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 Reference to Related Applications

[0002] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Serial No. 63 / 050,559, filed July 10, 2020, U.S. Provisional Application Serial No. 63 / 143,569, filed January 29, 2021, and U.S. Provisional Application Serial No. 63 / 217,950, filed July 2, 2021, the entire disclosures of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat diseases such as cancer. BACKGROUND

[0004] Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by responding to extracellular and intracellular stimuli to phosphorylate target proteins. 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, degenerative, immune, infectious, inflammatory, and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res., 2003, 36: 462-469). The molecular basis for various diseases includes kinase gain-of-function and loss-of-function mutations, gene amplification and deletion, splicing changes, 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 attractive targets for drug discovery, with 52 small molecule kinase inhibitors approved and 46 of them used for cancer targeted 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 cancer targeted therapies, 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 therapeutic 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 can target kinase oncogenic drivers, but also overcome the most common resistance mutations for better efficacy and longer disease control.

[0005] Non-small cell lung cancer (NSCLC) is a leading cause of cancer death worldwide (World Health Organisation. Cancer Fact Sheet 2017). Activating EGFR mutations have been reported in approximately 10-15% of white patients and 50% of Asian patients with adenocarcinoma cases (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 a short in-frame deletion of 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). The first generation reversible EGFR inhibitors erlotinib and gefitinib are superior to chemotherapy in advanced EGFR mutation-positive (Del19 or L858R) NSCLC patients and have been used as the first-line standard of care in this setting. However, with time on treatment, most patients will develop resistance to gefitinib or erlotinib, with 50-70% of tumors developing the EGFR T790M gatekeeper mutation (Sequist LV, et al. Genotypic and histologicalevolution 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 that also inhibit the ERB family members HER2 and ERB4 (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 Des Devel Ther 2015;9:5641-53). Although afatinib and dacomitinib are more potent EGFR inhibitors than gefitinib and erlotinib, approved as first-line therapy for advanced EGFR mutation-positive (Del19 or L858R) NSCLC with longer progression-free survival (PFS), EGFR T790M has been acquired during treatment with afatinib (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 confers 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, which targets both EGFR activating mutations (Del 19 and L858R) and the T790M resistance double mutation with selectivity over wild-type EGFR (Finlay MR, et al. 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. J Med Chem 2014;57:8249-67). Osimertinib was first approved for metastatic EGFR T790M mutation-positive NSCLC patients after failure of first-line EGFR inhibitors, and subsequently approved for first-line treatment of EGFR mutation-positive NSCLC patients after the phase III FLAURA trial and head-to-head trial compared with erlotinib or gefitinib (Soria JC, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113-25). Mutations C797S have been detected in osimertinib-resistant patients at the EGFR covalent binding residue with irreversible EGFR inhibitor osimertinib (Ramalingam SS, et al. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Presented at ESMO, 2018).

[0008] Genetic alterations that transfect the rearranged (RET) gene occur in different 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. Nat Rev Clin Oncol. 2018; 15: 151-167). Multiple kinase inhibitors, lenvatinib, sorafenib, and cabozantinib, are approved for certain thyroid cancers. Recently, the highly selective RET inhibitors selpercatinib and pralsetinib were approved for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced / metastatic RET-altered medullary thyroid cancer (MTC), and papillary thyroid cancer (PTC). Acquired resistance RET mutations following treatment with multiple kinase inhibitors or selective RET inhibitors from RET mutant patients or cell lines have been reported, including gatekeeper 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. 2020 Nov 5. S0923-7534(20)43127-8). Acquired compound mutations, such as RET M918T / V804M, M918T / V804M / G810C, V804M / G810C, or other combinations, can make it difficult to treat in the clinic with current multiple kinase and selective RET inhibitors under sequential treatment with multiple RET inhibitors. Therefore, it is necessary to develop a new generation of RET inhibitors that can target primary and secondary RET mutations in RET mutant patients treated with or without approved RET inhibitors.

[0009] Chronic myeloid leukemia (CML) is characterized by the Philadelphia (Ph) chromosome, which results from a t(9;22)(q34;q11) reciprocal translocation, leading to the creation of the BCR-ABL oncogene that 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 tyrosine kinase inhibitor approved and has revolutionized the treatment and outcome of CML patients. However, mutations in the BCR-ABL1 kinase domain confer resistance to imatinib therapy. Over 50 mutation sites and over 70 individual mutations that confer varying levels of resistance have been found in CML patients (Apperley J: Part I: Mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007, 8: 1018-1029). Although more potent second-generation BCR-ABL1 inhibitors have been approved, none of them are effective against all imatinib resistance mutations. Y253H, E255V, F359V, and Q252H have moderate resistance to nilotinib, E255V, F317L, Q252H have moderate resistance to dasatinib, and T315I has resistance to nilotinib, dasatinib, and bosutinib (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, however, it is not effective against T315L and T315M.Multiple compound mutations following sequential treatment with multiple BCR-ABL1 inhibitors present new challenges for 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 wide prescribing of 2ndor 3rdgeneration BCR-ABL1 inhibitors is hampered by their toxicities. Thus, there is a need to develop a new generation of 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 or precursor cells and plays an important role in early stages of myeloid and lymphoid lineage development. FLT3 mutations are found in approximately 30% of newly diagnosed AML cases and occur in the form of internal tandem duplications (ITD) (~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 proliferation and survival of AML. The multiple kinase inhibitor midostaurin is approved in combination with induction chemotherapy for first-line treatment of FLT3-mutated (ITD or TKD) AML patients, and the second-generation selective FLT3 inhibitor gilteritinib as a single agent is approved for relapsed or refractory FLT3-mutated AML patients. Despite encouraging results with FLT3 inhibitor-based therapies, many patients still fail to respond to FLT3 inhibitor therapy or subsequently relapse. One mechanism of resistance is the occurrence of secondary mutations in the FLT3 kinase domain, including mutations at activating residues (e.g., D835, 1836, D839, Y842) or gatekeeper residues (e.g., F691) (Short NJ, et al. Advances in the Treatment of Acute Myeloid Leukemia: New Drugs and New Challenges. Cancer Discov. 2020 Apr;10(4):506-525). Thus, there is a need to develop a new generation of FLT3 inhibitors that can target both primary and secondary FLT3 mutations in FLT3-mutated cancer patients treated with or without approved FLT3 inhibitors.

[0011] Gastrointestinal stromal tumors (GIST) are interstitial tumors of the gastrointestinal tract and account for 18% of all human sarcomas (Corless CL, et al. Gastrointestinal stromal tumors: Origin and molecular oncology. Nat Rev Cancer. 2011, 11:865-878). Gain-of-function mutations in the KIT or PDGFRA receptor tyrosine kinases have been characterized as oncogenic driver mutations in approximately 80-90% of GIST (O'Brien KM, et al. Gastrointestinal stromal tumors, somatic mutations and candidate genetic risk variants. PLoS One. 8: e621192013). The KIT and PDGFRA inhibitor imatinib has been approved as first-line therapy for GIST patients with unresectable, recurrent or metastatic disease, with the exception of patients with PDGFRA D842V mutations. Most patients with initial clinical benefit from imatinib eventually progress after 20-24 months of treatment (Blanke, C.D., 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. J. Clin. Oncol. 2008, 26, 620-625).As tumor subclones with heterogenous secondary KIT mutations reactivate KIT signaling, oncogenic activation of 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 tumours. 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- and third-line therapies, respectively. Thus, there is a need to develop a new generation of KIT and / or PDGFRA inhibitors that can target primary and the full spectrum of secondary mutations for GIST patients treated with or without approved KIT and / or PDGFR inhibitors.

[0012] Overall, there is an urgent need to develop next-generation kinase inhibitors that can target primary mutations and clinically emerging secondary mutations to achieve better efficacy and longer treatment duration as first-line therapy, or to overcome drug resistance mutations in refractory patients. For example, there is a need to develop a new generation of 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 against wild-type EGFR. SUMMARY

[0013] In one aspect, the disclosure relates to a compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0014]

[0015] wherein

[0016] A is 5- to 10-membered heteroarylene or C6-C 10 arylene;

[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 proviso that (L) n does not contain -O-O-, -O-S-, or -O-N(R 5 )-bond;

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

[0019] X 1 is N or C(R 7 );

[0020] X 2 is N or C(R 8 );

[0021] X 3 is N or C(R 9 );

[0022] X 4 is N or C(R 10 );

[0023] Y and Y 1 are each independently O or S;

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

[0025] Z is 3- to 7-membered heterocycloalkylene, C3-C6cycloalkylene, C6-C 10 arylene, 5- to 10-membered heteroarylene, -C(R 12 )(R 13 )-, -C(O)-, -O-, -N(R 14 )-, -S-, -S(O)-, or -S(O)2-, wherein each hydrogen atom of the 3- to 7-membered heterocycloalkylene, C 3- C6cycloalkylene, C6-C 10 arylene, and 5- to 10-membered heteroarylene is independently optionally substituted with deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 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 , -SRe -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;

[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-C10 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: 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 Rf -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)Re -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;

[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 Rd -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 two of R 10 each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3 to 7 membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -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;

[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 is 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 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 an aryl or 5- to 10-membered heteroaryl group is independently 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; the limiting condition is that R 7 or R 8 One of them is the Z-bond;

[0032] 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 Rb -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 eR 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.

[0033] each R a , R b , R c , R d , R e and R f is independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3 to 7 membered 10 heterocycloalkyl, C6-C10aryl, C1-C6alkyl-C6-C10aryl, and 5- to 10-membered heteroaryl; 10

[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, the present disclosure provides a compound of Formula II, or a pharmaceutically acceptable salt thereof,

[0037]

[0038] wherein 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 herein.

[0039] In some embodiments, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt thereof,

[0040] ​

[0041] wherein 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 herein.

[0042] In some embodiments, the present disclosure provides a compound of Formula IV, or a pharmaceutically acceptable salt thereof,

[0043]

[0044] wherein 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 herein.

[0045] In some embodiments, the present disclosure provides a compound of Formula V, or a pharmaceutically acceptable salt thereof,

[0046]

[0047] wherein 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 herein.

[0048] In some embodiments, the present disclosure provides a compound of Formula VI, or a pharmaceutically acceptable salt thereof,

[0049]

[0050] wherein 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 herein.

[0051] In some embodiments, the present disclosure provides a compound of Formula VII, or a pharmaceutically acceptable salt thereof,

[0052]

[0053] wherein 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 herein.

[0054] In some embodiments, the present disclosure provides a compound of Formula VIII, or a pharmaceutically acceptable salt thereof,

[0055]

[0056] wherein 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 herein.

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

[0059] In some aspects of the embodiments herein, the compound is not a compound wherein ring B(Z) is and R 9 and / or R 10 is not H. In some embodiments, the compound is not a compound wherein ring B(Z) is and R 9 and / or R 10 is not H. In some aspects of the embodiments herein, the compound is not a compound wherein X 1 is C(R 7 ), X 3 is C(R 9 ), X4 is C(R 10 ), R 9 and / or R 10 is not H, and ring B(Z) is In some aspects of the embodiments herein, the compound is not a compound wherein X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), R 9 and / or R 10 is not H, and ring B(Z) is In some aspects of the embodiments herein, the compound is not a compound wherein X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), R 9 and / or R 10 is -Cl, and ring B(Z) is In some aspects of the embodiments herein, the compound is not a compound wherein X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), R 9 and / or R 10 is -Cl, and ring B(Z) is In some aspects of the embodiments herein, X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), and R 9 and / or R 10 is not -Cl. In some embodiments, X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), R 9 and / or R 10 is not -Cl, and ring B(Z) is not In some aspects of the embodiments herein, X 1 is C(R7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), R 9 and / or R 10 is not -CI, and ring B(Z) is not

[0060] In certain embodiments of the above aspects, the compound of Formula (I)-(VIII) is a compound selected from those described or exemplified in the following embodiments.

[0061] In other aspects, the 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 the disclosure can additionally comprise a pharmaceutically acceptable excipient.

[0062] In other aspects, the disclosure relates to a compound of Formula (I)-(VIII), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0063] In other aspects, the 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 aspects, the disclosure relates to the use of a compound of Formula (I)-(VIII), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease, such as cancer, and the use of such compounds and salts for the treatment of such diseases.

[0065] In other aspects, the disclosure relates to a method of inhibiting a tyrosine kinase, such as EGFR, comprising contacting a cell comprising 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 the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.

[0066] Other embodiments, features, and advantages of the disclosure will be apparent from the following embodiments and from the practice of the disclosure. The compounds of the disclosure can be described as examples in any of the following enumerated clauses. It will be appreciated that any embodiment described herein can be used in combination with any other embodiment described herein to the extent that the described embodiments do not contradict each other.

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

[0068]

[0069] wherein

[0070] A is 5- to 10-membered heteroarylene or C6-C 10 arylene;

[0071] each L is independently -C(R 3 )(R 4 )-, -C(O)-, -O-, -N(R 5 )-, -S-, -S(O)-, or -S(O)2-, provided that (L) n does not contain an -O-O-, -O-S-, or -O-N(R 5 )- bond;

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

[0073] X 1 is N or C(R 7 );

[0074] X 2 is N or C(R 8 );

[0075] X 3 is N or C(R 9 );

[0076] X 4 is N or C(R 10 );

[0077] Y and Y 1 are each independently O or S;

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

[0079] Z is 3- to 7-membered heterocycloalkylene, C3-C6cycloalkylene, C6-C 10 arylene, 5- to 10-membered heteroarylene, -C(R 12 )(R 13 )-, -C(O)-, -O-, -N(R 14 )-, -S-, -S(O)-, or -S(O)2-, wherein each hydrogen atom in the 3- to 7-membered heterocycloalkylene, C3-C6cycloalkylene, C6-C 10 arylene, and 5- to 10-membered heteroarylene is independently optionally substituted with deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 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;

[0080] Z 1 is -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 is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3 to 7 membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -OR 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: 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;

[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)NRe 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 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)Rd ), -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 two of which, together with the carbon(s) to which they are attached, form a C3-C6cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -OR 10 , -OC(O)R e , -OC(O)NR e R e , -OS(O)R f , -OS(O)2R e , -OS(O)NR 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;

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

[0085] R 7 and R 8each independently a bond to Z, H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -OR 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 each hydrogen atom of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3 to 7 membered 10 heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -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; 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 -PRa 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 , -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 is independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3 to 7 membered 10 heterocycloalkyl, C6-C10aryl, C1-C6alkyl-C6-C10aryl, and 5- to 10-membered heteroaryl; 10

[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 of clause 1, having Formula IV

[0091]

[0092] or a pharmaceutically acceptable salt thereof.

[0093] 3. The compound of clause 1, having Formula VI

[0094]

[0095] or a pharmaceutically acceptable salt thereof.

[0096] ​4. The compound of any one of clauses 1 to 3, or a pharmaceutically acceptable salt thereof, wherein A is phenylene, furanylene, thienylene, pyrrolylene, oxazolyiene, isoxazolyiene, thiazolyiene, isothiazolyiene, pyrazolyiene, imidazolyiene, oxadiazolyiene, thiadiazolyiene, triazolyiene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or pyrazinylene.

[0097] 5. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein A is pyrrolylene.

[0098] 6. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein A is wherein R 1a is C1-C6 alkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b , or -P(O)2OR a , wherein each hydrogen atom in C1-C6 alkyl is independently 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)NRe R f R 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.

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

[0100] 8. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, each R 1 is -CN or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently 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 of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, each R 1 is -CN or methyl.

[0102] 10. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, R 1a is methyl.

[0103] 11. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 2 is H or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently 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 , -SRe -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 of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 2 is H or methyl.

[0105] 13. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z is 5- or 6-membered heteroarylene, wherein each hydrogen atom in the 5- or 6-membered heteroarylene is independently optionally substituted with deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -OR e -OC(O)R e -OC(O)NR eR 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. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z is pyrazylenyl, oxazolylenyl, thiazolylenyl, pyridylenyl, pyrimidylenyl, or pyridin-2-onylenyl, wherein each hydrogen atom in the pyrazylenyl, oxazolylenyl, thiazolylenyl, pyridylenyl, pyrimidylenyl, or pyridin-2- onylenyl is independently optionally substituted with deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -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.

[0107] 15. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z is or Z is not or Z is not

[0108] 16. The compound of any one of Clauses 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Z is C6-C 10 arylene, wherein each hydrogen atom in the C6-C 10 C6 arylene is independently 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 eS(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. The compound of any one of clauses 1 to 12 or 16, or a pharmaceutically acceptable salt thereof, wherein Z is phenylene, wherein each hydrogen atom in the phenylene is independently optionally substituted with deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -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.

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

[0111] 19. The compound of any one of clauses 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Z is 3- to 7-membered heterocycloalkylene, wherein each hydrogen atom of the 3- to 7-membered heterocycloalkylene is independently optionally substituted with deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -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 eC(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.

[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 ketone group or a zazonyl butyl group, wherein each hydrogen atom in the pyridine ketone group and the zazonyl butyl 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 -NRe 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.

[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 R13 with the carbon to which it is attached to form a C3-C6cycloalkyl or 4- to 6- membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6cycloalkyl or 4- to 6- membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -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)ORe , -P(O)2OR e , -CN or -NO2.

[0116] 24. The compound of any one of the preceding clauses, wherein R 12 is H and R 13 is methyl.

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

[0118] 26. The compound of any one of the preceding clauses, wherein R 12 and R 13 are H.

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

[0120] 28. The compound of any one of the preceding clauses, wherein R 12 is -OH and R 13 is methyl.

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

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

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

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

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

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

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

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

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

[0130] 38. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 6.

[0131] 39. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 7.

[0132] 40. The compound of any one of the preceding clauses, 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-.

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

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

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

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

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

[0138] 46. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein X 1 , when present, and X 3 is N.

[0139] 47. The compound of any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, wherein X 1 , when present, and X 4 is N.

[0140] 48. The compound of any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, wherein X 3 and X 4 is N.

[0141] 49. The compound of any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, wherein X 1 is N when present.

[0142] 50. The compound of any one of clauses 1 to 45, or a pharmaceutically acceptable salt thereof, wherein X 2 is N when present.

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

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

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

[0146] 54. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein C(R 7 ) is, independently when present, H, deuterium, fluoro, chloro, -CN, or methyl.

[0147] 55. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein C(R 8 ) is, independently when present, H, deuterium, fluoro, chloro, -CN, or methyl.

[0148] 56. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein C(R 9 ) is, independently when present, H, deuterium, fluoro, chloro, -CN, or methyl.

[0149] 57. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein C(R 10 ) is, independently when present, H.

[0150] 58. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein -(L) n-(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -C(0)NH-(CH2)20(CH2)2-, -C(0)N(CH3)-(CH2)20(CH2)2-, -NHC(0)CH20(CH2)2-, -N(CH3)-C(0)CH20(CH2)2-, -CH20(CH2)2-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, -0(CH2)2S(CH2)2-, -(CH2)2S02(CH2)2-, -0(CH2)2S02(CH2)2-, -(CH2)2SO(CH2)2-, -0(CH2)2SO(CH2)2-, -(CH2)20(C(H)(C(0)N(H)(azetidin-3-yl))-CH2-, -(CH2)20(C(H)(C(0)N(H)(CH3))-CH2-, -(CH2)20(C(H)(C(0)N(CH3)2)-CH2-, -(CH2)20(C(H)(C(0)N(H)(piperidin-4-yl))-CH2-, -(CH2)20(C(H)(C(0)N(H)(pyrrolidin-3-yl))-CH2-, -(CH2)20(C(H)(C(0)N(H)(4-methylpiperazin-1-yl))-CH2-, -(CH2)20(C(H)(C(0)OCH3)-CH2-, -(CH2)30(CH2)2-, -(CH2)20(CH2)3-, -CH2CH(CH3)-0(CH2)2-, -CH(CH3)-CH20(CH2)2-, -0(CH2)2-, -0-(CH2)3-, -OCH20(CH2)2-, -0-CH2CH(OH)CH2-, -0-(CH2)20(CH2)2-, -0-CH2CH(CH3)-0(CH2)2-, -0-CH(CH3)-CH20(CH2)2-, -0-(CH2)2NH-(CH2)2-, -0-CH2CH(CH3)-NH-(CH2)2-, -0-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -0-(CH2)2N(CH3)-(CH2)2-, -0-CH2CH(CH3)-N(CH3)-(CH2)2-, -0-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 -0-CH(CH3)-CH2N(CH3)-(CH2)2-.

