR e 、 -CN or -NO₂; Each R a R b R c R d R e and R f Independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkyl-C6-C 10 Aryl and 5- to 10-membered heteroaryl groups; m is 0, 1, 2, or 3; and n is 2, 3, 4, 5, or 6.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is furanyl, thiopheneyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiazolyl, or triazolyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a pyridine group.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is... or , , , or , where R 1a It is a C1-C6 alkyl group, -C(O)R a -C(O)OR a -C(O)NR a R b or -P(O)2OR a Each hydrogen atom in the C1-C6 alkyl group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f 、 -P(O)R e R f 、 -P(O)₂R e R f 、 -P(O)NR e R f 、 -P(O)₂NR e R f 、 -P(O)OR e 、 -P(O)₂OR e 、 -CN or -NO₂。 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is... or .

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, each R 1 It is -CN or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, each R 1 It is -CN or methyl.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, R 1a It is a methyl group.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is an H or C1-C6 alkyl group, wherein each hydrogen atom in the C1-C6 alkyl group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e' -CN or -NO2.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is H or methyl.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is a 5- or 6-membered heteroaryl group, wherein each hydrogen atom in the 5- or 6-membered heteroaryl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyridin-2-one, wherein each hydrogen atom in the pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyridin-2-one group is independently and optionally substituted by: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is or .

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is C6-C. 10 Aromatic compounds, of which C6-C 10 Each hydrogen atom in the arylene group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is phenylene, and each hydrogen atom in the phenylene is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is or .

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is a 3- to 7-membered heterocyclic alkyl group, wherein each hydrogen atom in the 3- to 7-membered heterocyclic alkyl group is independently and optionally substituted with: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is a pyrrolidone group or a zazonyl butyl group, wherein each hydrogen atom in the pyrrolidone group and the zazonyl butyl group is independently and optionally substituted with a deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR group. e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is -C(R) 12 (R) 13 )-、-O-、-N(R 14 -, -S-, -S(O)- or -S(O)2-.

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is -C(R) 12 (R) 13 )-.

21. The compound according to claim 1, wherein R 12 and R 13 Independently selected from the following groups: H, deuterium, fluorine, chlorine, bromine, -OR e and C1-C6 alkyl; or R 12 and R 13 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or the 4- to 6-membered heterocycloalkyl is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

22. The compound according to claim 1, wherein R 12 It is H and R 13 It is a methyl group.

23. The compound according to claim 1, wherein R 12 It is methyl and R 13 It's H.

24. The compound according to claim 1, wherein R 12 and R 13 It's H.

25. The compound according to claim 1, wherein R 12 It is methyl and R 13 It is -OH.

26. The compound according to claim 1, wherein R 12 It is -OH and R 13 It is a methyl group.

27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is -O-.

28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is -N(R 14 )-.

29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 14 It is H, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl.

30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 14 It is H, methyl, or cyclopropyl.

31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is -S-.

32. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is -S(O)2-.

33. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 3.

34. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 4.

35. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 5.

36. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 6.

37. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 7.

38. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each L is independently selected from the group consisting of: -C(O)-, -O-, -CH2-, -C(H)(CH3)-, -C(H)(OH)-, -C(H)(C(O)OR c )-、-C(H)(C(O)NR c R d -, -NH- and -NCH3-.

39. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 It's H.

40. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 When it exists and X 3 It is N.

41. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 and X 4 It is N.

42. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 It is N.

43. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 It is N.

44. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 3 It is N.

45. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 4 It is N.

46. ​​The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 It is C(R) 7 ), X 3 It is C(R) 9 ), and X 4 It is C(R) 10 ).

47. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein C(R) 7 When present, it is independently H, deuterium, fluorine, chlorine, -CN, or methyl.

48. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein C(R) 9 When present, it is independently H, deuterium, fluorine, chlorine, -CN, or methyl.

49. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein C(R) 10 When it exists, it is H.

50. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein -(L) n - is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -C(O)NH-(CH2)2O(CH2)2-, -C(O)N(CH3)-(CH2)2O(CH2)2-, -NHC(O)CH2O(CH2)2-, -N(CH3)-C(O)CH2O(CH2)2-, -CH2O(CH2)2-, -(CH2)2O(CH2)2-, -(CH2)2S(CH2)2-, -O(CH2)2S(CH2)2-, -(CH2)2SO2(CH2)2-, -O(CH2)2SO2(CH2)2-, -(CH2)2SO(CH2)2-, -O(CH2)2SO(CH2)2-, -(CH2)2O(C(H)(C(O)N(H)(azetidin-3-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(CH3))-CH2-, -(CH2)2O(C(H)(C(O)N(CH3)2)-CH2-, -(CH2)2O(C(H)(C(O)N(H)(piperidin-4-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(pyrrolidin-3-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(4-methylpiperazin-1-yl))-CH2-, -(CH2)2O(C(H)(C(O)OCH3)-CH2-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)3-, -CH2CH(CH3)-O(CH2)2-, -CH(CH3)-CH2O(CH2)2-, -O(CH2)2-, -O-(CH2)3-, -OCH2O(CH2)2-, -O-CH2CH(OH)CH2-, -O-(CH2)2O(CH2)2-, -O-CH2CH(CH3)-O(CH2)2-, -O-CH(CH3)-CH2O(CH2)2-, -O-(CH2)2NH-(CH2)2-, -O-CH2CH(CH3)-NH-(CH2)2-, -O-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -O-(CH2)2N(CH3)-(CH2)2-, -O-CH2CH(CH3)-N(CH3)-(CH2)2-, -O-CH(CH3)-CH2N(CH3)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -CH2N(CH2CH3)-(CH2)2--CH2N(CH(CH3))-(CH2)2-,-(CH2)2N(CH3)-(CH2)2-,-CH2CH(CH3)-N(CH3)-(CH2)2- or-O-CH(CH3)-CH2N(CH3)-(CH2)2-.

51. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [3a(4)] Z ]-10,11-dihydro-2 H ,13 H -16,1-(nitromethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4,11]Ozadiazetacyclotetradecyne-3,8(5 H 9 H )-Diketone; [3a(4) Z ]-9,10,11,12-tetrahydro-14 H -17,1-(nitromethyl)pyrazolo[3,4-] b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-9,10,11,12-tetrahydro-14 H -1,17-(nitromethyl)pyrazolo[3,4-] b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-9,10,11,12-tetrahydro-14 H -1,17-(diazonidinediylidene)pyrazolo[4,3- n Dipyrrolo[3,2-] g :3',4'- j [1,5]Oza-aza-acyclopentadecanyne-3,8(2) H 5 H )-Diketone; [3a(4) Z ]-9,10,11,12-tetrahydro-14 H -1,17-(ethylenedimethyl)pyrazolo[3,4-] b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-9,10,11,12-tetrahydro-14 H -17,1-(nitromethyl)pyrazolo[4,3- n Dipyrrolo[3,2-] g :3',4'- j [1,5]Oza-aza-acyclopentadecanyne-3,8(2) H 5 H )-Diketone; [3a(4) Z ]-9,10,11,12-tetrahydro-14 H -1,17-(nitromethyl)pyrazolo[4,3-] n Dipyrrolo[3,2-] g :3',4'- j [1,5]Oza-aza-acyclopentadecanyne-3,8(2) H 5 H )-Diketone; [3a(4) Z ]-9,10,11,12-tetrahydro-14 H -1,17-(ethylenedimethyl)pyrazolo[4,3- n Dipyrrolo[3,2-] g :3',4'- j [1,5]Oza-aza-acyclopentadecanyne-3,8(2) H 5 H )-Diketone; [3a(4) Z ,11 S ]-11-hydroxy-9,10,11,12-tetrahydro-14 H -1,17-(ethylenedimethyl)pyrazolo[3,4-] b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [19a(20) Z ]-2,5-Dimethyl-6,7,9,10-Tetrahydro-1 H ,12 H -15,17-(ethylenedimethyl)pyrazolo[4,3- p Dipyrrolo[3,2-] i :3',4'- l [1,4,7,14]dioxadiazazepine-4,19(5) H 18 H )-Diketone; [3a(4) Z ]-6-methyl-9,10,11,12-tetrahydro-14 H -1,17-(ethylenedimethyl)pyrazolo[3,4-] b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-3,8-dioxo-2,3,5,8,9,10,11,12-octahydro-14 H -1,17-(ethylenedimethyl)pyrazolo[3,4-] b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]Ozadiazepine-6-carboxynitrile; [3a(4) Z ]-6-methyl-9,10,11,12-tetrahydro-14 H -1,17-(ethylenedimethyl)imidazo[4,5-] i ]pyrazolo[3,4- b ]pyrrolo[3,4- f [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,15-dimethyl-9,10,11,12-tetrahydro-15 H -1,17-(ethylenedimethyl)pyrazolo[3,4-] b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4- b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,16-dimethyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4- b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethylenedimethyl)dipyrrolo[3,4- f :2',3'- i [1,2]thiazo[3,4-] b [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9-dimethyl-9,10,11,12-tetrahydro-14 H -1,17-(ethylenedimethyl)pyrazolo[3,4-] b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9-dimethyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4- b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9,16-trimethyl-9,10,11,12-tetrahydro-14 H -1,17-(ethylenedimethyl)pyrazolo[3,4-] b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9,16-trimethyl-9,10,11,12-tetrahydro-1,17-(ethylenediamide)[1,2]oxazolo[3,4- b Dipyrrolo[3,4-] f :2',3'- i [1,5,12]oxadiazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethylenedimethyl)pyrazolo[5,1- c Dipyrrolo[3,2-] j :3',4'- m [1,4,8]triazacyclotetradecyne-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6-methyl-9,10,11,12-tetrahydro-17,1-(methazine)pyrazolo[1,5- e Dipyrrolo[3,4-] i :2',3'- l [1,5]diazacyclic tetradecyne-3,8(2 H 5 H )-Diketone; [19a(20) Z ]-2-methyl-6,7,9,10-tetrahydro-1 H -15,17-(ethylenedimethyl)pyrazolo[1,5- d Dipyrrolo[3,4-] h :2',3'- k [1,4,7,14]oxatriazacyclohexadecyne-4,19(5 H 18 H )-Diketone; [19a(20) Z ]-2-methyl-6,7,9,10-tetrahydro-1 H -15,17-(nitromethyl)pyrazolo[1,5-] d Dipyrrolo[3,4-] h :2',3'- k [1,4,14]oxadiazazepine-4,19(5) H 18 H )-Diketone; [19a(20) Z ]-2-methyl-6,7,9,10-tetrahydro-1 H -15,17-(nitromethyl)pyrazolo[1,5-] d Dipyrrolo[3,4-] h :2',3'- k [1,4,7,14]oxatriazacyclohexadecyne-4,19(5 H 18 H )-Diketone; [19a(20) Z ]-2-methyl-6,7,9,10-tetrahydro-1 H -15,17-(ethylenedimethyl)pyrazolo[1,5- d Dipyrrolo[3,4-] h :2',3'- k [1,4,14]oxadiazazepine-4,19(5) H 18 H )-Diketone; [10 R ,19a(20) Z ]-2,10-dimethyl-6,7,9,10-tetrahydro-1 H -15,17-(ethylenedimethyl)pyrazolo[1,5- d Dipyrrolo[3,4-] h :2',3'- k [1,4,14]oxadiazazepine-4,19(5) H 18 H )-Diketone; [19a(20) Z ]-2,5-Dimethyl-6,7,9,10-Tetrahydro-1 H -15,17-(ethylenedimethyl)pyrazolo[1,5- d Dipyrrolo[3,4-] h :2',3'- k [1,4,14]oxadiazazepine-4,19(5) H 18 H )-Diketone; [19a(20) Z ]-2,5-Dimethyl-6,7,9,10-Tetrahydro-1 H -15,17-(nitromethyl)pyrazolo[1,5-] d Dipyrrolo[3,4-] h :2',3'- k [1,4,7,14]oxatriazacyclohexadecyne-4,19(5 H 18 H )-Diketone; [19a(20) Z ]-2-Methyl-5,6,7,8,9,10-hexahydro-15,17-(ethylenedimethyl)pyrazolo[1,5- g Dipyrrolo[3,4-] k :2',3'- n [1,4,7] Triazacyclohexadecyne-4,19(1 H 18 H )-Diketone; [19a(20) Z ]-2,5-Dimethyl-5,6,7,8,9,10-hexahydro-15,17-(ethylenedimethyl)pyrazolo[1,5- g Dipyrrolo[3,4-] k :2',3'- n [1,4,7] Triazacyclohexadecyne-4,19(1 H 18 H )-Diketone; [3a(4) Z ]-6-methyl-10,11,13,14-tetrahydro-2 H -1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4,11]Ozadiazepine-3,8(5) H 9 H )-Diketone; [3a(4) Z ]-6-methyl-10,11,13,14-tetrahydro-2 