[0151] 59. The compound of clause 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [3a(4)Z]-10,11-Dihydro-2H,13H-16,l-(hydrazono)methyl)pyrazolo[4,3- m]pyrrolo[3,2-f:3',4'-i][l,4,l l]oxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0152] [3a(4)Z]-9,10,11,12-Tetrahydro-14H-l,17-(hydrazono)methyl)pyrazolo[3,4- b]pyrrolo[3,4-f:2',3'-i][l,5,12]oxadiazacyclopentadecine-3,8(2H,5H)-dione;

[0153] [3a(4)Z]-9,10,11,12-Tetrahydro-14H-l,17-(hydrazono)methyl)pyrazolo[3,4- b]pyrrolo[3,4-f:2',3'-i][l,5,12]oxadiazacyclopentadecine-3,8(2H,5H)-dione;

[0154] [3a(4)Z]-9,10,11,12-Tetrahydro-14H-l,17-(hydrazono)methyl)pyrazolo[3,4- b]pyrrolo[3,4-f:2',3'-i][l,5,12]oxadiazacyclopentadecine-3,8(2H,5H)-dione;

[0155] [3a(4)Z]-9,10,11,12-Tetrahydro-14H-l,17-(hydrazono)methyl)pyrazolo[3,4- b]pyrrolo[3,4-f:2',3'-i][l,5,12]oxadiazacyclopentadecine-3,8(2H,5H)-dione;

[0156] [3a(4)Z]-9,10,11,12-Tetrahydro-14H-l,17-(hydrazono)methyl)pyrazolo[3,4- b]pyrrolo[3,4-f:2',3'-i][l,5,12]oxadiazacyclopentadecine-3,8(2H,5H)-dione;

[0157] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3-n]dipyrrrolo[3,2- g:3',4'-j][1,5]oxazapentacine-3,8(2H,5H)-dione;

[0158] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3-n]dipyrrrolo[3,2- g:3',4'-j][1,5]oxazapentacine-3,8(2H,5H)-dione;

[0159] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3-n]dipyrrrolo[3,2- g:3',4'-j][1,5]oxazapentacine-3,8(2H,5H)-dione;

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

[0161] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3-n]dipyrrrolo[3,2- g:3',4'-j][1,5]oxazapentacine-3,8(2H,5H)-dione;

[0162] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3-n]dipyrrrolo[3,2- g:3',4'-j][1,5]oxazapentacine-3,8(2H,5H)-dione;

[0163] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3-n]dipyrrrolo[3,2- g:3',4'-j][1,5]oxazapentacine-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-(ethenediyl)[1,2]oxazolo[3,4-b]dipyrrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadeca-3,8(2H,5H)-dione;

[0172] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethenediyl)pyrazolo[5,1-c]dipyrrrolo[3,2-j:3',4'-m][1,4,8]triazacyclotetradeca-3,8(2H,5H)-dione;

[0173] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-17,1-(nitrilomethylidenyl)pyrazolo[1,5-e]dipyrrrolo[3,4-i:2',3'-l][1,5]diazacyclotetradecine-3,8(2H,5H)-dione;

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

[0175] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(nitrilomethylidenyl)pyrazolo[1,5-d]dipyrrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecine-4,19(5H,18H)-dione;

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

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

[0178] [10R, 19a(20)Z]-2, 10-dimethyl-6, 7, 9, 10-tetrahydro-lH-15, 17- (ethenediyl) pyrazolo [1, 5-d] dipyrrrolo [3, 4-h: 2', 3'-k] [1, 4, 14] oxadiazacyclohexadecine-4, 19(5H, 18H)-dione;

[0179] [19a(20)Z]-2, 5-dimethyl-6, 7, 9, 10-tetrahydro-lH-15, 17- (ethenediyl) pyrazolo [1, 5-d] dipyrrrolo [3, 4-h: 2', 3'-k] [1, 4, 14] oxadiazacyclohexadecine-4, 19(5H, 18H)-dione;

[0180] [19a(20)Z]-2, 5-dimethyl-6, 7, 9, 10-tetrahydro-lH-15, 17- (ethenediyl) pyrazolo [1, 5-d] dipyrrrolo [3, 4-h: 2', 3'-k] [1, 4, 14] oxadiazacyclohexadecine-4, 19(5H, 18H)-dione;

[0181] [19a(20)Z]-2, 5-dimethyl-6, 7, 9, 10-tetrahydro-lH-15, 17- (ethenediyl) pyrazolo [1, 5-d] dipyrrrolo [3, 4-h: 2', 3'-k] [1, 4, 14] oxadiazacyclohexadecine-4, 19(5H, 18H)-dione;

[0182] [19a(20)Z]-2, 5-dimethyl-6, 7, 9, 10-tetrahydro-lH-15, 17- (ethenediyl) pyrazolo [1, 5-d] dipyrrrolo [3, 4-h: 2', 3'-k] [1, 4, 14] oxadiazacyclohexadecine-4, 19(5H, 18H)-dione;

[0183] [3a(4)Z]-6-methyl-10, 11, 13, 14-tetrahydro-2H-l, 17- (ethenediyl) pyrazolo [4, 3-m] dipyrrrolo [3, 2-f: 3', 4'-i] [1, 4, 11] oxadiazacyclopentadecine-3, 8(5H, 9H)-dione;

[0184] [3a(4)Z]-6-methyl-10, 11, 13, 14-tetrahydro-2H-l, 17- (ethenediyl) pyrazolo [4, 3-m] dipyrrrolo [3, 2-f: 3', 4'-i] [1, 4, 11] oxadiazacyclopentadecine-3, 8(5H, 9H)-dione;

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

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

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

[0188] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(nitrilomethylidenyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][1,4,9]triazapentacine-3,8(2H,5H)-dione;

[0189] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][1,4,9]triazapentacine-3,8(2H,5H)-dione;

[0190] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(nitrilomethylidenyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][1,4]diazapentacine-3,8(2H,5H)-dione;

[0191] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(nitrilomethylidenyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][1,4,9]triazapentacine-3,8(2H,5H)-dione;

[0192] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecine-3,8(2H,5H)-dione;

[0193] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecine-3,8(2H,5H)-dione;

[0194] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecine-3,8(2H,5H)-dione;

[0195] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecine-3,8(2H,5H)-dione;

[0196] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecine-3,8(2H,5H)-dione;

[0197] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecine-3,8(2H,5H)-dione;

[0198] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecine-3,8(2H,5H)-dione;

[0199] [3a(4)Z]-6, 16-dimethyl-9, 10, 11, 12, 13, 14-hexahydro-17, 1- (hydrazono-methyl) pyrazolo[4, 3-m]dipyrrrolo[3, 2-f: 3', 4'-i] [1, 4] diazacyclopentadecine-3, 8(2H, 5H)-dione;

[0200] [3a(4)Z]-6, 9, 16-trimethyl-9, 10, 11, 12, 13, 14-hexahydro-17, 1- (hydrazono-methyl) pyrazolo[4, 3-m]dipyrrrolo[3, 2-f: 3', 4'-i] [1, 4] diazacyclopentadecine-3, 8(2H, 5H)-dione;

[0201] [3a(4)Z]-16-cyclopropyl-6, 9-dimethyl-9, 10, 11, 12, 13, 14-hexahydro-17, 1- (hydrazono-methyl) pyrazolo[4, 3-m]dipyrrrolo[3, 2-f: 3', 4'-i] [1, 4] diazacyclopentadecine-3, 8(2H, 5H)-dione;

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

[0203] [3a(4)Z]-6, 9, 16-trimethyl-10, 11, 12, 13-tetrahydro-2H-17, 1- (hydrazono-methyl) [1, 2]oxazolo[4, 5-m]dipyrrrolo[3, 2-f: 3', 4'-i] [1, 4] diazacyclopentadecine-3, 8(5H, 9H)-dione;

[0204] [3a(4)Z]-6, 9, 16-trimethyl-10, 11, 12, 13-tetrahydro-2H-17, 1- (hydrazono-methyl) [1, 2]oxazolo[4, 3-m]dipyrrrolo[3, 2-f: 3', 4'-i] [1, 4] diazacyclopentadecine-3, 8(5H, 9H)-dione;

[0205] [3a(4)Z]-6, 14-dimethyl-10, 11, 13, 14-tetrahydro-2H-17, 1- (hydrazono-methyl) pyrazolo[4, 3-m]dipyrrrolo[3, 2-f: 3', 4'-i] [1, 4] oxazadiazacyclopentadecine-3, 8(5H, 9H)-dione;

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

[0207] [3a(4)Z]-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][1,4]diazapentacine-3,8(2H,5H)-dione;

[0208] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][1,4]diazapentacine-3,8(2H,5H)-dione;

[0209] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][1,4]diazapentacine-3,8(2H,5H)-dione;

[0210] [3a(4)Z]-6,9,16-trimethyl-10,11-dihydro-2H,13H-1,17-(ethenediyl)[1,2]oxazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][1,4]oxazapentacine-3,8(5H,9H)-dione;

[0211] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-1,17-(ethenediyl)[1,2]oxazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][1,4]diazapentacine-3,8(5H,9H)-dione;

[0212] [3a(4)Z]-6,9,12,14,16-pentamethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][1,4]diazapentacine-3,8(2H,5H)-dione;

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

[0214] [3a(4)Z]-6,9,14,16-tetramethyl-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3- n]pyrrolo[3,2-g:3',4'-j][1,5]oxazadiazacyclopentadeca-3,8(2H,5H)-dione;

[0215] [3a(4)Z]-6,9,14,16-tetramethyl-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3- n]pyrrolo[3,2-g:3',4'-j][1,5]oxazadiazacyclopentadeca-3,8(2H,5H)-dione;

[0216] [3a(4)Z]-6,9,14,16-tetramethyl-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3- n]pyrrolo[3,2-g:3',4'-j][1,5]oxazadiazacyclopentadeca-3,8(2H,5H)-dione;

[0217] [3a(4)Z]-6,9,14,16-tetramethyl-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3- n]pyrrolo[3,2-g:3',4'-j][1,5]oxazadiazacyclopentadeca-3,8(2H,5H)-dione;

[0218] [3a(4)Z]-6,9,14,16-tetramethyl-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3- n]pyrrolo[3,2-g:3',4'-j][1,5]oxazadiazacyclopentadeca-3,8(2H,5H)-dione;

[0219] [3a(4)Z]-6,9,14,16-tetramethyl-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3- n]pyrrolo[3,2-g:3',4'-j][1,5]oxazadiazacyclopentadeca-3,8(2H,5H)-dione;

[0220] [3a(4)Z]-9, 14-dimethyl-9, 10, 11, 12, 13, 14-hexahydro-l, 17-(ethenediyl) pyrazolo[4, 3-m]dipyrrrolo[3, 2-f:3', 4'-i][l, 4]diazacyclopentadeca-3, 8(2H, 5H)-dione;

[0221] [3a(4)Z]-6, 9-dimethyl-16-(propan-2-yl)-10, 11-dihydro-2H, 13H-l, 17-(ethenediyl)[l, 2]oxazolo[4, 3-m]dipyrrrolo[3, 2-f:3', 4'-i][l, 4]oxazacyclopentadeca-3, 8(5H, 9H)-dione;

[0222] [3a(4)Z]-9-methyl-16-(propan-2-yl)-10, 11-dihydro-2H, 13H-l, 17-(ethenediyl)[l, 2]oxazolo[4, 3-m]dipyrrrolo[3, 2-f:3', 4'-i][l, 4]oxazacyclopentadeca-3, 8(5H, 9H)-dione;

[0223] [3a(4)Z]-6, 9, 14-trimethyl-9, 10, 11, 12-tetrahydro-14H-l, 17-(ethenediyl)pyrazolo[4, 3-n]dipyrrrolo[3, 2-g:3', 4'-j][l, 5]oxazacyclopentadeca-3, 8(2H, 5H)-dione;

[0224] [3a(4)Z]-9, 14-dimethyl-9, 10, 11, 12-tetrahydro-14H-l, 17-(ethenediyl)pyrazolo[4, 3-n]dipyrrrolo[3, 2-g:3', 4'-j][l, 5]oxazacyclopentadeca-3, 8(2H, 5H)-dione;

[0225] [3a(4)Z]-6, 9, 12, 14-tetramethyl-9, 10, 11, 12, 13, 14-hexahydro-17, 1-(nitrilo- methylene)pyrazolo[4, 3-m]dipyrrrolo[3, 2-f:3', 4'-i][l, 4]diazacyclopentadeca-3, 8(2H, 5H)-dione;

[0226] [3a(4)Z]-9, 12, 14-trimethyl-9, 10, 11, 12, 13, 14-hexahydro-17, 1-(nitrilo- methylene)pyrazolo[4, 3-m]dipyrrrolo[3, 2-f:3', 4'-i][l, 4]diazacyclopentadeca-3, 8(2H, 5H)-dione;

[0227] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-l,17-(ethenediyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][l,4,9]triazacyclopentadecine-3,8(2H,5H)-dione; and

[0228] [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-l,17-(ethenediyl)pyrazolo[3,4- f]dipyrrrolo[3,4-j:2',3'-m][l,4,9]triazacyclopentadecine-3,8(2H,5H)-dione.

[0229] 60. The compound of clause 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-l,18-(ethenediyl)dipyrrrolo[3,2-g:3',4'- j][l,5,12]benzoxadiazacyclopentadecine-3,8(2H,5H)-dione;

[0230] [3a(4)Z]-6-methyl-10,11-dihydro-2H-l,17-(ethenediyl)dipyrrrolo[3,2-f:3',4'-i][l,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0231] [3a(4)Z]-6-methyl-10,11-dihydro-2H-l,17-(ethenediyl)dipyrrrolo[3,2-f:3',4'-i][l,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0232] [3a(4)Z]-6-methyl-10,11-dihydro-2H-l,17-(ethenediyl)dipyrrrolo[3,2-f:3',4'-i][l,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0233] [3a(4)Z]-6-methyl-10,11-dihydro-2H-l,17-(ethenediyl)dipyrrrolo[3,2-f:3',4'-i][l,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0234] [3a(4)Z]-6-methyl-10,11-dihydro-2H-l,17-(ethenediyl)dipyrrrolo[3,2-f:3',4'-i][l,4,11]benzoxadiazacyclotetradecine-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 tetradecyne-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 of clause 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-(nitrilomethylidenyl)tripyrrolo[1,2-a:3',2'-i:3",4"-l][1,4,7]triazacyclopentadecine-3,8(5H,9H)-dione;

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

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

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

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

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

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

[0250] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(ethenediyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetradecapenta ine-4,16(5H,15H)-dione;

[0251] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(ethenediyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetradecapenta ine-4,16(5H,15H)-dione;

[0252] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(ethenediyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetradecapenta ine-4,16(5H,15H)-dione;

[0253] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(ethenediyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetradecapenta ine-4,16(5H,15H)-dione;

[0254] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(ethenediyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetradecapenta ine-4,16(5H,15H)-dione;

[0255] [10R, 16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(ethenediyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetradecapenta ine-4,16(5H,15H)-dione;

[0256] [10S, 16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(ethenediyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetradecapenta ine-4,16(5H,15H)-dione;

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

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

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

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

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

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

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

[0264] [10S, 16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14- (nitrilomethylidenyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]oxadiazacyclopentadeca-4,16(lH, 15H)-dione;

[0265] [9R, 16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-lH-12,14- (nitrilomethylidenyl)dipyrrrolo[3,4-d:2',3'-g][l,13,3,10]dioxadiazacyclopenta-4,16(5H, 15H)-dione;

[0266] [9S, 16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-lH-12,14- (nitrilomethylidenyl)dipyrrrolo[3,4-d:2',3'-g][l,13,3,10]dioxadiazacyclopenta-4,16(5H, 15H)-dione;

[0267] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopenta-4,16(5H, 15H)-dione;

[0268] [10S, 16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopenta-4,16(5H, 15H)-dione;

[0269] [10R, 16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopenta-4,16(5H, 15H)-dione;

[0270] [10S, 16a(17)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopenta-4,16(5H, 15H)-dione;

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

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

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

[0274] [17a(18)Z]-2-methyl-6,7,10,l l-tetrahydro-lH,9H-13,15- (ethenediyl)dipyrrolo[3,2-f:3',4'-i][l,13,4]oxathiazacyclopentadecine-4,17(5H, 16H)-dione;

[0275] [17a(18)Z]-2-methyl-6,7,10,l l-tetrahydro-lH-13,15- (ethenediyl)dipyrrolo[3,2-f:3',4'-i][l,13,4]oxathiazacyclopentadecine-4,12,12,17(5H, 9H, 16H)-tetraone;

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

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

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

[0279] [12S, 17a(18)Z]-2, 12-dimethyl-6, 7, 9, 10-tetrahydro-lH, 12H-13, 15- (ethenediyl)dipyrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclohexadecine-4, 17(5H, 16H)- dione;

[0280] [17a(18)Z]-2, 5-dimethyl-6, 7, 11, 12-tetrahydro-lH-13, 15- (ethenediyl)dipyrrolo[3,2-f:3',4'-i][l,4,14]oxadiazacyclohexadecine-4, 10, 17(5H, 9H, 16H)-trione;

[0281] [17a(18)Z]-2, 5-dimethyl-6, 7, 11, 12-tetrahydro-lH-13, 15- (ethenediyl)dipyrrolo[3,2-f:3',4'-i][l,4,14]oxadiazacyclohexadecine-4, 10, 17(5H, 9H, 16H)-trione;

[0282] [17a(18)Z]-2, 5-dimethyl-6, 7, 11, 12-tetrahydro-lH-13, 15- (ethenediyl)dipyrrolo[3,2-f:3',4'-i][l,4,14]oxadiazacyclohexadecine-4, 10, 17(5H, 9H, 16H)-trione;

[0283] [17a(18)Z]-2, 5-dimethyl-6, 7, 11, 12-tetrahydro-lH-13, 15- (ethenediyl)dipyrrolo[3,2-f:3',4'-i][l,4,14]oxadiazacyclohexadecine-4, 10, 17(5H, 9H, 16H)-trione;

[0284] [12S, 17a(18)Z]-2, 12-dimethyl-6, 7, 9, 10-tetrahydro-lH, 12H-13, 15- (ethenediyl)dipyrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclohexadecine-4, 17(5H, 16H)- dione;

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

[0286] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1 H-13, 15-(ethenylidene)dipyrrolo[3,2- f:3',4'-i][1,4,14]oxadiazacyclohexadeca-4,10,17(5H,9H,16H)-trione;

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

[0288] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1 H-13, 15-(ethenylidene)dipyrrolo[3,2- f:3',4'-i][1,4,14]oxadiazacyclohexadeca-4,10,17(5H,9H,16H)-trione;

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

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

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

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

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

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

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

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

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

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

[0299] [16a(17)Z]-2-methyl-6,7,9,10-tetrahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-4,16(5H,15H)-dione;

[0300] [16a(17)Z]-19-chloro-2-methyl-6,7,9,10-tetrahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-4,16(5H,15H)-dione;

[0301] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-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-lH-12,14-(ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-7-carboxylic acid methyl ester;

[0303] [7R, 16a(17)Z]-N-(azetidin-3-yl)-19-chloro-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-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-lH-12,14-(ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-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-lH-12,14-(ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-7-carboxamide;

[0306] [7R, 16a(17)Z]-19-chloro-2,5-dimethyl-4, 16-dioxo-N-[(3R)-pyrrolidin-3-yl]- 4,5,6,7,9,10,15,16-octahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7] dioxazacyclopentadecine-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-lH-12,14-(ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine- 7-carboxamide;

[0308] [7R, 16a(17)Z]-19-chloro-2,5-dimethyl-7-(4-methylpiperazine-l-carbonyl)-6,7,9,10- tetrahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine- 4,16(5H, 15H)-dione;

[0309] [10S, 16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,2- i:3',4'-l][l,4,7]dioxazacyclopentadecine-4,16(5H, 15H)-dione;

[0310] [10S, 16a(17)Z]-19-chloro-2,5,10-trimethyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-4,16(5H, 15H)- dione;

[0311] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,2- i:3',4'-l][l,4,7]dioxazacyclopentadecine-4,16(5H, 15H)-dione;

[0312] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,2- i:3',4'-l][l,4,7]dioxazacyclopentadecine-4,16(5H, 15H)-dione;

[0313] [16a(17)Z]-19-chloro-2,5-dimethyl-5,6,7,8,9,10-hexahydro-12,14- (ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]oxadiazacyclopentadecine-4,16(lH, 15H)-dione;

[0314] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14- (ethenediyl)-8λ6-dipyrrrolo[3,2-i:3',4'-l][l,4,7]oxathiazacyclopentadecine- 4,8,8,16(lH,5H,15H)-tetraone;

[0315] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14- (ethenediyl)-8λ4-dipyrrrolo[3,2-i:3',4'-l][l,4,7]oxathiazacyclopentadecine- 4,8,16(lH,5H,15H)-trione;

[0316] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]oxathiazacyclopentadecine-4,16(5H, 15H)-dione;

[0317] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrrolo[3,4-g:2',3'-j][l,4,13]oxathiazacyclopentadecine-4,16(5H, 15H)-dione;

[0318] [16a(17)Z]-2,5-dimethyl-6,7-dihydro-lH,9H-12,14- (ethenediyl)-l lλ6-dipyrrrolo[3,4-g:2',3'-j][l,4,13]oxathiazacyclopentadecine- 4,11,11,16(5H,10H,15H)-tetraone;

[0319] [16a(17)Z]-5-methyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrrolo[3,4-g:2',3'-j][l,4,13]oxathiazacyclopentadecine-4,16(5H, 15H)-dione;

[0320] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrazolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-4,16(5H, 15H)- dione;

[0321] [16a(17)Z]-19-chloro-5-methyl-5,6,7,8,9,10-hexahydro-12,14- (ethenediyl)dipyrazolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-4,16(lH, 15H)- dione;

[0322] [16a(17)Z]-19-chloro-2,5,8-trimethyl-5,6,7,8,9,10-hexahydro-12,14- (ethenediyl)dipyrazolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-4,16(lH, 15H)- dione;

[0323] [16a(17)Z]-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-lH-12,14- (ethenediyl)dipyrazolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-19-carbonitrile;

[0324] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrazolo[3,4-g:2',3'-j][l,4,13]oxathiazacyclopentadecine-4,16(5H, 15H)- dione;

[0325] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrazolo[3,4-g:2',3'-j][l,4,13]oxathiazacyclopentadecine-4,16(5H, 15H)- dione; and

[0326] [16a(17)Z]-19-chloro-5-methyl-6,7-dihydro-lH,9H-12,14- (ethenediyl)-l lλ6-dipyrazolo[3,4-g:2',3'-j][l,4,13]oxathiazacyclopentadecine-4,11,11, 16(5H,10H,15H)-tetraone.

[0327] 63. A pharmaceutical composition comprising at least one compound of any one of clauses 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 of any one of clauses 1-62, or a pharmaceutically acceptable salt thereof.

[0329] 65. A compound of any one of clauses 1-62, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in an individual.

[0330] 66. A compound of any one of clauses 1-62, or a pharmaceutically acceptable salt thereof, for use in treating cancer in an individual.

[0331] 67. Use of a compound of any one of clauses 1-62, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer in an individual. DETAILED DESCRIPTION

[0332] Before further description of the disclosure, it should be understood that the disclosure is not limited to the particular embodiments described, and as such can of course vary. It should also be realized that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting as the scope of the disclosure will only be limited by the appended claims.

[0333] The disclosures of publications, including patents, cited herein are hereby incorporated 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 belongs. All patents, applications, published applications and other publications mentioned herein are incorporated by reference in their entirety. If definitions are provided in this section, and the definitions in this section are contrary to or otherwise inconsistent with the definitions set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definitions in this section prevail over and control the definitions in the patents, applications, published applications and other publications incorporated herein by reference.

[0334] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It should also be noted that the claim can be drafted to exclude any optional element. Thus, this statement serves as antecedent basis for the use of “only” or “solely” or similar exclusivity terms herein to the elements introduced therein.

[0335] As used herein, the terms “comprises,” “comprising,” “includes,” “including” and “contains,” “containing,” are used in their open, non-limiting sense.

[0336] For the sake of providing a more concise description, some quantitative expressions given herein are not qualified with the term "about." It is to be understood that every quantity given herein is intended to refer to both the actual value and to the approximation of the actual value that would be expected by one of ordinary skill in the art given the nature of the value and the context in which it is used. Whenever a ratio is given, the ratio is intended to be a mass ratio unless explicitly stated otherwise. Whenever a concentration is given in percentage, the concentration refers to a mass ratio, unless explicitly stated otherwise.

[0337] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0338] The methods and techniques of the present disclosure embodiments are generally performed according to conventional methods well-known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0339] Chemical nomenclature of the compounds described herein was generally obtained using the 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 12Alkenylene or C2-C6alkenylene or C2-C6alkenylene. Examples of alkenyl groups include ethenyl (vinyl), allyl, and but-3-en-1-yl. Examples of alkenylene groups include ethenylene (vinylene) (-CH=CH-), n-propenylene (-CH=CHCH2-), i-propenylene (-CH=CHCH3-), and the like. Included within this term are the cis- and trans-isomers and mixtures thereof. It will be appreciated that, as described herein, an alkenyl or alkenylene group can be unsubstituted or substituted. An alkenyl or alkenylene group can be substituted with any of the substituents described in various embodiments herein, including one or more of such substituents.

[0344] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical having one or more triple bonds. The term "alkynylene" refers to a straight-chain or branched-chain divalent hydrocarbon radical having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an "alkynyl" or "alkynylene" group to a certain range of atoms, e.g., C2-C6alkynyl or C2-C6alkynylene. Examples of alkynyl groups include ethynyl (-C≡CH) and propargyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), and the like. It will be appreciated that, as described herein, an alkynyl or alkynylene group can be unsubstituted or substituted. An alkynyl or alkynylene group can be substituted with any of the substituents described in various embodiments herein, including one or more of such substituents. 20 Alkynyl or C2-C 20 Alkynylene, C2-C 12 Alkynyl or C2-C 12 Alkynylene or C2-C6alkynylene or C2-C6alkynylene. Examples of alkynyl groups include ethynyl (-C≡CH) and propargyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), and the like. It will be appreciated that, as described herein, an alkynyl or alkynylene group can be unsubstituted or substituted. An alkynyl or alkynylene group can be substituted with any of the substituents described in various embodiments herein, including one or more of such substituents.

[0345] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic monovalent carbocyclic ring. The term "cycloalkylene" refers to a saturated or partially saturated monocyclic or polycyclic divalent carbocyclic ring. In some embodiments, it can be advantageous to limit the number of atoms in a "cycloalkyl" or "cycloalkylene" group to a certain range of atoms, e.g., having 3 to 12 ring atoms. Polycyclic carbocyclic rings include fused, bridged, and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include monovalent groups of the following entities, while cycloalkylene groups include divalent groups of the following entities, in the form of appropriate bonding moieties:

[0346]

[0347]

[0348] In particular, a cyclopropyl moiety can be depicted by the structural formula In particular, a cyclopropyl moiety can be depicted by the structural formula substituted. Cycloalkyl or cycloalkylene can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0349] The term "halogen" or "halo" means chlorine, fluorine, bromine, or iodine.

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

[0351] The term "aryl" means a monovalent, all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. The term "alkylene" means a divalent, all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. In some embodiments, it can be advantageous to limit the number of atoms in an "aryl" or "alkylene" group to a certain range, such as a monovalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 14 carbon atoms (C6-C14 aryl), a monovalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C10 aryl), a divalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 14 carbon atoms (C6-C14 alkylene), or a divalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C10 alkylene). Examples of aryl are, but are not limited to, phenyl, naphthyl, and anthryl. Examples of alkylene are, but are not limited to, phenylene, naphthylene, and anthrylene. It should be appreciated that an aryl or alkylene group, as described herein, can be unsubstituted or substituted. An aryl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. 14 aryl), a monovalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C10 aryl), a divalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 14 carbon atoms (C6-C14 alkylene), or a divalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C10 alkylene). Examples of aryl are, but are not limited to, phenyl, naphthyl, and anthryl. Examples of alkylene are, but are not limited to, phenylene, naphthylene, and anthrylene. It should be appreciated that an aryl or alkylene group, as described herein, can be unsubstituted or substituted. An aryl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. 10 aryl), a monovalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C10 aryl), a divalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 14 carbon atoms (C6-C14 alkylene), or a divalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C10 alkylene). Examples of aryl are, but are not limited to, phenyl, naphthyl, and anthryl. Examples of alkylene are, but are not limited to, phenylene, naphthylene, and anthrylene. It should be appreciated that an aryl or alkylene group, as described herein, can be unsubstituted or substituted. An aryl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. 14 aryl), a monovalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C10 aryl), a divalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 14 carbon atoms (C6-C14 alkylene), or a divalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C10 alkylene). Examples of aryl are, but are not limited to, phenyl, naphthyl, and anthryl. Examples of alkylene are, but are not limited to, phenylene, naphthylene, and anthrylene. It should be appreciated that an aryl or alkylene group, as described herein, can be unsubstituted or substituted. An aryl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. 10 aryl), a monovalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C10 aryl), a divalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 14 carbon atoms (C6-C14 alkylene), or a divalent, all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C10 alkylene). Examples of aryl are, but are not limited to, phenyl, naphthyl, and anthryl. Examples of alkylene are, but are not limited to, phenylene, naphthylene, and anthrylene. It should be appreciated that an aryl or alkylene group, as described herein, can be unsubstituted or substituted. An aryl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0352] The term "heterocycloalkyl" refers to a saturated or partially saturated monovalent monocyclic or polycyclic ring structure having one or more non-carbon ring atoms. The term "heterocycloalkylene" 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 can be advantageous to limit the number of atoms in "heterocycloalkyl" or "heterocycloalkylene" to a certain range of ring atoms, for example, 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 can be advantageous to limit the number and type of ring heteroatoms in "heterocycloalkyl" or "heterocycloalkylene" to a certain range or type of heteroatoms, for example, 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Polycyclic ring systems include fused, bridged, and spirocyclic systems. The ring structure can optionally contain an oxo on a carbon ring member or up to two oxos on one sulfur ring member. Illustrative examples of heterocycloalkyl include monovalent radicals of the following entities, while heterocycloalkylene includes divalent radicals of the following entities, in the form of an appropriate bonding moiety:

[0353]

[0354] A three-membered heterocyclic ring can contain at least one heteroatom ring atom, where the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of three-membered heterocyclic groups include the monovalent and divalent groups of oxirane, aziridine, and thiirane. A four-membered heterocyclic ring can contain at least one heteroatom ring atom, where the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocyclic groups include the monovalent and divalent groups of azetidine, oxtenane, and thietane. A five-membered heterocyclic ring can contain up to four heteroatom ring atoms, where (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 monovalent and divalent groups of pyrrolidine, tetrahydrofuran, 2,5-dihydro-lH-pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-lH-imidazole, dihydrothiophene-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolane-2-one, and oxazolidin-2-one. A six-membered heterocyclic ring can contain up to four heteroatom ring atoms, where (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 monovalent or divalent groups of piperidine, morpholine, 4H-l,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxazinane-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A "heterobicyclic ring" is a fused bicyclic ring system comprising one heterocyclic ring fused to a cycloalkyl or another heterocyclic ring.

[0355] It will be appreciated that, as described herein, a heterocycloalkyl or heterocycloalkylene group can be unsubstituted or substituted. A heterocycloalkyl or heterocycloalkylene group can be substituted with any of the substituents described in various embodiments herein, including one or more of such substituents.

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

[0357]

[0358] In some embodiments, a "monocyclic" heteroaryl group can be an aromatic five or six membered heterocycle. A five membered heteroaryl or heteroarylene group can contain up to four heteroatom ring atoms, where (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 radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-limiting examples of five membered heteroarylene groups include divalent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six membered heteroaryl or heteroarylene group can contain up to four heteroatom ring atoms, where (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 radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of six membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A "bicyclic heteroaryl" or "bicyclic heteroarylene" is a fused bicyclic ring system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinoline-3(2H)-one, thieno[3,2-b]thiophene, lH-pyrrolo[2,3-b]pyridine, lH-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole. Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinoline-3(2H)-one, thieno[3,2-b]thiophene, lH-pyrrolo[2,3-b]pyridine, lH-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.

[0359] In particular, a pyrrolyl moiety can be depicted by the structural formula In particular, a pyrrolyl moiety can be depicted by the structural formula

[0360] It will be appreciated that, as described herein, a heteroaryl or heteroarylene group can be unsubstituted or substituted. A heteroaryl or heteroarylene group can be substituted with any of the substituents described in various embodiments herein, including one or more of such substituents.

[0361] The term "oxo" represents a carbonyl oxygen. For example, a cyclopentyl group substituted with oxo 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., 2Heavy isotope substitution such as H) can yield certain therapeutic advantages resulting from greater metabolic stability, for example, increased half-life in vivo or reduced dosage requirements. Isotopically-labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes or in the Examples and Preparations described below by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent.

[0365] The term "(ATOM i-j " when applied to a class of substituents herein is intended to refer to embodiments of the present disclosure in which each of the number of atomic members from i to j, inclusive, is independently achieved. For example, the term C 1-3 independently refers to embodiments having one carbon member (Ci), embodiments having two carbon members (C2), and embodiments having three carbon members (C3).

[0366] Any disubstituted group mentioned herein is intended to include the various possibilities when more than one attachment is allowed. For example, a disubstituted group -A-B- (where A≠B) refers herein to such disubstituted group having A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituted group having A attached to a second substituted member and B attached to a first substituted member. For example, in certain embodiments, a compound moiety -(L) n -CH(CH3)-CH2NH-(CH2)2- is understood to include both embodiments A-CH(CH3)-CH2NH-(CH2)2-B and B-CH(CH3)-CH2NH-(CH2)2-A. More specifically, in the context of the present invention, a compound moiety of the formula -CH(CH3)-CH2NH-(CH2)2- having a linking group -Z- and -NR 2 - of the formula (I)-(VIII) is understood to include both embodiments -Z-CH(CH3)-CH2NH-(CH2)2-NR n - and -NR 2 -CH(CH3)-CH2NH-(CH2)2-A. 2 -CH(CH3)-CH2NH-(CH2)2-A.

[0367] The present disclosure also includes pharmaceutically acceptable salts of the compounds represented by formulae (I)-(VIII), preferably the above-mentioned compounds and the specific compounds exemplified herein, as well as pharmaceutical compositions comprising such salts and methods of using such salts.

[0368] "Pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented herein which is nontoxic, biologically tolerable, or otherwise biologically suitable for use in the subject. See generally S. M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those pharmacologically effective and suitable for use in contact with the tissues of the subject without undue toxicity, irritation, or allergic response. Compounds described herein can have a sufficiently acidic, a sufficiently basic, both types of functional groups, or more than one of each type, and accordingly react with a variety of inorganic or organic bases, and inorganic and organic acids to form pharmaceutically acceptable salts.

[0369] Examples of pharmaceutically acceptable salts include: sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, but- enedioates, pimelates, toluenesulfonates, methylsulfonates, propylsulfonates, phenylsulfonates, xylenesulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, benzenesulfonates, methylbenzenesulfonates, dinitrobenzenesulfonates, hydroxybenzenesulfonates, methoxybenzenesulfonates, phthalates, sulfonates, methylsulfonates, propylsulfonates, phenylsulfonates, xylene sulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, Pa., 1985.

[0370] For compounds of formulae (I)-(VIII) containing a basic nitrogen, pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like; or with an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosic acid (e.g., glucuronic or galacturonic acid), alpha-hydroxy acid (e.g., mandelic, citric or tartaric acid), amino acid (e.g., aspartic or glutamic acid), aromatic acid (e.g., benzoic, 2-acetoxybenzoic, naphthoic or cinnamic acid), sulfonic acid (e.g., lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid); any compatible mixture of acids such as those given as examples herein; and any other acid and mixtures thereof that are regarded as equivalent or acceptable alternatives in light of the level of ordinary skill in this art.

[0371] The present disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of formulae (I)-(VIII), and methods of treatment employing such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a designated compound that, upon administration to a subject, yields the designated compound in vivo by a chemical or physiological process (e.g., solvolysis or enzymatic cleavage) or under physiological conditions (e.g., a prodrug is converted to a compound of formulae (I)-(VIII) upon reaching physiological pH). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985.

[0372] The present disclosure also relates to pharmaceutically active metabolites of the compounds of Formulae (I)-(VIII), and the use of such metabolites in the methods of the present disclosure. By "pharmaceutically active metabolite" is meant a pharmacologically active product of metabolism of a compound of Formulae (I)-(VIII), or salt thereof, in the body. Prodrugs and active metabolites of a compound can be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, in Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

[0373] As used herein, the term "protecting group" or "PG" refers to any group that is generally known to one of ordinary skill in the art that can be introduced into a molecule through chemical modification of a functional group (e.g., amine or hydroxyl) to obtain chemical selectivity in subsequent chemical reactions. It will be appreciated that such protecting groups can be subsequently removed from the functional group at a later point in the synthesis to provide further opportunities for reactions at such functional groups, or in the case of final products, to mask such functional groups. Protecting groups have been described in, for example, Wuts, P.G.M., Greene, T.W., Greene, T.W., & John Wiley & Sons. (2006). Greene's Protective Groups in Organic Synthesis. Hoboken, N.J: Wiley Online Library. The skilled artisan will readily appreciate the chemical method conditions under which such protecting groups can be installed on a functional group. Suitable amine protecting groups suitable for use in connection with the present disclosure include, but are not limited to: 9-fluorenylmethyl-carbonyl (FMOC), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl (Ac), trifluoroacetyl, phthalimide, benzyl (Bn), triphenylmethyl (trityl, Tr), benzylidene, and p-toluenesulfonyl (tosyl, Ts).

[0374] Representative Examples

[0375] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0376]

[0377] wherein 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 herein.

[0378] In some embodiments, the present disclosure provides a compound of Formula II, or a pharmaceutically acceptable salt thereof,

[0379]

[0380] wherein R 1 , R 2 , A, L, X, X 1 , X 2 , X 3 , X4 , Y, Y 1 , Y 2 , Z, m, and n are as described herein.

[0381] In some embodiments, the present disclosure provides a compound of Formula III, or a pharmaceutically acceptable salt thereof,

[0382]

[0383] wherein 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 herein.

[0384] In some embodiments, the present disclosure provides a compound of Formula IV, or a pharmaceutically acceptable salt thereof,

[0385]

[0386] wherein 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 herein.

[0387] In some embodiments, the present disclosure provides a compound of Formula V, or a pharmaceutically acceptable salt thereof,

[0388]

[0389] wherein 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 herein.

[0390] In some embodiments, the present disclosure provides a compound of Formula VI, or a pharmaceutically acceptable salt thereof,

[0391]

[0392] wherein R 1 , R 2 , A, L, X, X 1 , X2 , X 3 , X 4 , Y, Y 1 , Y 2 , Z, m, and n are as described herein.

[0393] In some embodiments, the present disclosure provides a compound of Formula VII, or a pharmaceutically acceptable salt thereof,

[0394]

[0395] wherein 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 herein.

[0396] In some embodiments, the present disclosure provides a compound of Formula VIII, or a pharmaceutically acceptable salt thereof,

[0397]

[0398] wherein 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 herein.

[0399] In some embodiments, ring A is 5- to 10-membered heteroarylene and Z is 3- to 7-membered heterocycloalkylene, C3-C6cycloalkylene, C6-C 10 arylene, or 5- to 10-membered heteroarylene (also referred to as ring B). In some embodiments, ring A is 5- to 10-membered heteroarylene and ring B is 5- to 10-membered heteroarylene. In some embodiments, ring A is 5- to 10-membered heteroarylene and ring B is 3- to 7-membered heterocycloalkylene. In some embodiments, ring A is 5- to 10-membered heteroarylene and ring B is C3-C6cycloalkylene. In some embodiments, ring A is 5- to 10-membered heteroarylene and ring B is C6-C 10 arylene.

[0400] In some embodiments, ring A is C6-C 10 arylene and Z is 3- to 7-membered heterocycloalkylene, C3-C6cycloalkylene, C6-C 10A 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:

[0404]

[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)2ORa wherein each hydrogen atom in the C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -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:

[0407]

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

[0409]

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

[0411]

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

[0413]

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

[0415] In some embodiments, ring B(Z) is C6-C 10 arylene, wherein the C6-C10aryl and C6-C10arylene are optionally substituted with 1 to 5 groups R independently selected from the group consisting of: C1-C6alkyl, C1-C6haloalkyl, -OR 10 each hydrogen atom in the aryl is independently optionally substituted with C1-C6alkyl, C1-C6haloalkyl, -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 eC(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 phenylene, wherein each hydrogen atom in the phenylene is independently 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)ORf -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:

[0418]

[0419] In some embodiments, ring B(Z) is 3- to 7-membered heterocycloalkylene, wherein each hydrogen atom in the 3- to 7-membered heterocycloalkylene is independently optionally substituted with deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -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 pyrrolidinylene or azetidinylene group, wherein each hydrogen atom in the pyrrolidinylene and azetidinylene groups is independently optionally substituted with deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -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)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)NRa 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 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C3-C6 halocycloalkyl, 3- to 7-membered haloheterocycloalkyl, C6-C10 haloaryl and 5- to 10-membered haloheteroaryl are optionally substituted with one, two, three or four substituents selected from the group consisting of halogen, -CN, -NO2, -N3, -OH, -SH, -CO2H, -OC(O)H, -C(O)OH, -C(O)SH, -S(O)C(O)H, -SC(O)OH, -OC(O)OR 10each hydrogen atom in an aryl or 5- to 10-membered heteroaryl group is independently 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

[0423] R is, in some embodiments, -H, -halo, -C1-C6alkyl, -C1-C6haloalkyl, -OH, -C1-C6alkoxy, -C3-C6cycloalkyl, -C2-C6alkenyl, -C2-C6alkynyl, -CN, -OC(O)CF3, -OC(O)R 1 haloalkyl, -halo, -CN, -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 1 is -CN or methyl when present.

[0424] In some embodiments, R 1a is C1-C6 alkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b or -P(O)2OR a , wherein each hydrogen atom in C1-C6 alkyl is independently 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 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 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 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)Rf -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 is H or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently 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. 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 -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 R3 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 are each independently selected from the group consisting of H, deuterium, fluoro, chloro, bromo, -OR e , and C1-C6alkyl; or R 12 and R 13 together with the carbon to which they are attached form a C3-C6cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6cycloalkyl or 4- to 6-membered heterocycloalkyl is independently optionally substituted with deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -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 eS(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, when present, R 12 is H and R 13 is methyl. In some embodiments, when present, R 12 is methyl and R 13 is H. In some embodiments, when present, R 12 and R 13 are H. In some embodiments, when present, R 12 is methyl and R 13 is -OH. In some embodiments, when present, R 12 is -OH and R 13 is methyl.

[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-(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -C(0)NH-(CH2)20(CH2)2-, -C(0)N(CH3)-(CH2)20(CH2)2-, -NHC(0)CH20(CH2)2-, -N(CH3)-C(0)CH20(CH2)2-, -CH20(CH2)2-, -(CH2)20(CH2)2-, -(CH2)2S(CH2)2-, -0(CH2)2S(CH2)2-, -(CH2)2S02(CH2)2-, -0(CH2)2S02(CH2)2-, -(CH2)2SO(CH2)2-, -0(CH2)2SO(CH2)2-, -(CH2)20(C(H)(C(0)N(H)(azetidin-3-yl))-CH2-, -(CH2)20(C(H)(C(0)N(H)(CH3))-CH2-, -(CH2)20(C(H)(C(0)N(CH3)2)-CH2-, -(CH2)20(C(H)(C(0)N(H)(piperidin-4-yl))-CH2-, -(CH2)20(C(H)(C(0)N(H)(pyrrolidin-3-yl))-CH2-, -(CH2)20(C(H)(C(0)N(H)(4-methylpiperazin-1-yl))-CH2-, -(CH2)20(C(H)(C(0)OCH3)-CH2-, -(CH2)30(CH2)2-, -(CH2)20(CH2)3-, -CH2CH(CH3)-0(CH2)2-, -CH(CH3)-CH20(CH2)2-, -0(CH2)2-, -0-(CH2)3-, -OCH20(CH2)2-, -0-CH2CH(OH)CH2-, -0-(CH2)20(CH2)2-, -0-CH2CH(CH3)-0(CH2)2-, -0-CH(CH3)-CH20(CH2)2-, -0-(CH2)2NH-(CH2)2-, -0-CH2CH(CH3)-NH-(CH2)2-, -0-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -0-(CH2)2N(CH3)-(CH2)2-, -0-CH2CH(CH3)-N(CH3)-(CH2)2-, -0-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 -0-CH(CH3)-CH2N(CH3)-(CH2)2-. In some embodiments, -Z-(L), n -Z 1 - does not contain -0-0-, -0-S-, or -0-N(R x )- bond.

[0432] In some embodiments, R 5 is H or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently 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 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 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, is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -CN. In some embodiments, R 6 , when present, is H.

[0434] In some embodiments, X 1 is N or C(R 7 ); and X 2 is N or C(R 8 ); with the proviso that one of R 7 or R 8 is a bond to Z. In some embodiments, X 1 is N or C(R 7 ). In some embodiments, X 1 is N. In some embodiments, X 1 is C(R 7 ). In some embodiments, X 2 is N- or C(R 8 ). In some embodiments, X 2 is N. In some embodiments, X 2 is C(R 8 ). In some embodiments, X 3 is N or C(R 9 ). In some embodiments, X 3 is N. In some embodiments, X 3 is C(R 9 ). In some embodiments, X 4 is N or C(R 10 ). In some embodiments, X 4 is N. In some embodiments, X 4 is C(R10 ). In some embodiments, X 1 and X 3 are N. In some embodiments, X 1 and X 4 are N. In some embodiments, X 3 and X 4 are N. In some embodiments, X 1 is C(R 7 ), X 3 is C(R 9 ), and X 4 is C(R 10 ). In some embodiments, the compound is not a compound wherein X 1 is C(R 7 ), X 3 is C(R 9 ), and X 4 is C(R 10 ), and R 10 is not H. In some embodiments, the compound is not a compound wherein X 1 is C(R 7 ), X 3 is C(R 9 ), and X 4 is C(R 10 ), and R 9 is not H. In some embodiments, the compound is not a compound wherein X 1 is C(R 7 ), X 3 is C(R 9 ), and X 4 is C(R 10 ), and R 9 and R 10 are not H.

[0435] In some embodiments, R 7 and R 8 are each independently a bond to Z, H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7- membered 10 heterocycloalkyl, C6-C10aryl, 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; with the proviso that one of R 7 or R 8 is a bond to Z;

[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 to which they are attached form a C4-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-C 10 aryl group, wherein each hydrogen atom in the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C4-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl group is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -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, fluoro, chloro, -CN, or methyl. In some embodiments, C(R 8 ) is H, deuterium, fluoro, chloro, -CN, or methyl. In some embodiments, each C(R 9 ) is H, deuterium, fluoro, chloro, -CN, or methyl. In some embodiments, C(R 10 ) is H, deuterium, fluoro, chloro, -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 ) is not -Cl.

[0439] In some embodiments, the compound is not a compound wherein ring B(Z) is and R 9 and / or R 10 is not H. In some embodiments, the compound is not a compound wherein ring B(Z) is and R 9 and / or R 10is not H. In some embodiments, the compound is not a compound in which X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), R 9 and / or R 10 is not H, and ring B(Z) is In some embodiments, the compound is not a compound in which X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), R 9 and / or R 10 is not H, and ring B(Z) is In some embodiments, the compound is not a compound in which X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), R 9 and / or R 10 is -Cl, and ring B(Z) is In some embodiments, the compound is not a compound in which X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), R 9 and / or R 10 is -Cl, and ring B(Z) is In some embodiments, X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), and R 9 and / or R 10 is not -Cl. In some embodiments, X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), R 9 and / or R10 is not -Cl, and ring B(Z) is not In some embodiments, X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), R 9 and / or R 10 is not -Cl, and ring B(Z) is not

[0440] In some embodiments, 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, the present disclosure provides a compound selected from the group consisting of: [3a(4)Z]-10,11-dihydro-2H,13H-16,1-(hydrazono)methyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][l,4,l l]oxadiazacyclotetradecaine-3,8(5H,9H)-dione;

[0443] [3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(hydrazono)methyl)pyrazolo[3,4-b]dipyrrrolo[3,4- f:2',3'-i][l,5,12]oxadiazacyclopentadecine-3,8(2H,5H)-dione;

[0444] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(hydrazono)methyl)pyrazolo[3,4-b]dipyrrrolo[3,4- f:2',3'-i][l,5,12]oxadiazacyclopentadecine-3,8(2H,5H)-dione;

[0445] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(diazanediylidene)pyrazolo[4,3-n]dipyrrrolo[3,2- g:3',4'-j][l,5]oxadiazacyclopentadecine-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 pentadecadeyn-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-(ethenediyl)pyrazolo[3,4- b]dipyrrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadeca-6(2H)-ene-6-carbonitrile;

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

[0455] [3a(4)Z]-6,15-dimethyl-9,10,11,12-tetrahydro-15H-1,17-(ethenediyl)pyrazolo[3,4-b]dipyrrrolo[3,4- f:2',3'-i][1,5,12]oxadiazacyclopentadeca-3,8(2H,5H)-dione;

[0456] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethenediyl)[1,2]oxazolo[3,4-b]dipyrrrolo[3,4- f:2',3'-i][1,5,12]oxadiazacyclopentadeca-3,8(2H,5H)-dione;

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

[0458] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethenediyl)dipyrrrolo[3,4-f:2',3'-i][1,2]thiazolo[3,4- b][1,5,12]oxadiazacyclopentadeca-3,8(2H,5H)-dione;

[0459] [3a(4)Z]-6,9-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[3,4-b]dipyrrrolo[3,4- f:2',3'-i][1,5,12]oxadiazacyclopentadeca-3,8(2H,5H)-dione;

[0460] [3a(4)Z]-6, 9-dimethyl-9, 10, 11, 12-tetrahydro-l, 17-(ethenylene) [1, 2]oxazolopyrrolo [3, 4-b] pyrrolo [3, 4-f:2', 3'-i] [1, 5, 12] oxadiazacyclopentadeca-3, 8(2H, 5H)-dione;

[0461] [3a(4)Z]-6, 9, 16-trimethyl-9, 10, 11, 12-tetrahydro-l, 17-(ethenylene) pyrazolo [3, 4-b] pyrrolo [3, 4-f:2', 3'-i] [1, 5, 12] oxadiazacyclopentadeca-3, 8(2H, 5H)-dione;

[0462] [3a(4)Z]-6, 9, 16-trimethyl-9, 10, 11, 12-tetrahydro-l, 17-(ethenylene) [1, 2]oxazolopyrrolo [3, 4-b] pyrrolo [3, 4-f:2', 3'-i] [1, 5, 12] oxadiazacyclopentadeca-3, 8(2H, 5H)-dione;

[0463] [3a(4)Z]-6-methyl-9, 10, 11, 12-tetrahydro-l, 17-(ethenylene) pyrazolo [5, 1-c] pyrrolo [3, 2-j:3', 4'-m] [1, 4, 8] triazacyclotetradeca-3, 8(2H, 5H)-dione;