H -17,1-(nitromethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-6-methyl-10,11,13,14-tetrahydro-2 H -1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-6,9-dimethyl-10,11,13,14-tetrahydro-2 H -1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-6,9,16-trimethyl-10,11,13,14-tetrahydro-2 H -1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(methazine)pyrazolo[3,4- f Dipyrrolo[3,4-] j :2',3'- m [1,4,9]Triazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6-methyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4- f Dipyrrolo[3,4-] j :2',3'- m [1,4,9]Triazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(methazine)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(methazine)pyrazolo[3,4- f Dipyrrolo[3,4-] j :2',3'- m [1,4,9]Triazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4- f Dipyrrolo[3,4-] j :2',3'- m [1,4,9]Triazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(methazine)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-20-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-19-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9,20-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(methazine)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-9,20-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4- f Dipyrrolo[3,4-] j :2',3'- m [1,4,9]Triazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,16-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(methazine)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(methazine)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-16-Cyclopropyl-6,9-Dimethyl-9,10,11,12,13,14-Hexahydro-17,1-(N-dimethoxymethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-16-Cyclopropyl-6,9-Dimethyl-9,10,11,12,13,14-Hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4- f Dipyrrolo[3,4-] j :2',3'- m [1,4,9]Triazacyclopentadene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2 H -17,1-(methazine)[1,2]oxazolo[4,5- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(5 H 9 H )-Diketone; [3a(4) Z ]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2 H -17,1-(nitromethamine)[1,2]oxazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(5 H 9 H )-Diketone; [3a(4) Z ]-6,14-dimethyl-10,11,13,14-tetrahydro-2 H -17,1-(nitromethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-6,9,14-trimethyl-10,11,13,14-tetrahydro-2 H -1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9,12,14-Tetramethyl-9,10,11,12,13,14-Hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9,16-trimethyl-10,11-dihydro-2 H ,13 H -1,17-(ethylenediamide)[1,2]oxazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2 H -1,17-(ethylenediamide)[1,2]oxazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(5 H 9 H )-Diketone; [3a(4) Z ]-6,9,12,14,16-pentamethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9,14,16-Tetramethyl-9,10,11,12-Tetrahydro-14 H -1,17-(ethylenedimethyl)pyrazolo[4,3- n Dipyrrolo[3,2-] g :3',4'- j [1,5]Oza-aza-acyclopentadecanyne-3,8(2) H 5 H )-Diketone; [3a(4) Z ]-6,9,14,16-Tetramethyl-10,11,13,14-Tetrahydro-2 H -1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-9,14,16-trimethyl-9,10,11,12-tetrahydro-14 H -1,17-(ethylenedimethyl)pyrazolo[4,3- n Dipyrrolo[3,2-] g :3',4'- j [1,5]Oza-aza-acyclopentadecanyne-3,8(2) H 5 H )-Diketone; [3a(4) Z ]-9,14,16-trimethyl-10,11,13,14-tetrahydro-2 H -1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-12-Ethyl-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9,14-trimethyl-12-(propyl-2-yl)-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-16-Cyclopropyl-6,9-Dimethyl-10,11-Dihydro-2 H ,13 H -1,17-(ethylenediamide)[1,2]oxazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-9,14-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9-Dimethyl-16-(propyl-2-yl)-10,11-dihydro-2 H ,13 H -1,17-(ethylenediamide)[1,2]oxazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-9-Methyl-16-(propyl-2-yl)-10,11-dihydro-2 H ,13 H -1,17-(ethylenediamide)[1,2]oxazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]Ozazane-3,8(5) ... H 9 H )-Diketone; [3a(4) Z ]-6,9,14-trimethyl-9,10,11,12-tetrahydro-14 H -1,17-(ethylenedimethyl)pyrazolo[4,3- n Dipyrrolo[3,2-] g :3',4'- j [1,5]Oza-aza-acyclopentadecanyne-3,8(2) H 5 H )-Diketone; [3a(4) Z ]-9,14-Dimethyl-9,10,11,12-Tetrahydro-14 H -1,17-(ethylenedimethyl)pyrazolo[4,3- n Dipyrrolo[3,2-] g :3',4'- j [1,5]Oza-aza-acyclopentadecanyne-3,8(2) H 5 H )-Diketone; [3a(4) Z ]-6,9,12,14-Tetramethyl-9,10,11,12,13,14-Hexahydro-17,1-(methazine)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(methazine)pyrazolo[4,3- m Dipyrrolo[3,2-] f :3',4'- i [1,4]diazacyclic pentadecylene-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6,9,12,14-Tetramethyl-9,10,11,12,13,14-Hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4- f Dipyrrolo[3,4-] j :2',3'- m [1,4,9]Triazacyclopentadene-3,8(2 H 5 H )-dione; and [3a(4) Z ]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenedimethyl)pyrazolo[3,4- f Dipyrrolo[3,4-] j :2',3'- m [1,4,9]Triazacyclopentadene-3,8(2 H 5 H )-Diketone.

52. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [3a(4)] Z ]-6-methyl-9,10,11,12-tetrahydro-1,18-(ethylenedimethyl)dipyrrolo[3,2- g :3',4'- j [1,5,12]Benzoxadiazazetadecanyne-3,8(2 H 5 H )-Diketone; [3a(4) Z ]-6-methyl-10,11-dihydro-2 H -1,17-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,11]Benzoxadiazazotetradecyne-3,8(5 H 9 H )-Diketone; [3a(4) Z ]-6-methyl-10,11-dihydro-2 H -17,1-(nitromethamine)dipyrrolo[3,2-] f :3',4'- i [1,4]Benzoxaza-tetradecyne-3,8(5) H 9 H )-Diketone; [3a(4) Z ]-16-fluoro-6-methyl-10,11-dihydro-2 H -1,17-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,11]Benzoxadiazazotetradecyne-3,8(5 H 9 H )-Diketone; [3a(4) Z ]-15-Fluoro-6-methyl-10,11-dihydro-2 H -1,17-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,11]Benzoxadiazazotetradecyne-3,8(5 H 9 H )-Diketone; [3a(4) Z ]-14-Fluoro-6-methyl-10,11-dihydro-2 H -1,17-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,11]Benzoxadiazazotetradecyne-3,8(5 H 9 H )-Diketone; [3a(4) Z ]-13-fluoro-6-methyl-10,11-dihydro-2 H -1,17-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,11]Benzoxadiazazotetradecyne-3,8(5 H 9 H )-dione; and [3a(4) Z ]-6,9,12-trimethyl-10,11,12,13-tetrahydro-2 H -1,18-(ethylenedimethyl)dipyrrolo[3,2-] g :3',4'- j [2,5]Benzadioxanepentadecanyne-3,8(5) H 9 H )-Diketone.

53. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [3a(4)] Z ]-6-methyl-10,11-dihydro-2 H -1,17-(ethylenedimethyl)pyrido[3,2-] m Dipyrrolo[3,2-] f :3',4'- i [1,4,11]Ozadiazetacyclotetradecyne-3,8(5 H 9 H )-Diketone; [3a(4) Z ]-6-methyl-10,11-dihydro-2 H -1,17-(ethylenedimethyl)pyrimidino[5,4-] m Dipyrrolo[3,2-] f :3',4'- i [1,4,11]Ozadiazetacyclotetradecyne-3,8(5 H 9 H )-Diketone; [3a(4) Z ]-6,16-dimethyl-10,11-dihydro-2 H -1,17-(ethylenedimethyl)pyrido[3,4-] m Dipyrrolo[3,2-] f :3',4'- i [1,4,11]Ozadiazetacyclotetradecyne-3,8(5 H 9 H )-Diketone; [3a(4) Z ]-6-methyl-9,10,11,12-tetrahydro-14 H -1,18-(ethylenedimethyl)pyrido[2,1- c Dipyrrolo[3,2-] j :3',4'- m [1,4,8]triazacyclotetradecyne-3,8,14(2 H 5 H )-trione; and [3a(4) Z ]-6-methyl-9,10,11,12-tetrahydro-14 H -18,1-(nitromethamine)pyrido[1,2-] e Dipyrrolo[3,4-] i :2',3'- l [1,5]diazacyclic tetradecyne-3,8,14(2 H 5 H )-trione; Or its pharmaceutically acceptable salt.

54. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [3a(4)] Z ,13a R ]-6-methyl-10,11,12,13,13a,14,15,16-octahydro-2 H -18,1-(nitromethamine)tripyrrolo[1,2-] a :3',2'- i :3'',4''- l [1,4,7]Triazacyclopentadecanyne-3,8(5 H 9 H )-Diketone; [3a(4) Z ,13a R ]-6-methyl-9,10,11,12,13,13a,14,15-octahydro-17,1-(nitromethamine)azacyclobutane[1,2- a Dipyrrolo[3,2-] i :3',4'- l [1,4,7]Triazacyclopentadene-3,8(2 H 5 H )-Diketone; [16a(17) Z ]-2,11-dimethyl-6,7,10,11-tetrahydro-1 H 9 H -12,14-(nitromethamine)dipyrrolo[3,4-] g :2',3'- j [1,4,6,13]Oxatriazacyclopentadecanyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-2,5,11-trimethyl-6,7,10,11-tetrahydro-1 H 9 H -12,14-(nitromethamine)dipyrrolo[3,2-] f :3',4'- i [1,4,13]oxadiazacyclopentadecanyne-4,16(5 H 15 H )-Diketone; [17a(18) Z ]-2,12-dimethyl-6,7,9,10,11,12-hexahydro-1 H -13,15-(nitromethamine)dipyrrolo[3,2-] f :3',4'- i [1,4,13]oxadiazazepine-4,17(5) H ,16 H )-Diketone; [17a(18) Z ]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1 H -13,15-(nitromethamine)dipyrrolo[3,2-] f :3',4'- i [1,4,13]oxadiazazepine-4,17(5) H ,16 H )-Diketone; [17a(18) Z ]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1 H -13,15-(nitromethamine)dipyrrolo[3,2-] f :3',4'- i [1,4,11,13]Oxatriazacyclohexadecyne-4,17(5 H ,16 H )-Diketone; [16a(17) Z ]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1 H -12,14-(nitromethamine)dipyrrolo[3,2-] i :3',4'- l [1,4,7]Triazacyclopentadecanyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] k :3',4'- n [1,3,6,9]Tetraazacyclopentadecanyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1 H -12,14-(nitromethamine)dipyrrolo[3,2-] k :3',4'- n [1,3,6,9]Tetraazacyclopentadecanyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-11-Cyclopropyl-2,5-Dimethyl-6,7,8,9,10,11-Hexahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] k :3',4'- n [1,3,6,9]Tetraazacyclopentadecanyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-11-Cyclopropyl-2-methyl-6,7,8,9,10,11-Hexahydro-1 H -12,14-(nitromethamine)dipyrrolo[3,2-] k :3',4'- n [1,3,6,9]Tetraazacyclopentadecanyne-4,16(5 H 15 H )-Diketone; [10 R ,16a(17) Z ]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1 H -12,14-(nitromethamine)dipyrrolo[3,2-] i :3',4'- l [1,4,7]Triazacyclopentadecanyne-4,16(5 H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1 H -12,14-(nitromethamine)dipyrrolo[3,2-] i :3',4'- l [1,4,7]Triazacyclopentadecanyne-4,16(5 H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,5,10-trimethyl-6,7,10,11-tetrahydro-1 H 9 H -12,14-(nitromethamine)dipyrrolo[3,2-] f :3',4'- i [1,4,13]oxadiazacyclopentadecanyne-4,16(5 H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,5,10-trimethyl-6,7,10,11-tetrahydro-1 H 9 H -12,14-(nitromethamine)dipyrrolo[3,4-] g :2',3'- j [1,4,6,13]Oxatriazacyclopentadecanyne-4,16(5 H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1 H -12,14-(nitromethamine)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1 H -12,14-(nitromethamine)dipyrrolo[3,4-] d :2',3'- g [1,13,3,10]dioxadiazazepine-4,16(5) H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,4-] d :2',3'- g [1,13,3,10]dioxadiazazepine-4,16(5) H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(nitromethamine)dipyrrolo[3,4- d :2',3'- g [1,3,10,13]Oxatriazacyclopentadecanyne-4,16(1 H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,4- d :2',3'- g [1,3,10,13]Oxatriazacyclopentadecanyne-4,16(1 H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(nitromethamine)dipyrrolo[3,2- i :3',4'- l [1,4,7]Ozadiazepine-4,16(1 H 15 H )-Diketone; [9 R ,16a(17) Z ]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1 H -12,14-(nitromethamine)dipyrrolo[3,4-] d :2',3'- g [1,13,3,10]dioxadiazazepine-4,16(5) H 15 H )-Diketone; [9 S ,16a(17) Z ]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1 H -12,14-(nitromethamine)dipyrrolo[3,4-] d :2',3'- g [1,13,3,10]dioxadiazazepine-4,16(5) H 15 H )-Diketone; [16a(17) Z ]-2,5-Dimethyl-6,7,9,10-Tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [10 R ,16a(17) Z ]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,10-dimethyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [10 S ,16a(17) Z ]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2- i :3',4'- l [1,4,7]Ozadiazepine-4,16(1 H 15 H )-Diketone; [9 R ,16a(17) Z ]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [9 S ,16a(17) Z ]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [17a(18) Z ]-2-methyl-6,7,10,11-tetrahydro-1 H 9 H -13,15-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,13,4]oxasulfur-nitrogencyclopentadene-4,17(5) H ,16 H )-Diketone; [17a(18) Z ]-2-methyl-6,7,10,11-tetrahydro-1 H -13,15-(ethylenediamine)-12λ 6 -Dipyrrolo[3,2- f :3',4'- i [1,13,4]oxasulfur-nitrogencyclopentadecanyne-4,12,12,17(5 H 9 H ,16 H )-Tetraone; [17a(18) Z ]-2-methyl-6,7,9,10-tetrahydro-1 H ,12 H -13,15-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazonium-hexadecylene-4,17(5 H ,16 H )-Diketone; [12 R ,17a(18) Z ]-2,12-dimethyl-6,7,9,10-tetrahydro-1 H ,12 H -13,15-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazonium-hexadecylene-4,17(5 H ,16 H )-Diketone; [12 S ,17a(18) Z ]-2,12-dimethyl-6,7,9,10-tetrahydro-1 H ,12 H -13,15-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazonium-hexadecylene-4,17(5 H ,16 H )-Diketone; [12 S ,17a(18) Z ]-2,5,12-trimethyl-6,7,9,10-tetrahydro-1 H ,12 H -13,15-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazonium-hexadecylene-4,17(5 H ,16 H )-Diketone; [17a(18) Z ]-2,5-Dimethyl-6,7,11,12-tetrahydro-1 H -13,15-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,14]oxadiazazepine-4,10,17(5 H 9 H ,16 H )-trione; [17a(18) Z ]-2,5-Dimethyl-6,7,11,12-tetrahydro-1 H -13,15-(nitromethamine)dipyrrolo[3,4-] h :2',3'- k [1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5 H 9 H ,16 H )-trione; [17a(18) Z ]-2,5-Dimethyl-6,7,11,12-tetrahydro-1 H -13,15-(nitromethamine)dipyrrolo[3,2-] f :3',4'- i [1,4,14]oxadiazazepine-4,10,17(5 H 9 H ,16 H )-trione; [17a(18) Z ]-2,5-Dimethyl-6,7,11,12-tetrahydro-1 H -13,15-(ethylenedimethyl)dipyrrolo[3,4-] h :2',3'- k [1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5 H 9 H ,16 H )-trione; [12 S ,17a(18) Z ]-2,5,12-trimethyl-6,7,11,12-tetrahydro-1 H -13,15-(ethylenedimethyl)dipyrrolo[3,4-] h :2',3'- k [1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5 H 9 H ,16 H )-trione; [17a(18) Z ]-2-methyl-6,7,11,12-tetrahydro-1 H -13,15-(ethylenedimethyl)dipyrrolo[3,4-] h :2',3'- k [1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5 H 9 H ,16 H )-trione; [17a(18) Z ]-2,11-dimethyl-6,7,11,12-tetrahydro-1 H -13,15-(ethylenedimethyl)dipyrrolo[3,4-] h :2',3'- k [1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5 H 9 H ,16 H )-trione; [17a(18) Z ]-2,11-dimethyl-6,7,11,12-tetrahydro-1 H -13,15-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,14]oxadiazazepine-4,10,17(5 H 9 H ,16 H )-trione; [17a(18) Z ]-2,11-dimethyl-6,7,11,12-tetrahydro-1 H -13,15-(nitromethamine)dipyrrolo[3,4-] h :2',3'- k [1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5 H 9 H ,16 H )-trione; [17a(18) Z ]-2,11-dimethyl-6,7,11,12-tetrahydro-1 H -13,15-(nitromethamine)dipyrrolo[3,2-] f :3',4'- i [1,4,14]oxadiazazepine-4,10,17(5 H 9 H ,16 H )-trione; [18a(19) Z ]-2-methyl-6,7,10,11-tetrahydro-1 H 9 H -14,16-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,15]Ozadiazepine-4,12,18(5) H ,13 H 17 H )-trione; [18a(19) Z ]-2,5-Dimethyl-6,7,10,11-Tetrahydro-1 H 9 H -14,16-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,15]Ozadiazepine-4,12,18(5) H ,13 H 17 H )-trione; [18a(19) Z ]-2,11-dimethyl-6,7,10,11-tetrahydro-1 H 9 H -14,16-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,15]Ozadiazepine-4,12,18(5) H ,13 H 17 H )-trione; [13 S ,18a(19) Z ]-2,13-dimethyl-6,7,10,11-tetrahydro-1 H 9 H -14,16-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,15]Ozadiazepine-4,12,18(5) H ,13 H 17 H )-trione; [13 R ,18a(19) Z ]-2,13-dimethyl-6,7,10,11-tetrahydro-1 H 9 H -14,16-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,15]Ozadiazepine-4,12,18(5) H ,13 H 17 H )-trione; [18a(19) Z ]-2-methyl-6,7,10,11-tetrahydro-1 H 9 H -14,16-(nitromethamine)dipyrrolo[3,4-] i :2',3'- l [1,4,8,15]Oxatriazacycloheptadecyne-4,12,18(5 H ,13 H 17 H )-trione; [13 S ,18a(19) Z ]-2,13-dimethyl-6,7,10,11-tetrahydro-1 H 9 H -14,16-(ethylenedimethyl)dipyrrolo[3,4-] i :2',3'- l [1,4,8,15]Oxatriazacycloheptadecyne-4,12,18(5 H ,13 H 17 H )-trione; [13 S ,18a(19) Z ]-2,13-dimethyl-6,7,10,11-tetrahydro-1 H 9 H -14,16-(nitromethamine)dipyrrolo[3,2-] f :3',4'- i [1,4,15]Ozadiazepine-4,12,18(5) H ,13 H 17 H )-trione; [13 S ,18a(19) Z ]-13-hydroxy-2,13-dimethyl-6,7,10,11-tetrahydro-1 H 9 H -14,16-(ethylenedimethyl)dipyrrolo[3,2-] f :3',4'- i [1,4,15]Ozadiazepine-4,12,18(5) H ,13 H 17 H )-trione; [16a(17) Z ]-2-methyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-19-chloro-2-methyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-19-Chloro-2,5-Dimethyl-6,7,9,10-Tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [7 R ,16a(17) Z ]-19-Chloro-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7] Dioxazonium pentadecylene-7-carboxylate; [7 R ,16a(17) Z ]- N -(azacyclobutane-3-yl)-19-chloro-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazonide-7-carboxamide; [7 R ,16a(17) Z ]-19-Chloro-2,5-Dimethyl-4,16-dioxo- N -(piperidin-4-yl)-4,5,6,7,9,10,15,16-octahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazonide-7-carboxamide; [7 R ,16a(17) Z ]-19-Chloro- N 2,5-Trimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazonide-7-carboxamide; [7 R ,16a(17) Z ]-19-Chloro-2,5-Dimethyl-4,16-dioxo- N -[(3 R )-pyrrolidine-3-yl]-4,5,6,7,9,10,15,16-octahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazonide-7-carboxamide; [7 R ,16a(17) Z ]-19-Chloro- N , N 2,5-Tetramethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazonide-7-carboxamide; [7 R ,16a(17) Z ]-19-Chloro-2,5-dimethyl-7-(4-methylpiperazine-1-carbonyl)-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [10 S ,16a(17) Z ]-19-chloro-2,5,10-trimethyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-19-Chloro-2,5-Dimethyl-6,7,9,10-Tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]Oxythionylene-4,16(5) H 15 H )-Diketone; [16a(17) Z ]-19-chloro-2,5-dimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2- i :3',4'- l [1,4,7]Ozadiazepine-4,16(1 H 15 H )-Diketone; [16a(17) Z ]-19-Chloro-2,5-Dimethyl-6,7,9,10-Tetrahydro-12,14-(ethylenedimethyl)-8λ 6 -Dipyrrolo[3,2- i :3',4'- l [1,4,7]Oxythionylene-4,8,8,16(1 H 5 H 15 H )-Tetraone; [16a(17) Z ]-19-Chloro-2,5-Dimethyl-6,7,9,10-Tetrahydro-12,14-(ethylenedimethyl)-8λ 4 -Dipyrrolo[3,2- i :3',4'- l [1,4,7]Oxythionylene-4,8,16(1 H 5 H 15 H )-trione; [16a(17) Z ]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]Oxythionylene-4,16(5) H 15 H )-Diketone; [16a(17) Z ]-2,5-Dimethyl-6,7,9,10-Tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,4-] g :2',3'- j [1,4,13]oxasulfur-nitrogencyclopentadecanyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-2,5-Dimethyl-6,7-dihydro-1 H 9 H -12,14-(ethylenediamine)-11λ 6 -Dipyrrolo[3,4- g :2',3'- j [1,4,13]oxasulfur-nitrogencyclopentadecanyne-4,11,11,16(5 H 10 H 15 H )-Tetraone; [16a(17) Z ]-5-methyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,4-] g :2',3'- j [1,4,13]oxasulfur-nitrogencyclopentadecanyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)pyrazolo[4,3- i ]pyrrolo[3,4- l [1,4,7]dioxazine-5-decadecyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-19-chloro-5-methyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2- i :3',4'- l [1,4,7]Ozadiazepine-4,16(1 H 15 H )-Diketone; [16a(17) Z ]-19-chloro-2,5,8-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2- i :3',4'- l [1,4,7]Ozadiazepine-4,16(1 H 15 H )-Diketone; [16a(17) Z ]-19-chloro-5,8-dimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenedimethyl)dipyrrolo[3,2- i :3',4'- l [1,4,7]Ozadiazepine-4,16(1 H 15 H )-Diketone; [16a(17) Z ]-2,5-Dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,2-] i :3',4'- l [1,4,7]dioxazonide-19-carboxynitrile; [16a(17) Z ]-19-Chloro-2,5-Dimethyl-6,7,9,10-Tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,4-] g :2',3'- j [1,4,13]oxasulfur-nitrogencyclopentadecanyne-4,16(5 H 15 H )-Diketone; [16a(17) Z ]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1 H -12,14-(ethylenedimethyl)dipyrrolo[3,4-] g :2',3'- j [1,4,13]oxasulfur-nitrogencyclopentadecanyne-4,16(5 H 15 H )-dione; and [16a(17) Z ]-19-chloro-5-methyl-6,7-dihydro-1 H 9 H -12,14-(ethylenediamine)-11λ 6 -Dipyrrolo[3,4- g :2',3'- j [1,4,13]oxasulfur-nitrogencyclopentadecanyne-4,11,11,16(5 H 10 H 15 H )-Tetraone.

55. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

56. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 54 for the manufacture of a medicament for treating cancer in an individual.

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