[0464] [3a(4)Z]-6-methyl-9, 10, 11, 12-tetrahydro-17, 1-(hydrazono) pyrazolo [1, 5-e] pyrrolo [3, 4-i:2', 3'-l] [1, 5] diazacyclotetradeca-3, 8(2H, 5H)-dione;

[0465] [19a(20)Z]-2-methyl-6, 7, 9, 10-tetrahydro-lH-15, 17-(ethenylene) pyrazolo [1, 5-d] pyrrolo [3, 4-h:2', 3'-k] [1, 4, 7, 14] oxatriazacyclohexadeca-4, 19(5H, 18H)-dione;

[0466] [19a(20)Z]-2-methyl-6, 7, 9, 10-tetrahydro-lH-15, 17-(hydrazono) pyrazolo [1, 5-d] pyrrolo [3, 4-h:2', 3'-k] [1, 4, 14] oxadiazacyclohexadeca-4, 19(5H, 18H)-dione;

[0467] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-lH-15,17-(ethenediyl)pyrazolo[l,5- d]dipyrrolo[3,4-h:2',3'-k][l,4,7]triazacyclohexadecine-4,19(lH,18H)-dione;

[0468] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-lH-15,17-(ethenediyl)pyrazolo[l,5- d]dipyrrolo[3,4-h:2',3'-k][l,4,7]triazacyclohexadecine-4,19(lH,18H)-dione;

[0469] [10R, 19a(20)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-lH-15,17-(ethenediyl)pyrazolo[l,5- d]dipyrrolo[3,4-h:2',3'-k][l,4,7]triazacyclohexadecine-4,19(lH,18H)-dione;

[0470] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-lH-15,17-(ethenediyl)pyrazolo[l,5- d]dipyrrolo[3,4-h:2',3'-k][l,4,7]triazacyclohexadecine-4,19(lH,18H)-dione;

[0471] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-lH-15,17-(ethenediyl)pyrazolo[l,5- d]dipyrrolo[3,4-h:2',3'-k][l,4,7]triazacyclohexadecine-4,19(lH,18H)-dione;

[0472] [19a(20)Z]-2-methyl-5,6,7,8,9,10-hexahydro-15,17-(ethenediyl)pyrazolo[l,5-g]dipyrrolo[3,4-k:2',3'-n][l,4,7]triazacyclohexadecine-4,19(lH,18H)-dione;

[0473] [19a(20)Z]-2,5-dimethyl-5,6,7,8,9,10-hexahydro-15,17-(ethenediyl)pyrazolo[l,5-g]dipyrrolo[3,4-k:2',3'-n][l,4,7]triazacyclohexadecine-4,19(lH,18H)-dione;

[0474] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H- 1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][l,4,11]oxadiazacyclopentadeca ine-3,8(5H,9H)-dione;

[0475] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H- 1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][l,4,11]oxadiazacyclopentadeca ine-3,8(5H,9H)-dione;

[0476] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H- 1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][l,4,11]oxadiazacyclopentadeca ine-3,8(5H,9H)-dione;

[0477] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H- 1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][l,4,11]oxadiazacyclopentadeca ine-3,8(5H,9H)-dione;

[0478] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H- 1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][l,4,11]oxadiazacyclopentadeca ine-3,8(5H,9H)-dione;

[0479] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H- 1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][l,4,11]oxadiazacyclopentadeca ine-3,8(5H,9H)-dione;

[0480] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H- 1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][l,4,11]oxadiazacyclopentadeca ine-3,8(5H,9H)-dione;

[0481] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(hydrazono-methyl) pyrazolo[4,3-m]dipyrrrolo[3,2-f:3',4'-i][l,4]diazacyclopentadeca-3,8(2H,5H)-dione;

[0482] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(hydrazono-methyl) pyrazolo[3,4-f]dipyrrrolo[3,4-j:2',3'-m][l,4,9]triazacyclopentadeca-3,8(2H,5H)-dione;

[0483] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl) pyrazolo[3,4-f]dipyrrrolo[3,4-j:2',3'-m][l,4,9]triazacyclopentadeca-3,8(2H,5H)-dione;

[0484] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(hydrazono-methyl) pyrazolo[4,3-m]dipyrrrolo[3,2-f:3',4'-i][l,4]diazacyclopentadeca-3,8(2H,5H)-dione;

[0485] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl) pyrazolo[4,3-m]dipyrrrolo[3,2-f:3',4'-i][l,4]diazacyclopentadeca-3,8(2H,5H)-dione;

[0486] [3a(4)Z]-20-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl) pyrazolo[4,3-m]dipyrrrolo[3,2-f:3',4'-i][l,4]diazacyclopentadeca-3,8(2H,5H)-dione;

[0487] [3a(4)Z]-19-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl) pyrazolo[4,3-m]dipyrrrolo[3,2-f:3',4'-i][l,4]diazacyclopentadeca-3,8(2H,5H)-dione;

[0488] [3a(4)Z]-6, 9, 20-trimethyl-9, 10, 11, 12, 13, 14-hexahydro-17, 1- (hydrazono)methylpyrazolo[4, 3-m]dipyrrrolo[3, 2-f: 3', 4'-i][l, 4] diazacyclopentadecine-3, 8(2H, 5H)-dione;

[0489] [3a(4)Z]-9, 20-dimethyl-9, 10, 11, 12, 13, 14-hexahydro-l, 17- (ethenediyl)pyrazolo[3, 4-f]dipyrrrolo[3, 4-j: 2', 3'-m][l, 4, 9] triazacyclopentadecine-3, 8(2H, 5H)-dione;

[0490] [3a(4)Z]-6, 16-dimethyl-9, 10, 11, 12, 13, 14-hexahydro-17, 1- (hydrazono)methylpyrazolo[4, 3-m]dipyrrrolo[3, 2-f: 3', 4'-i][l, 4] diazacyclopentadecine-3, 8(2H, 5H)-dione;

[0491] [3a(4)Z]-6, 9, 16-trimethyl-9, 10, 11, 12, 13, 14-hexahydro-17, 1- (hydrazono)methylpyrazolo[4, 3-m]dipyrrrolo[3, 2-f: 3', 4'-i][l, 4] diazacyclopentadecine-3, 8(2H, 5H)-dione;

[0492] [3a(4)Z]-16-cyclopropyl-6, 9-dimethyl-9, 10, 11, 12, 13, 14-hexahydro- 17, 1- (hydrazono)methylpyrazolo[4, 3-m]dipyrrrolo[3, 2-f: 3', 4'-i][l, 4] diazacyclopentadecine-3, 8(2H, 5H)-dione;

[0493] [3a(4)Z]-16-cyclopropyl-6, 9-dimethyl-9, 10, 11, 12, 13, 14-hexahydro- 1, 17- (ethenediyl)pyrazolo[3, 4-j]dipyrrrolo[3, 4-j: 2', 3'-m][l, 4, 9] triazacyclopentadecine-3, 8(2H, 5H)-dione;

[0494] [3a(4)Z]-6, 9, 16-trimethyl-10, 11, 12, 13-tetrahydro-2H-17, 1- (hydrazono)methyl[1, 2]oxazolo[4, 5-m]dipyrrrolo[3, 2-f: 3', 4'-i][l, 4] diazacyclopentadecine-3, 8(5H, 9H)-dione;

[0495] [3a(4)Z]-6, 9, 16-trimethyl-10, 11, 12, 13-tetrahydro-2H-17, 1- (hydrazono) [1, 2] oxazolopyrrolo [3, 2-f: 3', 4'-i] [1, 4] oxazadodecine- 3, 8(5H, 9H)-dione;

[0496] [3a(4)Z]-6, 9, 16-trimethyl-10, 11, 12, 13-tetrahydro-2H-17, 1- (hydrazono) [1, 2] oxazolopyrrolo [3, 2-f: 3', 4'-i] [1, 4] oxazadodecine- 3, 8(5H, 9H)-dione;

[0497] [3a(4)Z]-6, 9, 16-trimethyl-10, 11, 12, 13-tetrahydro-2H-17, 1- (hydrazono) [1, 2] oxazolopyrrolo [3, 2-f: 3', 4'-i] [1, 4] oxazadodecine- 3, 8(5H, 9H)-dione;

[0498] [3a(4)Z]-6, 9, 16-trimethyl-10, 11, 12, 13-tetrahydro-2H-17, 1- (hydrazono) [1, 2] oxazolopyrrolo [3, 2-f: 3', 4'-i] [1, 4] oxazadodecine- 3, 8(5H, 9H)-dione;

[0499] [3a(4)Z]-6, 9, 16-trimethyl-10, 11, 12, 13-tetrahydro-2H-17, 1- (hydrazono) [1, 2] oxazolopyrrolo [3, 2-f: 3', 4'-i] [1, 4] oxazadodecine- 3, 8(5H, 9H)-dione;

[0500] [3a(4)Z]-6, 9, 16-trimethyl-10, 11, 12, 13-tetrahydro-2H-17, 1- (hydrazono) [1, 2] oxazolopyrrolo [3, 2-f: 3', 4'-i] [1, 4] oxazadodecine- 3, 8(5H, 9H)-dione;

[0501] [3a(4)Z]-6, 9, 16-trimethyl-10, 11, 12, 13-tetrahydro-2H-17, 1- (hydrazono) [1, 2] oxazolopyrrolo [3, 2-f: 3', 4'-i] [1, 4] oxazadodecine- 3, 8(5H, 9H)-dione;

[0502] [3a(4)Z]-6, 9, 16-trimethyl-10, 11, 12, 13-tetrahydro-2H-1, 17- (ethenediyl) [1, 2] oxazolo [4, 3-m] diazolopyrrolo [3, 2-f: 3', 4'-i] [1, 4] oxazadodecine-3, 8(5H, 9H)-dione;

[0503] [3a(4)Z]-6, 9, 12, 14, 16-pentamethyl-9, 10, 11, 12, 13, 14-hexahydro-1, 17- (ethenediyl) pyrazolo [4, 3-m] diazolopyrrolo [3, 2-f: 3', 4'-i] [1, 4] oxazadodecine-3, 8(2H, 5H)-dione;

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

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

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

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

[0508] [3a(4)Z]-12-ethyl-6, 9, 14-trimethyl-9, 10, 11, 12, 13, 14-hexahydro-1, 17- (ethenediyl) pyrazolo [4, 3-m] diazolopyrrolo [3, 2-f: 3', 4'-i] [1, 4] oxazadodecine-3, 8(2H, 5H)-dione;

[0509] [3a(4)Z]-6,9,14-trimethyl-12-(prop-2-yl)-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadeca-3,8(2H,5H)-dione;

[0510] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-10,11-dihydro-2H,13H-1,17-(ethenediyl)[1,2]oxazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][1,4]oxadiazacyclopentadeca-3,8(5H,9H)-dione;

[0511] [3a(4)Z]-9,14-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethenediyl)pyrazolo[4,3-m]dipyrrrolo[3,2- f:3',4'-i][1,4]diazacyclopentadeca-3,8(2H,5H)-dione;

[0512] [3a(4)Z]-6,9-dimethyl-16-(prop-2-yl)-10,11-dihydro-2H,13H-1,17-(ethenediyl)[1,2]oxazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][1,4]oxadiazacyclopentadeca-3,8(5H,9H)-dione;

[0513] [3a(4)Z]-9-methyl-16-(prop-2-yl)-10,11-dihydro-2H,13H-1,17-(ethenediyl)[1,2]oxazolo[4,3- m]dipyrrrolo[3,2-f:3',4'-i][1,4]oxadiazacyclopentadeca-3,8(5H,9H)-dione;

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

[0515] [3a(4)Z]-9,14-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethenediyl)pyrazolo[4,3-n]dipyrrrolo[3,2- g:3',4'-j][1,5]oxadiazacyclopentadeca-3,8(2H,5H)-dione;

[0516] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-17,1- (hydrazono)methylpyrazolo[4,3-m]dipyrrrolo[3,2-f:3',4'-i][l,4]diazapentacine- 3,8(2H,5H)-dione;

[0517] [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-17,1- (hydrazono)methylpyrazolo[4,3-m]dipyrrrolo[3,2-f:3',4'-i][l,4]diazapentacine- 3,8(2H,5H)-dione;

[0518] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17- (ethenediyl)dipyrrrolo[3,4-f]dipyrrrolo[3,4-j:2',3'-m][l,4,9]triazapentacine- 3,8(2H,5H)-dione; and

[0519] [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17- (ethenediyl)dipyrrrolo[3,4-f]dipyrrrolo[3,4-j:2',3'-m][l,4,9]triazapentacine- 3,8(2H,5H)-dione;

[0520] or a pharmaceutically acceptable salt thereof.

[0521] In other embodiments, the present disclosure provides a compound selected from the group consisting of: [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,18- (ethenediyl)dipyrrrolo[3,2-g:3',4'-j][l,5,12]benzoxadiazapentacine-3,8(2H,5H)-dione;

[0522] [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethenediyl)dipyrrrolo[3,2- f:3',4'-i][l,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0523] [3a(4)Z]-6-methyl-10,11-dihydro-2H-17,1-(hydrazono)methyl- dipyrrrolo[3,2-f:3',4'-i][l,4]benzoxazacyclotetradecine-3,8(5H,9H)-dione;

[0524] [3a(4)Z]- 6, 9, 12-trimethyl- 10, 11, 12, 13-tetrahydro-2H-l, 18-(ethenediyl)dipyrrolo[3,2- g:3',4'-j][2,5]benzodioxacyclopentadecine-3,8(5H,9H)-dione or a pharmaceutically acceptable salt thereof.

[0525] [3a(4)Z]- 6, 9, 12-trimethyl- 10, 11, 12, 13-tetrahydro-2H-l, 18-(ethenediyl)dipyrrolo[3,2- g:3',4'-j][2,5]benzodioxacyclopentadecine-3,8(5H,9H)-dione or a pharmaceutically acceptable salt thereof.

[0526] [3a(4)Z]- 6, 9, 12-trimethyl- 10, 11, 12, 13-tetrahydro-2H-l, 18-(ethenediyl)dipyrrolo[3,2- g:3',4'-j][2,5]benzodioxacyclopentadecine-3,8(5H,9H)-dione or a pharmaceutically acceptable salt thereof.

[0527] [3a(4)Z]- 6, 9, 12-trimethyl- 10, 11, 12, 13-tetrahydro-2H-l, 18-(ethenediyl)dipyrrolo[3,2- g:3',4'-j][2,5]benzodioxacyclopentadecine-3,8(5H,9H)-dione or a pharmaceutically acceptable salt thereof.

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

[0529] In other embodiments, the present disclosure provides a compound selected from the group consisting of: [3a(4)Z]- 6-methyl- 10, 11-dihydro-2H-l, 17- (ethenediyl)dipyrrolo[3,2-m]pyrrolo[3,2-f:3',4'-i][l,4,l l]oxadiazacyclotetradecine-3,8(5H,9H)- dione;

[0530] [3a(4)Z]- 6, 9, 12-trimethyl- 10, 11, 12, 13-tetrahydro-2H-l, 18-(ethenediyl)dipyrrolo[3,2- g:3',4'-j][2,5]benzodioxacyclopentadecine-3,8(5H,9H)-dione or a pharmaceutically acceptable salt thereof.

[0531] [3a(4)Z]- 6, 9, 12-trimethyl- 10, 11, 12, 13-tetrahydro-2H-l, 18-(ethenediyl)dipyrrolo[3,2- g:3',4'-j][2,5]benzodioxacyclopentadecine-3,8(5H,9H)-dione or a pharmaceutically acceptable salt thereof.

[0532] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,18-(ethenylidene)pyrrolo[2,1- c]pyrrolo[3,2-j:3',4'-m][1,4,8]triazacyclotetradecine-3,8,14(2H,5H)-trione;

[0533] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,18-(ethenylidene)pyrrolo[2,1- c]pyrrolo[3,2-j:3',4'-m][1,4,8]triazacyclotetradecine-3,8,14(2H,5H)-trione;

[0534] or a pharmaceutically acceptable salt thereof.

[0535] In other embodiments, the disclosure provides a compound selected from the group consisting of: [3a(4)Z,13aR]-6-methyl-10,11,12,13,13a,14,15,16-octahydro-2H-18,1- (nitrilomethylidene)tripyrrolo[1,2-a:3',2'-i:3",4"-l][1,4,7]triazacyclopentadecine- 3,8(5H,9H)-dione;

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

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

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

[0539] [17a(18)Z]-2, 12-dimethyl-6,7,9,10,11,12-hexahydro-lH-13,15- (nitrilomethylidenyl)dipyrrrolo[3,2-f:3',4'-i][l,4,13]oxadiazacyclohexadecine- 4,17(5H,16H)-dione;

[0540] [17a(18)Z]-2, 12-dimethyl-6,7,9,10,11,12-hexahydro-lH-13,15- (nitrilomethylidenyl)dipyrrrolo[3,2-f:3',4'-i][l,4,13]oxadiazacyclohexadecine- 4,17(5H,16H)-dione;

[0541] [17a(18)Z]-2, 12-dimethyl-6,7,9,10,11,12-hexahydro-lH-13,15- (nitrilomethylidenyl)dipyrrrolo[3,2-f:3',4'-i][l,4,13]oxadiazacyclohexadecine- 4,17(5H,16H)-dione;

[0542] [16a(17)Z]-2, 12-dimethyl-6,7,9,10,11,12-hexahydro-lH-13,15- (nitrilomethylidenyl)dipyrrrolo[3,2-f:3',4'-i][l,4,13]oxadiazacyclohexadecine- 4,17(5H,16H)-dione;

[0543] [16a(17)Z]-2, 12-dimethyl-6,7,9,10,11,12-hexahydro-lH-13,15- (nitrilomethylidenyl)dipyrrrolo[3,2-f:3',4'-i][l,4,13]oxadiazacyclohexadecine- 4,17(5H,16H)-dione;

[0544] [16a(17)Z]-2, 12-dimethyl-6,7,9,10,11,12-hexahydro-lH-13,15- (nitrilomethylidenyl)dipyrrrolo[3,2-f:3',4'-i][l,4,13]oxadiazacyclohexadecine- 4,17(5H,16H)-dione;

[0545] [16a(17)Z]-2, 12-dimethyl-6,7,9,10,11,12-hexahydro-lH-13,15- (nitrilomethylidenyl)dipyrrrolo[3,2-f:3',4'-i][l,4,13]oxadiazacyclohexadecine- 4,17(5H,16H)-dione;

[0546] [10R, 16a(17)Z]- 11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(nitrilomethylidenyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetrazapenta- decine-4,16(5H,15H)-dione;

[0547] [10R, 16a(17)Z]- 11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(nitrilomethylidenyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetrazapenta- decine-4,16(5H,15H)-dione;

[0548] [10R, 16a(17)Z]- 11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(nitrilomethylidenyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetrazapenta- decine-4,16(5H,15H)-dione;

[0549] [10R, 16a(17)Z]- 11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(nitrilomethylidenyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetrazapenta- decine-4,16(5H,15H)-dione;

[0550] [10R, 16a(17)Z]- 11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(nitrilomethylidenyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetrazapenta- decine-4,16(5H,15H)-dione;

[0551] [10R, 16a(17)Z]- 11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(nitrilomethylidenyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetrazapenta- decine-4,16(5H,15H)-dione;

[0552] [10R, 16a(17)Z]- 11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-lH- 12,14-(nitrilomethylidenyl)dipyrrrolo[3,2-k:3',4'-n][l,3,6,9]tetrazapenta- decine-4,16(5H,15H)-dione;

[0553] [10S, 16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrolo[3,4-d:2',3'-g][l,13,3,10]dioxadiazacyclopentadecine- 4,16(5H, 15H)-dione;

[0554] [10S, 16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14- (nitrilomethylidenyl)dipyrrolo[3,4-d:2',3'-g][l,3,10,13]oxatriazacyclopentadecine- 4,16(lH, 15H)-dione;

[0555] [10S, 16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14- (ethenediyl)dipyrrolo[3,4-d:2',3'-g][l,3,10,13]oxatriazacyclopentadecine- 4,16(lH, 15H)-dione;

[0556] [10S, 16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14- (nitrilomethylidenyl)dipyrrolo[3,2-i:3',4'-l][l,4,7]oxadiazacyclopentadecine- 4,16(lH, 15H)-dione;

[0557] [9R, 16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-lH-12,14- (nitrilomethylidenyl)dipyrrolo[3,4-d:2',3'-g][l,13,3,10]dioxadiazacyclopentadecine- 4,16(5H, 15H)-dione;

[0558] [9S, 16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-lH-12,14- (nitrilomethylidenyl)dipyrrolo[3,4-d:2',3'-g][l,13,3,10]dioxadiazacyclopentadecine- 4,16(5H, 15H)-dione;

[0559] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine-4,16(5H, 15H)- dione;

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

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

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

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

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

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

[0566] [17a(18)Z]-2-methyl-6, 7, 10, 11-tetrahydro-lH, 9H-13, 15- (ethenediyl)dipyrrolo[3,2-f:3',4'-i][l,13,4]oxathiazacyclopentadecine-4, 17(5H, 16H)-dione;

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

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

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

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

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

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

[0573] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1 H-13,15-(ethenediyl)dipyrrolo[3,2- f:3',4'-i][1,4,7,14]oxatriazacyclohexadeca-4,10,17(5H,9H,16H)-trione;

[0574] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1 H-13, 15-(ethenediyl)di pyrrolo[3,4- h:2',3'-k][1,4,7,14]oxatricyclohexadecine-4,10,17(5H,9H,16H)-trione;

[0575] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1 H-13, 15-(ethenediyl)di pyrrolo[3,4- h:2',3'-k][1,4,7,14]oxatricyclohexadecine-4,10,17(5H,9H,16H)-trione;

[0576] [12S,17a(18)Z]-2,5,12-trimethyl-6,7,11,12-tetrahydro-1 H-13, 15-(ethenediyl)di pyrrolo[3,4- h:2',3'-k][1,4,7,14]oxatricyclohexadecine-4,10,17(5H,9H,16H)-trione;

[0577] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1 H-13, 15-(ethenediyl)di pyrrolo[3,4- h:2',3'-k][1,4,7,14]oxatricyclohexadecine-4,10,17(5H,9H,16H)-trione;

[0578] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1 H-13, 15-(ethenediyl)di pyrrolo[3,4- h:2',3'-k][1,4,7,14]oxatricyclohexadecine-4,10,17(5H,9H,16H)-trione;

[0579] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1 H-13, 15-(ethenediyl)di pyrrolo[3,4- h:2',3'-k][1,4,7,14]oxatricyclohexadecine-4,10,17(5H,9H,16H)-trione;

[0580] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1 H-13, 15-(ethenediyl)di pyrrolo[3,4- h:2',3'-k][1,4,7,14]oxatricyclohexadecine-4,10,17(5H,9H,16H)-trione;

[0581] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1 H-13,15-(nitrilomethylidenyl)dipyrrrolo[3,2- f:3',4'-i][1,4,14]oxadiazacyclohexadecine-4,10,17(5H,9H,16H)-trione;

[0582] [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1 H,9H-14,16-(ethenediyl)dipyrrrolo[3,2- f:3',4'-i][1,4,15]oxadiazacycloheptadecine-4,12,18(5H,13H,17H)-trione;

[0583] [18a(19)Z]-2,5-dimethyl-6,7,10,11-tetrahydro-1 H,9H-14,16-(ethenediyl)dipyrrrolo[3,2- f:3',4'-i][1,4,15]oxadiazacycloheptadecine-4,12,18(5H,13H,17H)-trione;

[0584] [18a(19)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1 H,9H-14,16-(ethenediyl)dipyrrrolo[3,2- f:3',4'-i][1,4,15]oxadiazacycloheptadecine-4,12,18(5H,13H,17H)-trione;

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

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

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

[0588] [13S, 18a(19)Z]-2, 13-dimethyl-6, 7, 10, 11-tetrahydro-lH, 9H-14, 16- (ethenediyl)dipyrrolo[3, 2-f: 3', 4'-i] [l, 4, 15]oxadiazacycloheptadecine-4, 12, 18(5H, 13H, 17H)-trione;

[0589] [13S, 18a(19)Z]-2, 13-dimethyl-6, 7, 10, 11-tetrahydro-lH, 9H-14, 16- (ethenediyl)dipyrrolo[3, 2-f: 3', 4'-i] [l, 4, 15]oxadiazacycloheptadecine-4, 12, 18(5H, 13H, 17H)-trione;

[0590] [13S, 18a(19)Z]-2, 13-dimethyl-6, 7, 10, 11-tetrahydro-lH, 9H-14, 16- (ethenediyl)dipyrrolo[3, 2-f: 3', 4'-i] [l, 4, 15]oxadiazacycloheptadecine-4, 12, 18(5H, 13H, 17H)-trione;

[0591] [16a(17)Z]-2-methyl-6, 7, 9, 10-tetrahydro-lH-12, 14- (ethenediyl)dipyrrolo[3, 2-i: 3', 4'-l] [l, 4, 7]dioxazacyclopentadecine-4, 16(5H, 15H)-dione;

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

[0593] [16a(17)Z]-19-chloro-2-methyl-6, 7, 9, 10-tetrahydro-lH-12, 14- (ethenediyl)dipyrrolo[3, 2-i: 3', 4'-l] [l, 4, 7]dioxazacyclopentadecine-4, 16(5H, 15H)-dione;

[0594] [7R, 16a(17)Z]-19-chloro-2-methyl-6, 7, 9, 10-tetrahydro-lH-12, 14- (ethenediyl)dipyrrolo[3, 2-i: 3', 4'-l] [l, 4, 7]dioxazacyclopentadecine-4, 16(5H, 15H)-dione;

[0595] [7R, 16a(17)Z]-N-(azetidin-3-yl)-19-chloro-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16- octahydro-1 H-12, 14-(ethenediyl)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7- formamide;

[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-1 H-12, 14-(ethenediyl)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7- formamide;

[0597] [7R, 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- (ethenediyl)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

[0598] [7R, 16a(17)Z]-19-chloro-2,5-dimethyl-4,16-dioxo-N-[(3R)-pyrrolidin-3-yl]-4,5,6,7,9,10,15,16- octahydro-1 H-12, 14-(ethenediyl)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7- formamide;

[0599] [7R, 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- (ethenediyl)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

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

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

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

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

[0604] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrolo[3,2-i:3',4'-l][l,4,7]dioxathiazacyclopentadecine-4,16(5H, 15H)-dione;

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

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

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

[0608] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,2- i:3',4'-l][l,4,7]oxadiazacyclopentadeca-4,16(5H,15H)-dione;

[0609] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,4- g:2',3'-j][l,4,13]oxadiazacyclopentadeca-4,16(5H,15H)-dione;

[0610] [16a(17)Z]-2,5-dimethyl-6,7-dihydro-lH,9H-12,14-(ethenediyl)-l lλ6-dipyrrrolo[3,4- g:2',3'-j][l,4,13]oxadiazacyclopentadeca-4,11,11,16(5H,10H,15H)-tetraone;

[0611] [16a(17)Z]-5-methyl-6,7,9,10-tetrahydro-lH-12,14-(ethenediyl)dipyrrrolo[3,4- g:2',3'-j][l,4,13]oxadiazacyclopentadeca-4,16(5H,15H)-dione;

[0612] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-lH-12,14- (ethenediyl)dipyrrrolo[4,3-i]pyrrolo[3,4-l][l,4,7]dioxazacyclopentadeca-4,16(5H,15H)- dione;

[0613] [16a(17)Z]-19-chloro-5-methyl-5,6,7,8,9,10-hexahydro-12,14- (ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]oxadiazacyclopentadeca-4,16(lH,15H)-dione;

[0614] [16a(17)Z]-19-chloro-2,5,8-trimethyl-5,6,7,8,9,10-hexahydro-12,14- (ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]oxadiazacyclopentadeca-4,16(lH,15H)-dione;

[0615] [16a(17)Z]-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-lH-12,14- (ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadeca-19-carbonitrile;

[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):

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651] and pharmaceutically acceptable salts thereof.

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

[0653] Pharmaceutical compositions

[0654] For therapeutic purposes, a pharmaceutical composition comprising a compound described herein can additionally comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate 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, bulking agents, emulsifiers, or taste modulating agents. In preferred embodiments, the pharmaceutical compositions according to the present disclosure are sterile compositions. Pharmaceutical compositions can be prepared using compounding techniques known or utilizable by those skilled in the art.

[0655] The present disclosure also encompasses 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 in suitable pharmaceutical solvents or carriers, or formulated with solid carriers into pills, tablets, troches, suppositories, sachets, dragees, granules, powders, reconstitutable powders, or capsules, according to conventional methods known in the art for preparing various dosage forms. The pharmaceutical compositions of the present disclosure can be administered by a suitable route of delivery (e.g., oral, parenteral, rectal, nasal, topical, or ocular route) or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0657] For oral administration, the compounds of the present disclosure can be provided in solid form (e.g., tablets or capsules) or in solution, emulsion, or suspension form. To prepare the oral compositions, the compounds of the present disclosure can be formulated to yield, for example, a dosage of 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 can include the active ingredient in admixture with a pharmaceutical acceptable compatible excipient such as a diluent, disintegrant, binder, lubricant, sweetening, flavoring, coloring, and preservative. Suitable inert fillers include sodium and calcium carbonates, sodium and calcium phosphates, lactose, starches, sugars, dextrose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starches, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrants. Binders can include starch and gelatin. If present, lubricants can be magnesium stearate, stearic acid, or talc. If desired, tablets can be coated with a material such as a material such as glycerol monostearate or glycerol distearate to delay absorption in the gastrointestinal tract, or can 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, an oil such as peanut or olive oil, liquid paraffin, a mixture of mono- and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0659] Liquid for oral administration can be in the form of suspensions, solutions, emulsions, or syrups or can be lyophilized or in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions can optionally contain: pharmaceutically acceptable excipients such as suspending agents (for example sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and the like); non-aqueous vehicles, for example, oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents, for example, lecithin; and, if desired, flavoring or coloring agents.

[0660] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the present disclosure can be provided in the form of sterile aqueous solutions or suspensions, buffered to an appropriate pH and rendered isotonic for administration, or in the form of a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms can be provided in unit-dose form, for example, in ampules or single-use disposable injection devices; in multi-dose form, for example, in vials from which the appropriate dose can be withdrawn; or in solid form or pre-concentrate form for reconstitution as a solution or suspension for injection. Illustrative infusion doses range from about 1 to 1000 pg / kg of agent per minute of mixture of agent and pharmaceutical carrier over a period ranging from a few minutes to several days.

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

[0662] For topical administration, the compounds of the present disclosure are preferably formulated in a cream or ointment or similar vehicle suitable for topical administration. For topical administration, the compounds of the present invention can be mixed with a pharmaceutical carrier at concentrations of about 0.1% to about 10% drug: vehicle. Another mode of administration of the agents of the present disclosure can utilize a patch formulation for transdermal delivery.

[0663] As used herein, the terms "treat" and "treatment" encompass both "prophylactic" and "curative" treatment. "Prophylactic" treatment is intended to indicate delaying the development of a disease, a symptom of a disease, or a medical condition, inhibiting a symptom from occurring, or reducing the risk of developing or experiencing a recurrence of a disease or a symptom. "Curative" treatment includes reducing the severity of an existing disease, symptom, or condition or inhibiting its worsening. Thus, treatment includes ameliorating an existing disease symptom or preventing its worsening; preventing other symptoms from occurring; ameliorating or preventing an underlying systemic cause of symptoms; inhibiting a disorder or disease, for example, arresting the development of a disorder or disease; relieving a disorder or disease; causing regression of a disorder or disease; relieving conditions caused by a disease or disorder; or halting symptoms of a disease or disorder.

[0664] The term "individual" refers to a mammalian patient, such as a human, in need of such treatment.

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

[0666] In one aspect, the compounds and pharmaceutical compositions of the present disclosure specifically target tyrosine receptor kinases, particularly EGFR. Accordingly, these compounds and pharmaceutical compositions are useful for preventing, reversing, slowing, or inhibiting the activity of one or more of these kinases. In preferred embodiments, the methods of treatment target cancer. In other embodiments, the methods are used to treat lung cancer or non-small cell lung cancer.

[0667] In the inhibition methods of the present disclosure, an "effective amount" means an amount sufficient to inhibit a target protein. Such target modulation can be measured by routine analytical methods, such as those described below. Such modulation is applicable to a variety of situations, including in vitro assays. In such methods, the cells are preferably cancer cells that have aberrant signaling due to upregulation of EGFR.

[0668] In methods of treatment according to the present disclosure, an "effective amount" means an amount or dose of a compound of the present disclosure typically sufficient to produce a desired therapeutic benefit in a subject in need thereof. An effective amount or dose of a compound of the present disclosure can be determined by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine 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 health status and weight of the subject, the judgment of the treating physician, and the like. An exemplary dose is in the range of 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. The total dose can be administered in single or divided dosage units (e.g., BID, TID, QID).

[0669] Once improvement of the patient's disease has occurred, the dose can be adjusted to a maintenance dosage regimen for continued treatment or prophylactic treatment. For example, the dosage or frequency of administration, or both, can be reduced to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if an adverse effect only occurs at a certain dosage or frequency level, the treatment can be stopped altogether.

[0670] Pharmaceutical Combinations

[0671] The compounds of the present invention described herein can be used in pharmaceutical compositions or methods in combination with one or more other active ingredients to treat the diseases and conditions described herein. Other active ingredients include other therapies or agents that ameliorate the adverse effects of the therapy intended for the target disease. Such combinations can be used to increase efficacy, improve other disease symptoms, reduce one or more side effects, or reduce the desired dose of the compounds of the present invention. The other active ingredients can be administered separately, by a separate pharmaceutical composition from the compounds of the present disclosure, or can be included in a single pharmaceutical composition with the compounds of the present disclosure. The other active ingredients can be administered simultaneously, prior to, or after the administration of the compounds of the present disclosure.

[0672] Combination agents include other active ingredients known or discovered to be effective in treating the diseases and conditions described herein, including active ingredients active against another target associated with the disease. For example, the compositions and formulations of the disclosure and methods of treatment can additionally comprise other drugs or agents, such as other active agents useful in treating or ameliorating the 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 chemotherapeutics, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinums, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory drugs, such as NSAIDs. The pharmaceutical compositions of the disclosure can additionally comprise one or more such active agents, and the methods of treatment can additionally comprise administering an effective amount of one or more such active agents.

[0673] Chemical synthesis methods

[0674] The following examples are provided for illustration, and not limitation of the disclosure. Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified to obtain other compounds of Formulae (I)-(VIII) by selecting appropriate starting materials and reagents.

[0675] In some embodiments, the disclosure provides a compound of Formula (IX)

[0676]

[0677] A' is 5- to 10-membered heteroaryl or C6-C 10 aryl, optionally substituted with one or more of deuterium, halogen, -OCi-C6alkyl, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, 5- to 10-membered heteroaryl, -OR 10 aryl, optionally substituted with one or more of deuterium, halogen, -OCi-C6alkyl, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Ci0aryl, 5- to 10-membered heteroaryl, -OR a , -OC(0)R a , -OC(0)NR a R b , -OS(0)R a , -OS(0)2R a , -SR a , -S(0)R a , -S(0)2R a , -S(0)NR a R b , -S(0)2NR a Rb , -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 , -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 each hydrogen atom in -OC1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -OR 10 , -OC(O)R e , -OC(O)NR e R e , -OS(O)R f , -OS(O)2R e , -OS(O)NR, -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;

[0678] Z' is 3- to 7-membered heterocycloalkyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -C(R a )(R b )H, -C(O)R a , -OR a , -NRa R b -SR a -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)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;

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

[0680] X 1 is -N-, -C(R 7 )- or a bond to Z'; X 2 is -N-, -C(R 8 )- or a bond to Z'; with the proviso that one of X 1 or X 2 is a bond to Z';

[0681] X 3 is -N- or -C(R 9 )-;

[0682] X 4 is -N- or -C(R 10 )-;

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

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

[0685] R 6 is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or -CN;

[0686] R 7 , R 8 , R 9 and R 10 are each independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -OC1-C6alkyl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)Ra -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 to which they are attached form a C4-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-C 10 aryl group, wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C4-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10each hydrogen atom in aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently 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;

[0687] R 11 independently H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3 to 7 membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -OR 10 independently H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3 to 7 membered heterocycloalkyl, C6-C 10 each hydrogen atom in aryl and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -OR e -CN, -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 aryl and 5- to 10-membered heteroaryl is independently optionally substituted by -OH, -OPG, -CN, -OCi-C6alkyl, -NH2, -NHPG, -NH(Ci-C6alkyl), -N(Ci-C6alkyl)2, -NHC(O)Ci-C6alkyl, -N(Ci-C6alkyl)C(O)Ci-C6alkyl, -NHC(O)NH2, -NHC(O)NHCi-C6alkyl, -N(Ci-C6alkyl)C(O)NH2, -N(Ci-C6alkyl)C(O)NHCi-C6alkyl, -NHC(O)N(Ci-C6alkyl)2, -N(Ci-C6alkyl)C(O)N(Ci-C6alkyl)2, -NHC(O)OCi-C6alkyl, -N(Ci-C6alkyl)C(O)OCi-C6alkyl, -NHS(O)(Ci-C6alkyl), -NHS(O)2(Ci-C6alkyl), -N(Ci-C6alkyl)S(O)(Ci-C6alkyl), -N(Ci-C6alkyl)S(O)2(Ci-C6alkyl), -NHS(O)NH2, -NHS(O)2NH2, -N(Ci-C6alkyl)S(O)NH2, -N(Ci-C6alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6alkyl), -NHS(O)2NH(Ci-C6alkyl), -NHS(O)N(Ci-C6alkyl)2, -NHS(O)2N(Ci-C6alkyl)2, -N(Ci-C6alkyl)S(O)NH(Ci-C6alkyl), -N(Ci-C6alkyl)S(O)2NH(Ci-C6alkyl), -N(Ci-C6alkyl)S(O)N(Ci-C6alkyl)2, -N(Ci-C6alkyl)S(O)2N(Ci-C6alkyl)2, -CO2H, -COOPG, -C(O)OCi-C6alkyl, -C(O)NH2, -C(O)NHPG, -C(O)NH(Ci-C6alkyl), -C(O)N(Ci-C6alkyl)2, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)NH(Ci-C6alkyl), -S(O)2NH(Ci-C6alkyl), -S(O)N(Ci-C6alkyl)2, -S(O)2N(Ci-C6alkyl)2, -P(Ci-C6alkyl)2, -P(O)(Ci-C6alkyl)2, C3-C6cycloalkyl, or 3- to 7-membered heterocycloalkyl; and

[0689] PG is a protecting group.

[0690] Abbreviations: The examples described herein use materials described by the following

[0691]

[0692]

[0693] General Method A

[0694]

[0695] A mixture of oxindole 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 upon cooling the reaction mixture, the mixture was concentrated and purified by column chromatography.

[0696] Intermediates A-1 to A-26 can be prepared by General Method A using the corresponding starting materials A1 and A2 as shown in the table below:

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703] General Method B-I

[0704]

[0705] Step 1. To a solution of B1-1 (1.0 eq.) and B2-1 (1.5 eq.) in DMF (0.25 M) was added Cs2CO3 (2.0 eq.) and the mixture was heated at 60-80 °C under nitrogen until the reaction was complete. Water (5 eq. volume of DMF) was added to the cooled DMF solution and the product was extracted with ethyl acetate (1 eq. volume of water) three times. The combined extracts were washed with water, aqueous HC1 (1 N), brine, and dried over magnesium sulfate. After filtration and condensation, the crude product was purified on a silica gel column to give the pure product B3-1.

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

[0707] Step 2. To a solution of B3-1 (1.0 eq.) in anhydrous acetonitrile (0.25 M) add N- bromosuccinimide (1.05 eq.) and stir the solution at ambient temperature until the reaction is complete. Quench the reaction with aqueous sodium thiosulfate (0.1 N) followed by removal of acetonitrile in vacuo. 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 give the pure product B4-1.

[0708] Step 3. A mixture of B4-1 (1.0 eq), bis(pinacolato)diboron (1.2 eq), KOAc (3.0 eq) and catalyst Pd(dppf)Cl2 / CH2Cl2(0.05 eq) in anhydrous DMF (0.5 M) is purged with nitrogen. Heat it at about 95 °C under nitrogen for about 15 h. Cool the reaction solution and dilute with ethyl acetate (5 volumes of DMF) and filter through a silica gel column and concentrate. Further purify the residue by silica gel flash chromatography to give the pure product B-I-1.

[0709] The following pinacol boronates B-I-1 to B-I-16 were prepared by General Method B-I using the corresponding starting materials B1 and B2:

[0710]

[0711]

[0712]

[0713] General Method B-II

[0714]

[0715] Step 1. To a solution of B5-1 (1.0 eq.) and B2-2 (1.5 eq.) in DMF (0.25 M) was added Cs2CO3 (2 eq.) and the mixture was heated at 60-80 °C under nitrogen until the reaction was complete. Water (5 volumes of DMF) was added to the cooled DMF solution and the product was extracted with ethyl acetate (1 volume of water) three times. The combined extracts were washed with water, aqueous HC1 (1 N), brine, and dried over MgSO4. After filtration and condensation, the crude product was purified on a silica gel column to give the pure product B6-1.

[0716] Step 2. A mixture of B6-1 (1.0 eq), bis(pinacolato)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. It was heated at about 95 °C under nitrogen for about 15 hours. The reaction solution was cooled and diluted with ethyl acetate (5 volumes of DMF) and filtered through a silica gel column and concentrated. The residue was further purified by silica gel flash chromatography to give the pure product B-II-1.

[0717] The following pinacol boronates B-II-1 to B-II-10 were prepared by General Method B-II using the corresponding starting materials B5 and B2 as shown in the table below:

[0718]

[0719]

[0720] General Method B-III

[0721]

[0722] Step 1. At ambient temperature, B7-1 (1.0 eq.) was added to a suspension of NaH (60% in mineral oil, 1.1 eq.) in THF (0.5 M). After 30 minutes, B8-1 (1.0 eq) was added to the above suspension. The mixture was stirred at ambient temperature until the reaction was complete, quenched with saturated aqueous ammonium chloride solution, and extracted with EtOAc three times. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated and purified on a silica gel column to give B9-1.

[0723] Step 2. To a solution of B9-1 (1.0 eq.) in dry THF (0.2 M) was added n-BuLi (2.5 M in hexanes, 1.1 eq.) at 0 °C. The reaction solution was stirred at ambient temperature for 1 h, then cooled to -78 °C. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.05 eq.). After 15 min at -78 °C, the reaction was allowed to warm to 0 °C over 1 h. The reaction was diluted with saturated NH4Cl solution and extracted with DCM. The organics were dried over Na2SO4, concentrated and purified on a silica gel column to give B-III-1.

[0724] The following pinacol boronates B-III-1 to B-III-6 were prepared by General Method B-III using the corresponding starting materials B7 and B8 as shown in the table below:

[0725]

[0726]

[0727] General Method B-IV

[0728]

[0729] Step 1. To a solution of B10-1 (1 eq.) in methanol (0.2 M) and acetic acid (1.5 eq.) was added B11-1 (1 eq.) and NaCNBH3 (2 eq.) at ambient temperature. The mixture was stirred for 1 h and partitioned between water and ethyl acetate. The organic phase was separated, washed sequentially with saturated NaHCO3 and brine, concentrated and dried in vacuo. The residue was dissolved in CH2Cl2(0.2 M) and the solution was cooled to 0 °C. To the solution was added di-(tert-butyl)dicarbonate (1.2 eq) portionwise. The ice bath was removed and the mixture was stirred at ambient temperature overnight. The reaction solution was diluted with dichloromethane, washed with water, and dried over magnesium sulfate. After filtration and condensation, the residue was purified on a silica gel column to give B12-1.

[0730] Steps 2 and 3 were the same as steps 2 and 3 in General Method B-I to give B-IV-1.

[0731] The following pinacol boronates B-IV-1 to B-IV-7 were prepared by General Method B-IV using the corresponding starting materials B10 and B11 as shown in the table below:

[0732]

[0733]

[0734] General Method C

[0735]

[0736] To a solution of A-1 (1.0 eq.) and B-1 (1.2 eq.) and Cs2C03(3 eq.) in DME / H20 (5:1, 0.2 M) was added Pd(PPh3)2Cl2(0.05 eq.) under N2. The mixture was stirred at 85 °C overnight, cooled to ambient temperature, and quenched with H20. The resulting mixture was extracted with EtOAc three times. The combined extracts were washed with brine and dried over anhydrous Na2S04. After filtration and condensation, the resulting residue was purified by silica gel column chromatography to give the desired product C-1.

[0737] The following intermediates C-1 to C-66 were prepared by General Method C using two corresponding starting materials A and B as shown in the following table:

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754] General Method D

[0755]

[0756] To a stirred solution of A-9 (1.0 eq.) in toluene (0.2 M) under nitrogen was added D1-1 (1.5 eq.) and sodium tert-butoxide (3 eq.), BINAP (0.05 eq.) and Pd(OAc)2(0.05). The mixture was heated at 85 °C for 20 h and cooled to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride 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 General Method D with two corresponding starting materials A and D1 as shown in the table below:

[0758]

[0759]

[0760]

[0761]

[0762] General Method E

[0763]

[0764] To a solution of A-23 (1.0 eq.) and E1-1 (1.5 eq.) in DMF (0.25 M) was added Cs2CO3(2.0 eq.) and the mixture was heated at 60-80 °C under nitrogen until the reaction was complete. Water (5 volumes of DMF) was added to the cooled DMF solution and the product was extracted with ethyl acetate (1 volume of water) three times. The combined extracts were washed with water, aqueous HC1 (1 N), brine, and dried over magnesium sulfate. After filtration and condensation, the crude product was purified on a silica gel column to give the pure product E-1.

[0765] The following intermediates E-1 to E-16 were prepared using General Method E with two corresponding starting materials A and E1 as shown in the table below:

[0766]

[0767]

[0768]

[0769]

[0770] General Method F

[0771]

[0772] To a solution of E-16 (1.0 eq.) in DCM (0.2 M) at 0 °C was added m- chloroperbenzoic acid (m-CPBA) (3 eq.). The reaction mixture was allowed to warm to ambient temperature and stirred for 4 h. The mixture was quenched with aqueous 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 flash column chromatography to give F-1.

[0773] General Method G

[0774]

[0775] Step 1. To a solution of A1-19 (1.0 eq.) in DCM (0.2 M) and Et3N (4 eq.) was added MsCl (3 eq.) in an ice bath and the mixture was stirred at 0 °C to ambient temperature overnight. The reaction was diluted with DCM, washed with ice water and brine, and dried over Na2S04. After filtration and condensation, the residue was dried under vacuum to give G1-1 which was 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 min, G1-1 (1.0 eq) was added to the above suspension. Upon completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc three times. The combined extracts were washed with brine, dried over Na2S04, filtered, concentrated and dried under vacuum. The residue was dissolved in THF / water (1 : 1, 0.5 M) and to the mixture was added aqueous NaOH (6 M, 3 eq.). The resulting mixture was stirred at 60 °C until hydrolysis was complete. The cooled reaction solution was diluted with EtOAc, washed with brine and dried over Na2S04. After filtration and condensation, the residue was purified by silica gel column to give G3-1.

[0777] Step 3. Following General Procedure A, G3-1 was reacted with A2-2 to give G-1.

[0778] The following intermediates G-1 to G-4 were prepared by General Method G using two corresponding starting materials A1 and G2 as shown in the table below:

[0779]

[0780]

[0781] General Method H

[0782]

[0783] Step 1. To a solution of A1-22 (1.0 eq.) and H1-1 (1.0 eq.) in DMF (0.2 M) was added DIPEA (3 eq.) and diphenylphosphoric acid pentfluorophenyl ester (FDPP) (1.1 eq). The solution was stirred at ambient temperature until amide formation was complete. The mixture was diluted with water and extracted with EtOAc three times. The combined extracts were washed with water, aqueous HC1 (1 N), saturated aqueous Na2C03, and brine three times, dried over Na2S04, and concentrated. The resulting residue was purified by silica gel column to give H2-1.

[0784] Step 2. Following general procedure A, H2-1 was reacted with A2-2 to give H-1.

[0785] The following intermediates H-1 to H-10 were prepared by General Method H using two corresponding starting materials A1 and H1 as shown in the table below:

[0786]

[0787]

[0788]

[0789] General Method I

[0790]

[0791] Step 1. To a solution of A1-31 (1.0 eq.) and D1-13 (1.0 eq.) in DMF (0.2 M) was added DIPEA (3 eq.) and diphenylphosphoric acid pentfluorophenyl ester (FDPP) (1.1 eq). The solution was stirred at ambient temperature until amide formation was complete. The mixture was diluted with water and extracted with EtOAc three times. The combined extracts were washed with water, aqueous HC1 (1 N), saturated aqueous Na2C03, and brine three times, dried over Na2S04, and concentrated. The resulting residue was purified by silica gel column to give 11-1.

[0792] Step 2. Following general procedure A, 11-1 was reacted with A2-2 to give I-1.

[0793] The following intermediates I-1 to I-5 were prepared by General Method I using two corresponding starting materials A1 and D1 as shown in the table below:

[0794]

[0795]

[0796]

[0797] General Procedure J

[0798]

[0799] Step 1. To a solution of C-1 (1.0 eq.) in MeOH (0.2 M) was added LiOH (3 eq) in H2O (1 M). The mixture was stirred at 60 °C until the hydrolysis reaction was complete. The solution was cooled to ambient temperature, concentrated to remove methanol, acidified with aqueous HC1 (1 N) until the pH was about 4-5, and then extracted with CH2Cl2. The combined extracts were dried over Na2SO4, concentrated and dried in vacuum. The resulting crude solid was dissolved in CH2Cl2(0.2 M) and to the solution was added a solution of HC1 in dioxane (4 eq HC1). The solution was stirred at 40 °C until the de-Boc was complete. The solvent was removed in a rotary evaporator and the residue was dried in vacuum to give crude product J-1, which was used in the next step without purification.

[0800] Step 2. To a solution of J-1 (1 eq.) in DMF (0.2 M) was added DIPEA (3 eq.) and diphenyl phosphoric acid pentfluorophenyl ester (FDPP) (1.1 eq). The solution was stirred at ambient temperature until the amide formation was complete. The mixture was diluted with water and extracted with EtOAc three times. The combined extracts were washed with water, aqueous HC1 (1 N), saturated aqueous Na2CO3, and brine three times, dried over Na2SO4, and concentrated. The resulting residue was purified by silica gel column to give compound 1.

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

[0802] General Procedure K

[0803]

[0804] To a mixture of [2-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]ethyl]pyrazol-3-yl]boronic acid (1 eq), 5-bromoindolin-2-one (1.3 eq) and Cs2CO3(3 eq) in dioxane and H2O was added Pd(PPh3)2Cl2(0.1 eq) under nitrogen. The mixture was stirred at 100 °C under N2for 16 h, then cooled and concentrated in vacuo. The residue was purified by column chromatography (SiO2) to give tert-butyl N-methyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate (K-1).

[0805] General Method I

[0806]

[0807] To a solution of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]-N- methyl-carbamate (1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (1.5 eq) in dioxane (17 mL) was added Pd(dppf)Cl2(0.1 eq) and aqueous Na2CO3(2 M, 3.0 eq) under nitrogen. The mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. Upon completion, the mixture was concentrated in vacuo to give the title crude compound. The residue was purified by silica gel column to give tert-butyl N-methyl-N-[2-[[2-methyl-4-(2-oxoindolin-5-yl)pyrazol-3-yl]methoxy]ethyl]carbamate (L-1).

[0808] General Method M

[0809]

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

[0811] General Method N

[0812]

[0813] Step 1. To a solution of tert-butyl N-methyl-N-[2-[2-[5-(2-oxoindolin-5- yl)pyrazol-l-yl]ethoxy]ethyl]carbamate (1 eq) in DCM was added HC1 / dioxane (4 M, 10 eq) and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give 5-[2-[2-[2-(methylamino)ethoxy]ethyl]pyrazol-3-yl]indolin-2-one hydrochloride.

[0814] Step 2. To a solution of 5-[2-[2-[2-(methylamino)ethoxy]ethyl]pyrazol-3-yl]indolin-2- one hydrochloride (0.34 mmol), 2-formyl-5-methyl-lH-pyrrole-3-carboxylic acid (1 eq) in acetonitrile was added 1-methylimidazole (3 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium hexafluorophosphate (1.5 eq) and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography. The crude product was triturated with MeOH at 25 °C for 10 min followed by filtration to give 2-formyl-N,5-dimethyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-l- yl]ethoxy]ethyl]-lH-pyrrole-3-carboxamide (N-l).

[0815] General Method O

[0816]

[0817] To a solution of N-l (1 eq) in EtOH was added piperidine (2 eq). The mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled and concentrated in vacuo. The crude product was triturated with MeOH at 25 °C for 10 min to give the title compound (41).

[0818] Example 1

[0819] Methyl 2-[(Z)-(5-chloro-2-oxo-lH-pyrrolo[2,3-c]pyridine-3-ylidene)methyl]-lH- pyrrole-3-carboxylate (A-27) was prepared according to General Method A

[0820]

[0821] A mixture of 5-chloro-l,3-dihydropyrrolo[2,3-c]pyridin-2-one (1.0 g, 5.93 mmol, 1 eq), methyl 2-formyl-lH-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 h. Upon completion, the mixture was cooled to ambient temperature and the product was precipitated out. The solid was filtered, washed with EtOH (30 mL) and dried under vacuum to give methyl 2-[(Z)-(5-chloro-2-oxo-lH-pyrrolo[2,3-c]pyridine-3- ylidene)methyl]-lH-pyrrole-3-carboxylate (1.6 g, 4.21 mmol, 71 % yield) as a yellow powder. 1 H NMR (400 MHz, DMSO-d6) δ (ppm).

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

[0823]

[0824] Example 2

[0825] tert-Butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazole-l-carboxylate (B-l-2) was prepared according to General Procedure B-I.

[0826]

[0827] Step 1: To a solution of l,2-dihydropyrazol-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) was added (Boc)20 (14.28 g, 65.4 mmol, 15.0 mL, 1.1 eq) at 25 °C. The mixture was stirred at 25 °C for 4 h. Upon completion, the mixture was diluted with DCM (200 mL), washed with brine (100 mL). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to give tert-butyl 5-oxo-lH-pyrazole-2-carboxylate (9.0 g, 47.4 mmol, 79.7 % yield, 97 % purity) as a light yellow powder. 1 H NMR (400 MHz, CDC13) δ (ppm) 7.81 (d, J = 3.2 Hz, 1H), 5.90 (d, J = 3.2 Hz, 1H), 1.63 (s, 9H).

[0828] Step 2. To a solution of tert-butyl 5-oxo-lH-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) was added K2CO3 (7.88 g, 57.0 mmol, 1.5 eq). The mixture was stirred at 80 °C for 16 h. Upon completion, the mixture was diluted with EtOAc (100 mL), washed with brine (2 x 40 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by combi-flash (40 g silica gel column, 0-40 EtOAc / PE, eluted about 10%) to give tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]pyrazole-l- carboxylate (8.2 g, 22.8 mmol, 60% yield, 95% purity) as a white oil. 1 H NMR (400 MHz, DMSO-d6) d (ppm) 8.08 (d, J = 3.2 Hz, 1H), 6.93-6.83 (m, 1H), 6.08 (d, J = 3.2 Hz, 1H), 4.16 (t, J = 6.3 Hz, 2H), 3.10-2.99 (m, 2H), 2.53-2.50 (m, 2H), 1.55 (s, 9H), 1.37 (s, 9H).

[0829] Step 3. To a solution of tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]pyrazole-l- carboxylate (1.50 g, 4.39 mmol, 1 eq) and Pin2B2 (2.23 g, 8.7 mmol, 2.0 eq) in THF (30 mL) was added (l,5-cyclooctadiene)(methoxy)iridium(l) dimer (291.2 mg, 439 pmol, 0.1 eq) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (235 mg, 878 pmol, 0.2 eq) under nitrogen atmosphere. The mixture was stirred at 70 °C for 16 h. Upon completion, the mixture was diluted with EtOAc (50 mL), washed with brine (2 x 20 mL). The organic layer was dried over Na2SO4, concentrated in vacuo and purified by silica gel column (40 g, 0-100% EA / PE, eluted about 35%) to give tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole-l- carboxylate (B-I-2, 2.3 g, 2.9 mmol, 67.2% yield) as a white oil. 1H NMR (400 MHz, DMSO-d6) d (ppm) 8.10 (s, 1 H), 6.81 (t, J = 5.2 Hz, 1 H), 3.80-3.76 (m, 2 H), 3.06 (q, J = 6.4 Hz, 2 H), 1.84-1.82 (m, 1 H), 1.55 (s, 9 H), 1.37 (s, 9 H), 1.25 (s, 12 H).

[0830] Example 3

[0831] N-[3-[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]oxypropyl]tert- butylcarbamate (B-I-5) was prepared according to General Procedure B-I

[0832]

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

[0834] Step 2. To a solution of tert-butyl N-[3-(l-methylpyrazol-3-yl)oxypropyl]carbamate (7 g, 27.42 mmol, 1 eq) in ACN (40 mL) was added NBS (5.03 g, 28.24 mmol, 1.03 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. Upon 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 tert-butyl N-[3-(4-bromo-l-methyl-pyrazol-3-yl)oxypropyl]carbamate (7.3 g, 21.84 mmol, 79.6% yield) as colorless oil. 1 H NMR (400 MHz, CDC13) d (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. To a mixture of tert-butyl N-[3-(4-bromo-l-methyl-pyrazol-3-yl)oxypropyl]carbamate (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) was added Xphos-Pd-G2 (706 mg, 897 pmol, 0.1 eq) under nitrogen. The mixture was stirred at 60 °C for 16 h under nitrogen atmosphere. Upon completion, the mixture was cooled to ambient temperature, diluted with PE (200 mL) and filtered. The organic layer was concentrated in vacuo to give a grassy oil. The crude material was purified by silica gel column (20 g, 0-100% EtOAc / PE, 15 min, eluted ~ 60%) to give tert-butyl N-[3-[l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-3-yl]oxypropyl]carbamate (B-l-5, 2.9 g, 6.08 mmol, 68% yield) as brown gum. LCMS: m / z 381.9 (M+l) + .

[0836] Example 4

[0837] Preparation of tert-butyl N-[3-[2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy]propyl]carbamate (B-II-l) according to general method B-II

[0838]

[0839] To a mixture of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-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) was added tert-butyl N-(3-bromopropyl)carbamate (11.9 g, 50.0 mmol, 1.1 eq). The mixture was stirred at 80 °C for 16 h. Upon completion, the mixture was cooled, diluted with ethyl acetate (200 mL), washed with brine (2 x 50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-100% EtOAc / PE, eluted ~25%) to give tert-butyl N-[3-[2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]propyl]carbamate (B-II-l, 10 g, 22.5 mmol, 49.5% yield, 85% purity) as a colorless gum. 1 H NMR (400 MHz, CDC13) 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] tert-Butyl N-[3-[2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate (B-II-2) was prepared according to General Procedure B-II.

[0842] B-II-2 was prepared using a similar procedure to B-II-l.

[0843] Example 6

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

[0845]

[0846] To a mixture of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (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 was added MsCl (16.7 g, 146 mmol, 11.3 mL, 1.5 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was quenched with water (300 mL), the combined organic layers were washed with saturated NaHCO3(80 mL), brine (300 mL), dried over sodium sulfate, concentrated in vacuo to give methyl 2-[2-(tert-butoxycarbonylamino)ethoxy]ethanesulfonate (25.0 g, 75.0 mmol, 76.9% yield) as a light yellow gum. 1 H NMR (400 MHz, DMSO-d6) δ = 6.79 (s, 1H), 4.30 (t, J = 4.8 Hz, 2H), 3.64 (t, J = 4.8 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H), 3.18 (s, 3H), 3.09 (t, J = 6.0 Hz, 2H), 1.38 (s, 9H).

[0847] Step 2. To a solution of methyl 2-[2-(tert-butoxycarbonylamino)ethoxy]ethanesulfonate (16.0 g, 56.5 mmol, 1 eq) in DMF (80 mL) was added 1H-pyrazole (3.84 g, 56.5 mmol, 1.0 eq) and Cs2CO3(36.8 g, 112 mmol, 2 eq). The mixture was stirred at 50 °C for 2 h. Upon completion, the mixture was quenched with water (200 mL), diluted with EA (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, concentrated in vacuo to give crude material. The residue was purified by column chromatography (SiO2, DCM:MeOH = 20:1) to give tert-butyl N-[2-(2-pyrazol-l- ylethoxy)ethyl]carbamate (13.0 g, 48.3 mmol, 85.6% yield) as a colorless oil. LCMS: m / z 256.0 (M+l) + .

[0848] Step 3. To a solution of tert-butyl N-[2-(2-pyrazol-l-ylethoxy)ethyl]carbamate (2.00 g, 7.83 mmol, 1 eq) in 2-MeTHF (150 mL) was added n-BuLi (2.5 M, 9.40 mL, 3 eq) dropwise at -70 °C. The mixture was stirred at 25 °C for 0.5 h, then added triisopropyl borate (2.21 g, 11.7 mmol, 2.70 mL, 1.5 eq) in 2-MeTHF (150 mL) at -70 °C. The mixture was stirred at 25 °C for 1.5 h. Upon completion, the mixture was quenched with MeOH (50 mL), concentrated in vacuo and purified by reverse phase HPLC to give [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 (400 MHz, DMSO-d6) δ (ppm) 8.36 (m, 2H), 7.39 (s, 1H), 6.71 (s, 2H), 4.50 (t, J = 4.8 Hz, 2H,), 3.68 (t, J = 4.8 Hz, 2H), 3.33 (t, J = 6.0 Hz, 2H), 3.01 (t, J = 6.0 Hz, 2H), 1.37 (s, 9H). LCMS: m / z 300 (M+l) + .

[0849] Example 7

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

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

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

[0853]

[0854] Step 1. To a mixture of tert-butyl N-(2-hydroxyethyl)carbamate (1.00 g, 6.20 mmol, 1 eq.) and TEA (941 mg, 9.31 mmol, 1.5 eq.) in DCM (30 mL) was added MsCl (852 mg, 7.44 mmol, 1.2 eq.) in an ice bath. The mixture was stirred at 25 °C for 3 h. Upon completion, the mixture was quenched with water (10 mL) and diluted with DCM (20 mL). The organic layer was washed with saturated NaHC03(50 mL), brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give methylsulfonic acid (2-(tert-butoxycarbonylamino)ethyl) ester (1.20 g, 4.51 mmol, 72% yield, 90% purity) as a light yellow oil. 1 H NMR (400 MHz, CDC13) δ = 4.90 (s, 1H), 4.21 (t, J = 5.2 Hz, 2H), 3.41 (dd, J = 10.8, 5.6 Hz, 2H), 2.97 (s, 3H), 1.38 (s, 9H).

[0855] Step 2. Methylsulfonic acid 2-(tert-butoxycarbonylamino)ethyl ester (9.00 g, 37.0 mmol, 1.0 eq.) and 2-aminoethanol (22.9 g, 376 mmol, 10 eq.) were heated to 80 °C for 16 h. The mixture was quenched with water (200 mL) and diluted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, concentrated in vacuo to give tert-butyl (N-[2-(2-hydroxyethylamino)ethyl]carbamate (10.0 g, 36.7 mmol, 97.6% yield) as a light yellow solid. 1 H NMR (400 MHz, 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. To a solution of tert-butyl N-[2-(2-hydroxyethylamino)ethyl]carbamate (3.00 g, 14.6 mmol, 1 eq.) in THF (50 mL) and H20 (12 mL) was added NaHC03(3.70 g, 44.0 mmol, 3 eq.) and CbzCl (3.26 g, 19.0 mmol, 1.3 eq.). The mixture was stirred at 20 °C for 16 h. Upon completion, the mixture was quenched with water (150 mL), extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, concentrated in vacuo, and the residue was purified by flash chromatography (40 g silica gel column, 0% to 100% EtOAc / PE) to give benzyl N-[2-(tert-butoxycarbonylamino)ethyl]-N-(2- hydroxyethyl)carbamate (3.40 g, 9.54 mmol, 64.9% yield) as a colorless gum. 1 H NMR (400 MHz, DMSO-d6) d = 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 = 3.5 Hz, 2H), 3.31-3.24 (m, 4H), 3.07 (d, J = 6.3 Hz, 2H), 1.37 (s, 9H); LCMS: m / z 239.1 (M+1-100) + .

[0857] Step 4. To a solution of benzyl 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) was added MsCl (1.73 g, 15.0 mmol, 1.17 mL, 1.5 eq.) in an ice bath. The mixture was stirred at 25 °C for 3 h. Upon completion, the mixture was quenched with water (150 mL), diluted with DCM (3 x 150 mL). The combined organic layers were washed with saturated NaHC03(100 mL), brine (80 mL), dried over sodium sulfate, concentrated in vacuo to give the crude material (2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino]ethyl methanesulfonate, 4.00 g, 9.60 mmol, 95% yield) as a light yellow gum. LCMS: m / z 317.1 (M+1-100) + .

[0858] Step 5. To a solution of methylsulfonic acid 2-[benzyloxycarbonyl-[2-(tert- butoxycarbonylamino)ethyl]amino]ethyl ester (5.30 g, 12.7 mmol, 1.2 eq.) in DMF (40 mL) was added 1H-pyrazole (721 mg, 10.6 mmol, 1 eq.) and Cs2CO3(6.91 g, 21.2 mmol, 2 eq.). The mixture was stirred at 50 °C for 3 h. Upon completion, the mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (12 g silica gel column, EtOAc / PE 0% to 100%) to give benzyl N-[2-(tert-butoxycarbonylamino)ethyl]-N-(2-pyrazol-1- ylethyl)carbamate (3.60 g, 7.88 mmol, 74.2% yield) as a light yellow gum. LCMS: m / z 389.4 (M+1) + .

[0859] Step 6. To a mixture of benzyl N-[2-(tert-butoxycarbonylamino)ethyl]-N-(2-pyrazol-1- ylethyl)carbamate (1.60 g, 4.12 mmol, 1 eq.) in 2-MeTHF (70 mL) was added LDA (2 M, 6.18 mL, 3 eq.) dropwise at -70 °C under N2atmosphere. The mixture was stirred at -70 °C for 0.5 h, and then triisopropyl borate (1.55 g, 8.24 mmol, 2 eq.) was added. The resulting mixture was stirred at -70 °C under N2atmosphere for 1.5 h. Upon completion, the mixture was quenched with MeOH (10 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with pure water (70 mL) and the aqueous phase was lyophilized. The residue was purified by reverse phase preparative HPLC (0.5% FA as additive) to give [2-[2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)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 tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]carbamate (B-V-1) and tert-butyl N-[2-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3- yl]methoxy]ethyl]carbamate (B-VI-1)

[0862]

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

[0864] Step 2. To a solution of (4-bromo-2-methyl-pyrazol-3-yl)methanol (7.75 g, 40.6 mmol, 1 eq) in DCM (70 mL) was added CBr4(16.2 g, 48.7 mmol, 1.2 eq) at 0 °C, followed by dropwise addition of a solution 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 quenched slowly with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2S04, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE:EA = 25:1 to 3:1) to give 4-bromo-5-(bromomethyl)-1-methyl-pyrazole (7.60 g, 29.9 mmol, 73.8% yield) as colorless oil. 1 H NMR (400 MHz, DMSO-d6) d (ppm) 7.56 (s, 1H), 4.75 (s, 2H), 3.87 (s, 3H).

[0865] Step 3. To a solution of 4-bromo-5-(bromomethyl)-l-methyl-pyrazole (1.00 g, 3.94 mmol, 1 eq) in THF (2 mL) was added tert-butyl N-(2-hydroxyethyl)carbamate (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). The mixture was stirred at 25 °C under N2for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]carbamate (B-V-l, 1.2 g, 3.12 mmol, 79.3% yield) as a yellow oil. 1 H NMR (400 MHz, CDC13) 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 = 5.2 Hz, 2H), 1.44 (s, 9H).

[0866] Step 4. To a solution of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-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) was added [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphine (235 mg, 0.299 mmol, 0.1 eq) at 25 °C under nitrogen. The mixture was stirred at 60 °C under N2for 12 h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 25:1 to 3:1) to give tert-butyl N-[2-[[2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-3-yl]methoxy]ethyl]carbamate (B-VI-l, 1.55 g, 2.64 mmol, 88.3% yield) as a yellow oil. 1H NMR (400 MHz, CDC13) δ = 7.70 (s, 1H), 4.73 (s, 2H), 3.90 (s, 3H), 3.50 (d, J = 4.8 Hz, 2H), 3.32 (d, J = 4.8 Hz, 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-carbamic acid tert-butyl ester (B-V-2)

[0869]

[0870] To a solution of N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl] carbamic acid tert-butyl ester (640 mg, 1.91 mmol, 1 eq) in 2-MeTHF (30 mL) was added NaH (191 mg, 4.79 mmol, 60%, 2.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then CH3I (407.71 mg, 2.87 mmol, 1.5 eq) was added. The mixture was stirred at ambient temperature for 1.5 h. Upon completion, the mixture was poured into ice water (40 mL), extracted with EtOAc (80 mL), washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (PE:EA = 100:0 to 100:35) to give N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamic acid tert-butyl ester (630 mg, 1.81 mmol, 94% yield) as 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-carbamic acid tert-butyl ester (B-V-3)

[0873]

[0874] Step 1. To a solution of 4-bromo-2-methyl-pyrazine-3-carboxaldehyde (4.55 g, 24.1 mmol, 1 eq) and N-(2-aminoethyl)-N-methyl-carbamic acid tert-butyl ester (8.39 g, 48.2 mmol, 8.61 mL, 2 eq) in MeOH (90 mL) was added AcOH (1.45 g, 24.1 mmol, 1.38 mL, 1 eq). The reaction was stirred at 25 °C for 0.5 h, cooled to 0 °C and treated with NaBH(OAc)3 (7.66 g, 36.1 mmol, 1.5 eq). The mixture was stirred at 25 °C for 13 h, quenched with water (100 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. 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-carbamic acid 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. To a mixture of N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methylamino]ethyl]-N- methyl-carbamic acid tert-butyl ester (2.74 g, 7.89 mmol, 1 eq) in THF (80 mL) and NaHCO3 (1.99 g, 23.7 mmol, 3 eq) in H2O (20 mL) was added CbzCl (1.75 g, 10.3 mmol, 1.46 mL, 1.3 eq). The mixture was stirred at 20 °C for 16 h, quenched with water (80 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. 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-carbamic acid tert-butyl ester (B-V-3, 2.89 g, 5.83 mmol, 73.9% yield) as a colorless oil. 1 H NMR (400 MHz, CDC13) 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-carbamic acid tert-butyl ester (B-V-4) and N-methyl-N-[2-[methyl-[[2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]methyl]amino]ethyl]carbamic acid tert-butyl ester (B-IV-4) were prepared.

[0878]

[0879] To a solution of N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methylamino]ethyl]-N- methyl-carbamic acid tert-butyl ester (3.30 g, 9.50 mmol, 1 eq), (CH20)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) was added NaBH3CN (716 mg, 11.4 mmol, 1.2 eq) at 20 °C. The mixture was stirred for 16 h. Upon completion, the mixture was quenched with saturated NH4CI (10 mL), concentrated in vacuo, diluted with EtOAc (100 mL) and washed with brine (2 x 70 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column (PE:EA = 1 :0 to 100:40) to give N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methyl- amino]ethyl]-N-methyl-carbamic acid tert-butyl ester (B-V-4, 3 g, 8.30 mmol, 87% yield) as a colorless gum. 1 H NMR (400 MHz, CDCI3) d (ppm) 7.37 (s, 1 H), 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).

[0880]

[0881] To a solution of N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methyl- amino]ethyl]-N-methyl-carbamic acid tert-butyl ester (1.10 g, 3.04 mmol, 1.0 eq) in 2-MeTHF (45.0 mL) was added n-BuLi (2.5 M, 3.04 mL, 2.5 eq) at -70 °C. The mixture was stirred at -70 °C for 0.5 h, then 2- isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (849 mg, 4.57 mmol, 931 μί, 1.5 eq) was added at this temperature and stirred at -70 °C for 1.5 h. Upon completion, the mixture was quenched with saturated NH4CI (50.0 mL), extracted with EtOAc (100 mL). The organic layer was washed with brine (2 x 25.0 mL), dried over sodium sulfate, concentrated in vacuo to give N-methyl-N-[2-[methyl-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazol-3-yl]methyl]amino]ethyl]carbamic acid tert-butyl ester (1.6 g, 2.35 mmol, 77.2% yield).

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

[0883]

[0884] B-V-5 was prepared using a similar procedure as B-V-3. 1 H NMR (400 MHz, 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-carbamic acid tert-butyl ester (B-V-6)

[0886]

[0887] B-V-6 was prepared using a similar procedure as B-V-2, starting from (5- methylisoxazol-3-yl)methanol. 1H NMR (400 MHz, CDC13) δ = 4.55 (s, 2H), 3.62 (t, J = 5.6 Hz, 2H), 3.41 (d, J = 5.6 Hz, 2H), 2.91 (s, 3H), 2.42 (s, 3H), 1.44 (s, 9H).

[0888] Preparation of N-[2-[benzyloxycarbonyl-[(4-bromo-5-methyl-isoxazol-3- yl)methyl]amino]ethyl]-N-methyl-carbamic acid tert-butyl ester (B-V-7)

[0889]

[0890] Step 1. To a solution of (5-methylisoxazol-3-yl)methanol (10.0 g, 88.0 mmol, 1 eq.) in DCM (100 mL) was added Mn02(38.4 g, 442 mmol, 5 eq.). The mixture was stirred at 25 °C for 16 h and filtered. The filtrate was concentrated in vacuo to give 5-methylisoxazole-3-carbaldehyde (6.50 g, 35.0 mmol, 39.71% yield) as a yellow oil. 1 H NMR (400 MHz, CDC13) δ = 10.12 (s, 1H), 6.40 (s, 1H) 2.53 (s, 3H).

[0891] Step 2. To a solution of 5-methylisoxazole-3-carbaldehyde (6.50 g, 58.0 mmol, 1 eq.), N-(2-aminoethyl)-N-methyl-carbamic acid tert-butyl ester (11.2 g, 64.4 mmol, 11.5 mL, 1.1 eq.) in DCE (50 mL) was added AcOH (3.50 g, 58.0 mmol, 1 eq) and NaBH(OAc)3(24.8 g, 117 mmol, 2 eq). The mixture was stirred at 25 °C for 16 h. Upon completion, 50 mL of water was added and the reaction was extracted with EtOAc (3 x 50 ml). The combined extracts were concentrated in vacuo. The residue was purified by column chromatography (Si02, DCM / MeOH, 100:0 to 100:10) to give N-methyl-N-[2-[(5-methylisoxazol-3-yl)methylamino]ethyl]carbamic acid tert-butyl ester (1.30 g, 4.20 mmol, 7.18% yield) as a colorless oil. LC-MS: m / z 270.2 (M+l) + .

[0892] Step 3. To a solution of tert-butyl N-methyl-N-[2-[(5-methylisoxazol-3- yl)methylamino]ethyl]carbamate (1.20 g, 4.50 mmol, 1 eq.), benzyl chloroformate (912 mg, 5.30 mmol, 1.2 eq.) in THF (10 mL) and H2O (10 mL) was added NaHCO3(1.10 g, 13.4 mmol, 3 eq.). The mixture was stirred at 25 °C for 16 h. Upon completion, the reaction was extracted with EtOAc (3 x 10 ml) followed by concentration in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc, 100:1 to 100:25) to give tert-butyl N-[2-[benzyloxycarbonyl-[(5-methylisoxazol-3-yl)methyl]amino]ethyl]-N- methyl-carbamate (1.20 g, 2.60 mmol, 58% yield) as colorless oil. 1 H NMR (400 MHz, CDC13) 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. To a solution of tert-butyl N-[2-[benzyloxycarbonyl-[(5-methylisoxazol-3- yl)methyl]amino]ethyl]-N-methyl-carbamate (700 mg, 1.70 mmol, 1 eq.) in DMF (25 mL) was added NBS (462 mg, 2.60 mmol, 1.5 eq.). The mixture was stirred at 60 °C for 20 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (4 x 40 mL). The organic layer was dried over Na2SO4, concentrated in vacuo, purified by silica gel column (petroleum ether: EtOAc, 100:0 to 100:30) to give tert-butyl N-[2-[benzyloxycarbonyl-[(4-bromo-5-methyl- isoxazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate (B-V-7, 320 mg, 630 pmol, 36.4% yield) as colorless gum. 1 H NMR (400 MHz, CDC13) 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] tert-Butyl N-[2-[(4-bromo-2,5-dimethyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N- methyl-carbamate (B-V-8)

[0895]

[0896] Step 1. To a mixture of 2,5-dimethylpyrazole-3-carboxaldehyde (2.00 g, 16.1 mmol, 1 eq), tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (4.55 g, 24.2 mmol, 1.5 eq) in DCE (2 mL) was added AcOH (967 mg, 16.1 mmol, 1 eq). After 0.5 h at 25 °C, NaBH(OAc)3 (10.2 g, 48.3 mmol, 3 eq) was added at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was quenched by pouring into water, followed by extraction with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using silica gel (DCM:MeOH = 25:1 to 10:1) to give tert-butyl N-[2-[(2,5-dimethylpyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (1.80 g, 5.82 mmol, 36% yield) as a yellow oil. 1 H NMR (400 MHz, CDC13) δ = 9.93 (s, 1H), 5.92 (s, 1H), 3.80 (s, 3H), 3.60-3.48 (m, 2H), 3.40-3.28 (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. To a solution of tert-butyl N-[2-[(2,5-dimethylpyrazol-3-yl)methyl- methyl-amino]ethyl]-N-methyl-carbamate (1.7 g, 5.74 mmol, 1 eq) in DMF (2 mL) was added NBS (1.22 g, 6.88 mmol, 1.2 eq) at 25 °C. The mixture was stirred at 60 °C under N2for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography using silica gel (DCM:MeOH = 25:1 to 10:1) to give tert-butyl N-[2-[(4-bromo-2,5-dimethyl-pyrazol-3-yl)methyl-methyl- amino]ethyl]-N-methyl-carbamate (M-V-8, 1.3 g, 3.38 mmol, 58.9% yield, 97.5% purity) as a yellow oil. 1 H NMR (400 MHz, CDC13) 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 tert-butyl N-[2-[(2-bromophenyl)methyl-methyl-amino]ethyl]-N- methyl-carbamate (B-V-9)

[0899]

[0900] To a solution of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (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) was added NaBH(OAc)3(3.44 g, 16.2 mmol, 1.5 eq). The mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, concentrated in vacuo and purified by flash silica gel chromatography (40 g silica gel column, DCM / MeOH, 0% to 100%) to give tert-butyl N-[2-[(2-bromophenyl)methyl-methyl-amino]ethyl]-N-methyl- carbamate (M-V-9, 3.50 g, 8.82 mmol, 81.5% yield) as a colorless gum. LC-MS: m / z 357.9 (M+1) + .

[0901] Preparation of tert-butyl N-[3-(4-bromo-2,5-dimethyl-pyrazol-3-yl)oxypropyl]-N- methyl-carbamate (B-V-10)

[0902]

[0903] Step 1. To a solution of 2,5-dimethylpyrazol-3-ol (5 g, 44.59 mmol, 1 eq) and tert-butyl N-(3-bromopropyl)carbamate (12.74 g, 53.51 mmol, 1.2 eq) in DMF (180 mL) was added K2CO3(9.24 g, 66.8 mmol, 1.50 eq). The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove DMF. To the residue was added 1,4-dioxane (300 mL), and the mixture was filtered, washed with petroleum ether (30 mL x 3). The filtrate was washed with brine (15 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl N-(3-chlorophenyl)-N-methyl-carbamate (24.5 g, crude). 1 H NMR (400 MHz, DMSO-d6) d = 6.89 (s, 1H), 5.40 (s, 1H), 4.02-3.95 (m, 2H), 3.43 (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. To a solution of tert-butyl N-[3-(2,5-dimethylpyrazol-3-yl)oxypropyl]carbamate (5 g, 18.6 mmol, 1 eq) in THF (50 mL) at 0 °C under N2was added NaH (1.11 g, 27.8 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then Mel (3.95 g, 27.8 mmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 1 h, quenched by slow addition of water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl N-[3-(2,5-dimethylpyrazol-3-yl)oxypropyl]-N-methyl-carbamate (10 g, 31.7 mmol, 85.5% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) d = 5.39 (s, 1H), 4.00-3.96 (m, 2H), 3.44 (s, 3H), 3.33-3.29 (m, 2H), 2.77 (s, 3H), 2.02 (s, 3H), 1.93-1.85 (m, 2H), 1.33 (s, 9H).

[0905] Step 3. To a solution of N-[3-(2,5-dimethylpyrazol-3-yl)oxypropyl]-N- methyl-carbamic acid tert-butyl ester (6 g, 21.2 mmol, 1 eq) in ACN (30 mL) was added NBS (3.77 g, 21.2 mmol, 1 eq) at 25 °C and stirred under N2for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 25:1 to 2:1) to give N-[3-(4-bromo-2,5-dimethyl-pyrazol-3-yl)oxypropyl]-N- methyl-carbamic acid tert-butyl ester (B-V-10, 6.8 g, 18.2 mmol, 86% yield) as yellow oil. 1 H NMR (400 MHz, CDC13) 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-carbamic acid tert-butyl ester (B-V-11)

[0907]

[0908] Step 1. To a solution of ethyl 2,5-dimethylpyrazole-3-carboxylate (10 g, 59.4 mmol, 1 eq) in DCE (200 mL) was added NBS (12.7 g, 71.3 mmol, 1.2 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 25:1 to 2:1) to give ethyl 4-bromo-2,5-dimethyl-pyrazole-3-carboxylate (12 g, 45.2 mmol, 75.9% yield) as yellow oil. 1 H NMR (400 MHz, CDC13) δ = 4.35-4.29 (m, 2H), 4.02 (s, 3H), 2.17 (s, 3H), 1.34-1.32 (m, 3H).

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

[0910] Step 3. To a solution of (4-bromo-2,5-dimethyl-pyrazol-3-yl)methanol (6.2 g, 30.24 mmol, 1 eq) in DCM (120 mL) was added PBr3(8.18 g, 30.2 mmol, 1 eq) dropwise at 0-25 °C. The mixture was stirred at 25 °C for 4 h, quenched by slow addition of water and extracted with EtOA (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 25:1 to 3:1) to give 4-bromo-5-(bromomethyl)-1,3-dimethyl-pyrazole (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-dimethyl-pyrazole (4 g, 14.9 mmol, 1 eq) in THF (80 mL) was added tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (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). The mixture was stirred at 25 °C under N2for 16 h. After completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give tert-butyl N-[2-[(4-bromo-2,5-dimethyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (B-V-11, 5.5 g, 14.6 mmol, 97.6% yield) as a yellow oil. 1H NMR (400 MHz, CDC13) 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-carbamic acid tert-butyl ester (B-V-12)

[0913]

[0914] B-V-12 was prepared using a similar procedure to B-V-1 starting with 5- cyclopropylisoxazole-3-carboxylic acid. The bromination procedure was similar to that in B-V-7. 1 H NMR (400 MHz, CDC13) 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-cyclopropyl-isoxazol-3-yl)methoxy]ethyl]-N- methyl-carbamic acid tert-butyl ester (B-V-12)

[0916]

[0917] B-V-13 was prepared using a similar procedure to B-V-1 starting with ethyl 5- isopropylisoxazole-3-carboxylate. The bromination procedure was similar to that in B-V-7. 1 H NMR (400 MHz, CDC13) 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 = 7.2 Hz, 6H). LCMS: m / z 277.1 (M-Boc) + .

[0918] Preparation of N-[3-(4-bromo-2-methyl-pyrazol-3-yl)oxypropyl]-N-methyl- carbamic acid tert-butyl ester (B-V-14)

[0919]

[0920] B-V-14 was prepared using a similar procedure to B-V-10 using 2-methylpyrazole-3-ol as the starting material. 1 H NMR (400 MHz, CDC13) 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] B-V-14 was prepared using a similar procedure to B-V-10 using 2-methylpyrazole-3-ol as the starting material.

[0922]

[0923] To a solution of methyl 2-[(Z)-(5-chloro-2-oxo-lH-pyrrolo[2,3-c]pyridine-3- ylidene)methyl]-lH-pyrrole-3-carboxylate (500 mg, 1.65 mmol, 1 eq) and tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazole-l-carboxylate (3.85 g, 8.23 mmol, 5 eq) in dioxane (10 mL) and H20 (1 mL) was added Cs2C03(1.61 g, 4.94 mmol, 3 eq) and Pd(PPh3)2Cl2(115 mg, 0.165 mmol, 0.1 eq). The resulting mixture was stirred at 90 °C under N2atmosphere for 14 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH = 100:1 to 20:1) to give C-6a (251 mg, 0.412 mmol, 25% yield) as a white solid.

[0924] C-67 to C-73 were prepared following a similar procedure to C-6a.

[0925]

[0926]

[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.

[0928]

[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. 1H NMR (400 MHz, 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. To a solution of 2-[(Z)-[5-[3-(3-aminopropoxy)-1H-pyrazol-4-yl]-2-oxo-1H- pyrrolo[2,3-c]pyridine-3-ylidene]methyl]-1H-pyrrole-3-carboxylic acid (70 mg, HC1) in DMF (3.5 mL) was added DIPEA (114 mg, 0.887 mmol, 0.154 mL, 5 eq) and FDPP (136 mg, 0.355 mmol, 2 eq). The mixture was stirred at 20 °C for 0.5 h. Upon completion, the reaction was quenched with H2O (30 mL) and filtered. The filter cake was concentrated in vacuo to give the crude product which was then triturated with MeOH (2 mL), filtered and dried in vacuo to give 6 as a yellow solid (23.4 mg, 32.5% yield). 1 H NMR (400 MHz, 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, 2H), 8.03 (d, J = 1.6 Hz, 1H), 7.35 (t, J = 2.4 Hz, 1H), 6.83 (s, 1H), 4.43 (t, J = 6.4 Hz, 2H), 3.75 (s, 2H), 2.22 (s, 2H); LCMS m / z 377.4 (M+1) + .

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

[0933]

[0934]

[0935] N-methyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamic acid tert-butyl ester (K-1) was prepared according to general procedure K

[0936]

[0937] 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-bromoindolin-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) was added Pd(PPh3)2Cl2(131 mg, 0.187 mmol, 0.1 eq) under nitrogen. The mixture was stirred at 100 °C under N2for 16 h, then cooled and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM / MeOH = 30 / 1 to 10 / 1) to give tert-butyl N-methyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate (K-1, 150 mg, 17% yield) as a yellow oil. 1 H NMR (400 MHz, CDC13) δ (ppm) 8.17 (s, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.41-7.35 (m, 2H), 6.96 (d, J = 2.4 Hz, 1H), 6.25 (d, J = 1.6 Hz, 1H), 4.27 (t, J = 5.6 Hz, 2H), 3.92 (t, J = 5.6 Hz, 2H), 3.61 (s, 2H), 3.48 (s, 2H), 3.30 (d, J = 5.6 Hz, 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

[0939]

[0940] N-methyl-N-[2-[[2-methyl-4-(2-oxoindolin-5-yl)pyrazol-3-yl]methoxy]ethyl]carbamic acid tert-butyl ester (L-1) was prepared according to General Method L

[0941]

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

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

[0944]

[0945]

[0946]

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

[0948]

[0949] Step 1. To a mixture of tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (5.0 g, 28.5 mmol, 1 eq) and Rh(OAc)2(315 mg, 1.43 mmol, 0.05 eq) in DCM (80 mL) was added ethyl 2-diazoacetate (9.77, 85.6 mmol, 3 eq) in DCM (50 mL) dropwise. The mixture was stirred at 25 °C for 16 h and partitioned by adding H2O (5 mL). The organic phase was separated, washed with H2O (10 mL x 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) as a yellow oil. 1H NMR (400 MHz, CDC13) δ = 4.23 (d, J = 2.4 Hz, 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. 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) was added LiAlH4(1.31 g, 34.4 mmol, 1.5 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was quenched with water (1 mL), followed by the addition of aqueous NaOH (15%, 3 mL) and H2O (3 mL). Na2SO4was added to the combined mixture, followed by stirring for 10 min. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1 to 4 / 1) to give tert-butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (3.00 g, 13.7 mmol, 60% yield) as a light yellow oil. 1 H NMR (400 MHz, CDC13) δ = 3.73-3.68 (m, 2H), 3.63-3.55 (m, 4H), 3.41 (d, J = 5.2 Hz, 2H), 2.90 (s, 3H), 2.31 (s, 1H), 1.45 (s, 9H)

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

[0952]

[0953] Step 1. To a mixture of methyl (2R)-2-hydroxypropanoate (20.0 g, 192 mmol, 1 eq.) and benzyl 2,2,2-trichloroethanimidate (51.0 g, 202 mmol, 1.05 eq.) in DCM (66.5 mL) and hexanes (133 mL) was added trifluoromethanesulfonic acid (1.11 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 50 h, and then filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column (petroleum ether: EtOAc, 100:1 to 100:3) to give methyl (2S)-2-benzyloxypropanoate (8.00 g, 37.0 mmol, 19% yield) as a colorless oil. 1H NMR (400 MHz, CDC13) δ = 7.32-7.17 (m, 5H), 4.61 (d, J = 11.6 Hz, 1H), 4.37 (d, J = 11.6 Hz, 1H), 3.99 (m, 1H), 3.67 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H).

[0954] Step 2. To a mixture of methyl (2R)-2-benzyloxypropanoate (8.00 g, 41.0 mmol, 1.0 eq.) in 2-MeTHF (100 mL) was added LAH (2.30 g, 62.0 mmol, 1.5 eq.) slowly at 0 °C. The mixture was stirred at 20 °C for 2 h. Upon completion, the mixture was quenched with water (2.3 mL) slowly at 0 °C, and then with 15% aq. NaOH (2.3 mL) and water (7.0 mL). After filtration, the filtrate was concentrated in vacuo and purified by silica gel column (petroleum ether:EtOAc, 100:0 to 100:40) to give (2R)-2-benzyloxypropan-1-ol (7.00 g, 34.0 mmol, 81.79% yield) as colorless oil. 1 H NMR (400 MHz, CDC13) δ = 7.32-7.17 (m, 5H), 4.61 (d, J = 11.6 Hz, 1H), 4.37 (d, J = 11.6 Hz, 1H), 3.99 (m, 1H), 3.67 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H).

[0955] Step 3. To a mixture of (2R)-2-benzyloxypropan-1-ol (7.00 g, 42 mmol, 1.0 eq.) and 2-chloro-N-methyl-acetamide (6.80 g, 63.0 mmol, 1.5 eq.) in t-BuOH (100 mL) was added t-BuOK (14.2 g, 126 mmol, 3.0 eq.). The mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was diluted with EtOAc (80 mL), washed with water (30 mL), saturated NH4Cl (30 mL), and brine (30 mL). The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by silica gel column (DCM:MeOH, 100:0 to 100:2) to give 2-[(2R)-2-benzyloxypropoxy]-N-methyl-acetamide (4.50 g, 17.0 mmol, 40.5% yield) as colorless oil.

[0956] 1H NMR (400 MHz, CDC13) δ = 7.32-7.19 (m, 5H), 7.02 (s, 1H), 4.59 (d, J = 11.2 Hz, 1H), 4.39 (d, J = 11.2 Hz, 1H), 3.92 (d, J = 16.0 Hz, 1H), 3.83 (d, J = 16.0 Hz, 1H), 3.70 (t, J = 6.4, 3.2 Hz, 1H), 3.50 (dd, J = 10.0, 3.2, 1H), 3.36 (dd, J = 10.4, 6.8 Hz, 1H), 2.49 (d, J = 4.8 Hz, 3H), 1.14 (d, J = 6.4 Hz, 3H); LCMS: m / z 238.4 (M + 1) + .

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

[0958] Step 5. A mixture of 2-[(2R)-2-benzyloxypropoxy]-N-methyl-ethylamine (3.77 g, 16.9 mmol, 1.0 eq.), DMAP (206 mg, 1.69 mmol, 0.1 eq.), (Boc)20 (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 h. The mixture was concentrated in vacuo to give the crude material, which was purified by silica gel column (petroleum ether: EtOAc, 100:0 to 100:10) to give N-[2-[(2R)-2-benzyloxypropoxy]ethyl]-N-methyl-carbamic acid tert-butyl ester (4.00 g, 10.51 mmol, 62.28% yield) as colorless oil. LCMS: m / z 234.3 (M + 1) + .

[0959] Step 6. To a mixture of N-[2-[(2R)-2-benzyloxypropoxy]ethyl]-N-methyl- carbamic acid tert-butyl ester (3.80 g, 11.7 mmol, 1.0 eq.) in MeOH (40 mL) was added Pd(OH)2(825 mg, 1.17 mmol, 20% purity, 0.1 eq) under nitrogen atmosphere. The mixture was stirred at 25 °C under 50 Psi H2for 16 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo and purified by silica gel column (petroleum ether: EtOAc, 100:0 to 100:30) to afford N-[2-[(2R)-2-hydroxypropoxy]ethyl]-N-methyl-carbamic acid tert-butyl ester (M5, 2.10 g, 9.00 mmol, 76.6% yield) as colorless oil. 1 H NMR (400 MHz, DMSO-d6) d = 4.53 (d, J = 4.0 Hz, 1H), 3.70 (t, J = 5.6 Hz, 1H), 3.52-3.43 (m, 2H), 3.31-3.25 (m, 3H), 3.21-3.14 (m, 1H), 2.80 (d, J = 7.2 Hz, 3H), 1.38 (s, 9H), 1.02 (d, J = 6.4 Hz, 3H).

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

[0961]

[0962] Step 1. A solution of (2R)-oxirane-2-carboxylic acid methyl ester (7.00 g, 68.4 mmol, 1 eq.) and N-methyl-1-phenyl-methanamine (8.48 g, 69.9 mmol, 2.26 mL, 1.02 eq.) in MeOH (25 mL) was stirred at 70 °C for 16 h. LCMS showed desired MS in the main peak. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (220 g silica gel column, EtOAc / PE, 0% to 100%) to afford (2R)-3-[benzyl(methyl)amino]-2-hydroxy- propanoic acid methyl ester (15.3 g, 68.5 mmol, 99.9% yield) as brown oil. 1 H NMR (400 MHz, CDCl3) d = 7.40-7.19 (m, 5H), 4.27 (t, J = 6.0 Hz, 1H), 3.74 (s, 3H), 3.65 (d, J = 13.2 Hz, 1H), 3.52 (d, J = 13.2 Hz, 1H), 2.78 (d, J = 5.6 Hz, 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-hydroxy- propionic acid methyl ester (19.0 g, 85.1 mmol, 1 eq.) and Rh(OAc)2(940 mg, 4.25 mmol, 0.05 eq.) in DCM (200 mL) was added a solution of tert-butyl 2-diazoacetate (24.2 g, 170 mmol, 2 eq.) in DCM (50 mL) dropwise, the mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (330 g silica gel column, EtOAc / PE, 0% to 100%) to give (2R)-3-[benzyl(methyl)amino]-2-(2-tert-butoxy 2-oxo-ethoxy)propanoic acid methyl ester (9.80 g, 29.0 mmol, 34.1% yield) as a brown oil. 1 H NMR (400 MHz, CDC13) δ = 7.32-7.23 (m, 5H), 4.28 (t, J = 5.2 Hz, 1H), 4.20 (d, J = 16.4 Hz, 1H), 3.95 (d, J = 16.4 Hz, 1H), 3.75 (s, 3H), 3.66 (d, J = 13.2 Hz, 1H), 3.58 (d, J = 13.2 Hz, 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. To a solution of (2R)-3-[benzyl(methyl)amino]-2-(2-tert-butoxy 2-oxo- ethoxy)propanoic acid methyl ester (9.80 g, 29.0 mmol, 1 eq.) in DCM (50 mL) was added TFA (77.0 g, 675 mmol, 50 mL, 23.2 eq.). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo and the residue was purified by 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 (400 MHz, CDC13) δ = 7.57-7.55 (m, 2H), 7.49-7.47 (m, 3H), 4.28 (t, J = 5.2 Hz, 1H), 4.20 (d, J = 16.4 Hz, 1H), 3.95 (d, J = 16.4 Hz, 1H), 3.75 (s, 3H), 3.66 (d, J = 13.2 Hz, 1H), 3.58 (d, J = 13.2 Hz, 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. 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) was added BH3-Me2S (10 M, 8.85 mL, 3 eq.) at 0 °C. The mixture was stirred at 15 °C for 16 h. The mixture was quenched with MeOH (3 mL) and concentrated in vacuo. 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)propanoate (4.60 g, 10.8 mmol, 36.7% yield) as brown oil. LC-MS: m / z 238.1 (M+1) + .

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

[0967] Step 6. To a solution of methyl (2R)-2-(2-hydroxyethoxy)-3-(methylamino)propanoate (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) was added DMAP (186 mg, 1.52 mmol, 0.1 eq.) and Boc20 (4.99 g, 22.8 mmol, 5.25 mL, 1.5 eq.). The mixture was stirred at 15 °C for 16 h. The mixture was concentrated in vacuo and the residue was purified by combi flash (20 g silica gel column, EtOAc / PE 0% to 100%) to give methyl (2R)-3-[tert-butoxycarbonyl(methyl)amino]-2-(2- hydroxyethoxy)propanoate (1.15 g, 4.15 mmol, 27.22% yield) as colorless oil. LC-MS: m / z 278.1 (M+1) + .

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

[0969]

[0970] Step 1. To a solution of tert-butyl N-(2-sulfanylethyl)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) was added K2CO3 (5.77 g, 41.75 mmol, 2 eq). The mixture was stirred at 25 °C for 10 h. After completion, the mixture was quenched with water (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was 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 tert-butyl N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylthio]ethyl]carbamate (5.5 g, 16.39 mmol, 78.5% yield) as a pale yellow solid product. 1 HNMR (400 MHz, DMSO-d6) d = 6.84 (t, J = 5.6 Hz, 1H), 3.66 (t, J = 6.8 Hz, 2H), 3.06-2.97 (m, 2H), 2.55 (t, J = 6.8 Hz, 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. To a mixture of tert-butyl N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfanyl]ethyl]carbamate (5.5 g, 16.4 mmol, 1 eq) in THF (90 mL) was added NaH (983 mg, 24.6 mmol, 60% purity, 1.5 eq) at 0 °C. The reaction was stirred at 0 °C under N2for 15 min, then CH3I (3.49 g, 24.6 mmol, 1.5 eq) was added dropwise. The reaction was stirred at 25 °C under N2for 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 x 3). The combined organic phase was 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 tert-butyl N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfanyl]ethyl]-N-methyl-carbamate (4 g, 11.1 mmol, 67.7% yield, 97% purity) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) d = 3.67 (t, J = 6.8 Hz, 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. To a solution of tert-butyl N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfanyl]ethyl]-N-methyl-carbamate (4 g, 11.4 mmol, 1 eq) in THF (160 mL) was added TBAF (1 M, 34.3 mL, 3 eq). The mixture was stirred at 25 °C for 2 h. After completion, the mixture was quenched with saturated aqueous ammonium chloride solution (100 mL) at 0 °C, then diluted with H2O (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give tert-butyl N-[2-(2-hydroxyethylsulfanyl)ethyl]-N-methyl-carbamate (M8, 2.6 g, 10.5 mmol, 91.7% yield) as a light yellow solid product. 1 H NMR (400 MHz, DMSO-d6) d = 4.82 (t, J = 5.2 Hz, 1H), 3.62-3.54 (m, 2H), 3.34-3.32 (m, 2H), 2.82 (s, 3H), 2.66 (t, J = 7.2 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 1.43 (s, 9H).

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

[0974]

[0975] Step 1. To a solution of N-(2-aminoethyl)-N-methyl-carbamic acid 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) was added K2CO3 (23.8 g, 172 mmol, 3 eq). The mixture was stirred at 80 °C for 16 h. Upon completion, the mixture was quenched with water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash 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-carbamic acid tert-butyl ester (7.50 g, 18.0 mmol, 31.4% yield) as a colorless gum. LC-MS: m / z 333.8 (M+1) + .

[0976] Step 2. To a solution of N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]ethyl]-N- methyl-carbamic acid tert-butyl ester (2.70 g, 8.12 mmol, 1 eq) in THF (80 mL) and H2O (20 mL) was added CbzCl (1.80 g, 10.5 mmol, 1.50 mL, 1.3 eq) and NaHCO3 (2.05 g, 24.3 mmol, 947 μL, 3 eq). The mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 80 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash 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-carbamic acid tert-butyl ester (3.80 g, 7.33 mmol, 90.2% yield) as a colorless gum. 1H NMR (400 MHz, 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 = 10.8 Hz, 9H), 0.07-0.09 (m, 6H); LC-MS: m / z 367.6 (M-99) + .

[0977] Step 3. To a solution of tert-butyl N-[2-[benzyloxycarbonyl-[2-[tert- butyl(dimethyl)silyl]oxyethyl]amino]ethyl]-N-methyl-carbamate (1.00 g, 2.14 mmol, 1 eq) in THF (20 mL) was added tetrabutylammonium fluoride trihydrate (1 M, 4.29 mL, 2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was quenched with NH4CI (8 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (12 g silica gel column, DCM / MeOH 0% to 100%) to give tert-butyl N-[2-[benzyloxycarbonyl(2-hydroxyethyl)amino]ethyl]-N-methyl-carbamate (M9, 500 mg, 1.21 mmol, 56.2% yield) as a colorless gum. 1 H NMR (400 MHz, DMSO-d6) δ = 7.31-7.05 (m, 5H), 4.86 (s, 2H), 4.59-4.48 (m, 1H), 3.29 (s, 2H), 3.18 (d, J = 5.3 Hz, 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 tert-butyl N-[2-[2-(6-chloro-2-oxo-indolin-5-yl)oxyethyl- methyl-amino]ethyl]-N-methyl-carbamate (M10)

[0979]

[0980] Step 1. To a solution of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (15.0 g, 79.6 mmol, 1 eq) and 2-bromoethoxy-tert-butyl-dimethyl-silane (19.0 g, 79.6 mmol, 1 eq) in ACN (300 mL) was added K2CO3 (11.0 g, 79.6 mmol, 1 eq). The mixture was stirred at 80 °C for 16 h. Upon completion, the mixture was quenched with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash silica gel chromatography (220 g silica gel column, DCM / MeOH 0% to 100%) to give tert-butyl N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-methyl-amino]ethyl]-N-methyl-carbamate (16 g, 39.2 mmol, 49.2% yield) as a colorless gum. 1 H NMR (400 MHz, DMSO-d6) d = 3.62 (t, J = 6.4 Hz, 2H), 3.20 (t, J = 6.8 Hz, 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. To a solution of tert-butyl 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) was added tetrabutylammonium fluoride trihydrate (1 M, 86.5 mL, 2 eq). The mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was diluted with water (200 mL) and extracted with DCM (3 x 180 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (180 g silica gel column, DCM / MeOH 0% to 100%) to give tert-butyl N-[2-[2-hydroxyethyl(methyl)amino]ethyl]-N-methyl-carbamate (M10, 9 g, 34.8 mmol, 80.5% yield) as a colorless gum. 1 H NMR (400 MHz, DMSO-d6) d = 4.30 (s, 1H), 3.48-3.40 (m, 2H), 3.20 (t, J = 7.0 Hz, 2H), 2.76 (s, 3H), 2.43 (q, J = 6.7 Hz, 4H), 2.20 (s, 3H), 1.38 (s, 9H).

[0982] N-methyl-N-[2-[2-(2-oxoindolin-5-yl)oxyethoxy]ethyl]carbamic acid tert-butyl ester (M-1) was prepared according to General Method M.

[0983]

[0984] To a solution of 5-hydroxyindolin-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-carbamic acid tert-butyl ester (1.18 g, 5.36 mmol, 2.0 eq) in 2-MeTHF (20 mL) was added DIAD (1.19 g, 5.90 mmol, 1.15 mL, 2.2 eq) in an ice bath. The mixture was stirred at 50 °C for 16 h, quenched with MeOH (1 mL), and concentrated in vacuo. The residue was purified by silica gel column (DCM:MeOH = 100:0 to 100:3) to give N-methyl-N-[2-[2-(2-oxoindolin-5-yl)oxyethoxy]ethyl]carbamic acid tert-butyl ester (M-1, 400 mg, 0.719 mmol, 26.8% yield) as a light brown gum. LCMS: m / z 251.3 (M+1) + .

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

[0986]

[0987]

[0988]

[0989] N-methyl-N-[2-[2-(2-oxoindolin-5-yl)oxyethoxy]ethyl]carbamic acid tert-butyl ester (M-1) was prepared according to General Method M.

[0990]

[0991] Step 1. To a mixture of N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamic acid 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) was added TosCl (1.30 g, 6.84 mmol, 1.5 eq) at 0 °C. 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 x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]ethyl 4-methylbenzenesulfonate (1.70 g, 4.28 mmol, 93.8% yield) as a light yellow oil. LCMS: m / z 275 (M-Boc) + .

[0992] Step 2. To a solution of 5-sulfanylindolin-2-one (330 mg, 2.00 mmol, 1 eq) in DMF (5 mL) was added K2CO3 (303 mg, 2.20 mmol, 1.1 eq) and 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]ethyl 4-methylbenzenesulfonate (597 mg, 1.60 mmol, 0.8 eq). The mixture was stirred at 25 °C under N2atmosphere for 2 h and partitioned between H2O (10 mL) and EtOAc (10 mL). The organic phase was separated, washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give tert-butyl N-methyl-N-[2-[2-(2-oxoindolin-5-yl)sulfanyl- ethoxy]ethyl]carbamate (M-1s, 450 mg, 1.06 mmol, 52.8% yield) as a yellow oil. LCMS: m / z 267.4 (M-Boc) + .

[0993] Preparation of tert-butyl N-[2-[2-(6-chloro-2-oxo-indolin-5-yl)sulfanyl-ethoxy]ethyl]-N- methyl-carbamate (M-2s)

[0994]

[0995] M-2s was prepared using a similar procedure to M-1s using 6-chloro-5-sulfanylindolin-2- one. 1H 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.

[0997]

[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]indolin-2- one hydrochloride (113 mg, 0.34 mmol), 2-formyl-5-methyl-lH-pyrrole-3-carboxylic acid (51.4 mg, 0.34 mmol, 1 eq) in acetonitrile (1 mL) was added 1-methylimidazole (82.6 mg, 1.01 mmol, 3 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium hexafluorophosphate (141.2 mg, 0.50 mmol, 1.5 eq) and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (DCM:MeOH = 30:1 to 10:1). The crude product was triturated with MeOH (5 mL) at 25 °C for 10 min and then filtered to give 2-formyl-N,5-dimethyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-l-yl]ethoxy]ethyl]-lH-pyrrole-3- carboxamide (N-l, 110 mg, 0.21 mmol, 62% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) d (ppm) 12.06 (s, 1H), 10.50 (s, 1H), 9.43-9.20 (m, 1H), 8.57 (s, 2H), 7.49 (d, J = 1.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.25 (d, J = 2.0 Hz, 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+l) + .

[1000] N-2-N-39 was prepared following a similar procedure to N-l using the corresponding intermediates K-2, L-l to L-13, M-l to M-10, M-l s and M-2 s and the corresponding pyrrole aldehyde.

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-lH-15,17-(ethenediyl)pyrazolo[l,5- d]dipyrrolo[3,4-h:2',3'-k][l,4,14]oxadiazacyclohexadecine-4,19(5H,18H)-dione (41) was prepared according to General Procedure O.

[1010]

[1011] To a solution of N-l (110 mg, 0.25 mmol, 1 eq) in EtOH (30 mL) was added piperidine (43.0 mg, 0.50 mmol, 2 eq). The mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled and concentrated in vacuo. The crude product was triturated with MeOH (5 mL) at 25 °C for 10 min to give 41 as an orange solid (42.2 mg, 0.100 mmol, 40% yield). 1 HNMR (400 MHz, 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, 1.6 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 4.40-4.27 (m, 3H), 4.18-4.16 (m, 1H), 4.04-3.91 (m, 2H), 3.70-3.68 (m, 1H), 3.18-3.07 (m, 1H), 2.98 (s, 3H), 2.41 (s, 3H). LCMS: m / z 418.2 (M+l) + .

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

[1013]

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

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

[1016]

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

[1018] Step 2. To a solution of 132-1 (50.0 mg, 0.112 mmol, 1 eq.) and tert-butyl 3- aminoazetidine-1-carboxylate (23.2 mg, 0.134 mmol, 1.2 eq.), DIEA (43.5 mg, 0.336 μmol, 3 eq.) in DMF (10 mL) was added HATU (51.2 mg, 0.135 mmol, 1.2 eq.) at 0 °C. 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 x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give 133-1 as a yellow solid (19.0 mg, 30% yield). LC-MS: m / z 600.5 (M+1) + .

[1019] Step 3. To a mixture of 133-1 (19.0 mg, 0.032 mmol, 1 eq.) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at 15 °C for 3 h. The mixture was concentrated in vacuo and the residue was purified 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 were oxidized to 148 and 149, respectively, as shown below:

[1021]

[1022] To a solution of 144 (20 mg, 47.9 pmol, 1 eq) in DMF (2 mL), MeOH (2 mL) and H2O (2 mL) was added oxone (588 mg, 0.957 mmol, 20 eq). The mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was filtered and the solid was trituration with H2O and MeOH and filtered to give 148 (1.2 mg) as a light yellow solid product. The filtrate was evaporated and purified by preparative HPLC to give 149 (2.3 mg) as a light yellow solid product.

[1023] By reductive amination, 125 was converted to 152 or 156 using acetaldehyde or acetone, as shown below for 152:

[1024]

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

[1026] Using the method as shown below, 154 and 170 were oxidized to 155 and 171, respectively:

[1027]

[1028] To a mixture of 154 (20 mg, 0.052 mmol, 1 eq) in DCM (3 mL) was added m-CPBA (22.0 mg, 0.104 mmol, 85% purity, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h, quenched by the addition of saturated NaHC03(1 mL), followed by extraction with DCM (5 mL x 3). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, 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.

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

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

[1040]

[1041] Step 1. 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) was added MOMCI (18.1 g, 225 mmol, 1.5 eq) at 0 °C. The mixture was heated to 40 °C and stirred for 2 h. Upon completion, the mixture was quenched with water (30 mL) and concentrated in vacuo to give a mixture (50 mL), which was diluted with brine (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over sodium sulfate, concentrated in vacuo to give crude material, which was purified by silica gel column (PE:EA = 2:1) to give ethyl 1- (methoxymethyl)pyrazole-4-carboxylate (17.1 g, 83 mmol, 59% yield) as colorless oil. 1 H NMR (400 MHz, DMSO-d6) d = 8.51 (s, 1H), 7.94 (s, 1H), 5.42 (s, 2H), 4.22 (q, J = 6.8 Hz, 2H), 3.25 (s, 3H), 1.26 (t, J = 6.8 Hz, 3H).

[1042] Step 2. To a solution of DIPA (9.8 g, 97 mmol, 2.0 eq) in 2-MeTHF (90 mL) was added n-BuLi (2.5 M, 39.09 mL, 2.0 eq) at -70 °C. The mixture was stirred at -70 °C for 25 min. The resulting LDA mixture was transferred to a solution of ethyl 1- (methoxymethyl)pyrazole-4-carboxylate (9.0 g, 48.86 mmol, 1.0 eq) in 2-MeTHF (45 mL) at -70 °C and stirred for 5 min. To the mixture was added anhydrous DMF (35.72 g, 488 mmol, 10.0 eq) and stirred at -70 °C for another 1 h. Upon completion, the mixture was quenched with saturated NH4CI (300 mL) and extracted with EtOAc (300 mL). The organic layer was washed with brine (80 mL), dried over sodium sulfate, concentrated in vacuo to give crude material. The crude material was purified by silica gel column (PE:EA = 100:15) to give ethyl 5-formyl-1- (methoxymethyl)pyrazole-4-carboxylate (4.0 g, 16.96 mmol, 34.72% yield) as colorless oil. 1 H NMR (400 MHz, DMSO-d6) d = 10.33 (s, 1H), 8.10 (s, 1H), 5.69 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 1.98 (s, 2H), 1.32 (t, J = 7.2 Hz, 3H).

[1043] Step 3. To a solution of 5-formyl-l-(methoxymethyl)pyrazole-4-carboxylic acid ethyl ester (90 mg, 0.424 mmol, 1.0 eq) in EtOH (22 mL) was added 6-chloro-5-[2-[2- (methylamino)ethoxy]ethoxy]indolin-2-one (M-4-deboc, 120.76 mg, 0.424 mmol, 1.0 eq) and piperidine (144 mg, 1.70 mmol, 4.0 eq). The mixture was stirred at 80 °C for 16 h. After completion, the reaction mixture was concentrated in vacuo to give the crude material. The crude material was purified by silica gel column (DCM:MeOH = 100:13) to give 159a (150 mg, 0.288 mmol, 66% yield) as a red solid. LCMS: m / z 479.3 (M+l) + .

[1044] Step 4. To a mixture of 159a (100 mg, 0.208 pmol, 1.0 eq) in MeOH (8.0 mL) and H2O (8.0 mL) was added LiOH H2O (105 mg, 2.51 mmol, 12.0 eq). The mixture was stirred at 20 °C for 16 h. After completion, the mixture was concentrated in vacuo, redissolved in water (20.0 mL), adjusted to pH = 6-7 with aqueous HC1 (1 M), and then lyophilized. The residue was redissolved in DCM / MeOH (10:1), then filtered and concentrated in vacuo to give 159b (120 mg, 0.186 mmol, 89.2% yield) as a red solid. LCMS: m / z 451.2 (M+l) + .

[1045] Step 5. 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) was added FDPP (93.7 mg, 0.244 mmol, 1.1 eq). The mixture was stirred at 20 °C for 1 h. After completion, the mixture was diluted with EtOAc (100 mL) and washed with brine (3 x 30 mL). The organic layer was concentrated in vacuo and purified by silica gel column (DCM:MeOH = 100:4) to give 159c (30.0 mg, 55.4 pmol, 25.0% yield) as a red solid. LCMS: m / z 433.2 (M+l) + .

[1046] Step 6. A mixture of 159c (20.0 mg, 46.2 μmol, 1.0 eq) in TFA (1 mL) was stirred at 60 °C for 2 h. Upon completion, the mixture was concentrated in vacuo, adjusted to neutral pH with saturated NaHC03, and then lyophilized. The residue was purified by silica gel column (DCM:MeOH = 100:5) to give 159 (2.05 mg, 5.27 μmol, 11.4% yield) as a yellow solid. 1 H NMR (400 MHz, 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 = 11.2 Hz, 2H), 3.49 (d, J = 3.2 Hz, 1H), 3.44 (dd, J = 5.2, 7.2 Hz, 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- (ethenediyl)dipyrrrolo[3,2-i:3',4'-l][l,4,7]oxadiazacyclopentadecine-4,16(lH,15H)- dione (164)

[1048]

[1049] Step 1. To a solution of tert-butyl N-[2-[2-(6-chloro-2-oxo-indolin-5-yl)oxyethyl- methyl-amino]ethyl]-N-methyl-carbamate (M-10, 1.50 g, 3.77 mmol, 1 eq) in DCM (30 mL) was added HC1 / dioxane (4 M, 18.8 mL, 20 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated to give M-10-deboe HC1 salt, which was used directly for the next step. LCMS: m / z 298.0 (M+1) + .

[1050] Step 2. To a solution of 2-formyl-5-methyl-lH-pyrrole-3-carboxylic acid (183 mg, 1.20 mmol, 1 eq) in DCM (15 mL) was added EDCI (458 mg, 2.39 mmol, 2 eq), DIEA (464 mg, 3.59 mmol, 625 μί, 3 eq) and DMAP (146 mg, 1.20 mmol, 1 eq). The mixture was stirred at 25 °C for 0.5 h. And then 6-chloro-5-[2-[methyl-[2-(methylamino)ethyl]amino]ethoxy]indolin-2-one (M-10-deboc HC1 salt) (400 mg, 1.20 mmol, 1 eq) was added to the mixture. The mixture was stirred at 25 °C for 2 h. After completion, the mixture was concentrated to give a residue. The residue was purified by flash 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 (400 MHz, DMSO-d6) δ = 11.48 (d, J = 0.8 Hz, 1H), 10.61 (s, 1H), 8.41 (s, 1H), 7.39 (s, 1H), 6.83 (s, 1H), 6.22 (d, J = 1.8 Hz, 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-lH-12,14-(ethenediyl)dipyrrolo[3,2-i:3',4'-l][l,4,7]dioxazacyclopentadecine- 19-carbonitrile (168)

[1052]

[1053] Step 1. To a solution of dimethyl malonate (4.11 g, 31.0 mmol, 3.57 mL, 1.2 eq) in DMF (80 mL) was added K2CO3 (4.28 g, 31.0 mmol, 1.2 eq) in small portions at 0 °C and stirred for 1.0 h, then 2,4-difluoro-5-nitrobenzonitrile (4.77 g, 25.9 mmol, 1.0 eq) was added portionwise and the mixture was stirred at 70 °C for 16 h. Upon 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, concentrated in vacuo to give the crude material. The crude material was purified by silica gel column to give dimethyl 2-(4-cyano-5-fluoro-2-nitrophenyl)propanedioate (168-2, 3.65 g, 12.3 mmol, 47.6% yield).

[1054] Step 2. To a solution of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methyl- carbamate (3.00 g, 13.7 mmol, 1 eq) in DMF (40 mL) was added NaH (1.09 g, 27.4 mmol, 60% purity, 2 eq) and the mixture was stirred at 0 °C, then 2-(4-cyano-5-fluoro-2-nitrophenyl)propanedioic acid dimethyl ester (3.65 g, 12.3 mmol, 0.9 eq) was added. The mixture was stirred at 20 °C for 30 min and heated to 80 °C for 2 h. The reaction mixture was quenched by adding H2O (80 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (40 mL x 3), dried over anhydrous Na2SO4, filtered and dried. 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]propanedioate (168-3, 850 mg, 1.68 mmol, 12.3% yield) as brown oil. LCMS: 518.1 (M+Na) + .

[1055] Step 3. A 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 h. The reaction mixture was concentrated under reduced pressure to give compound 168-4 (80 mg, 0.184 mmol, 60.8% yield) as brown oil. 1H NMR (400 MHz, CDC13) 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-lH-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, and quenched by adding H20 (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2S04, filtered and dried. The residue was purified by preparative TLC (Si02, 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. To a mixture of 168-5 (110 mg, 0.207 mmol, 1 eq) in AcOH (2 mL) was added Fe (57.9 mg, 1.04 mmol, 5 eq). The reaction mixture was stirred at 100 °C for 4 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified 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 (400 MHz, 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, 14.4 Hz, 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-(nitrilosylidene)pyrazolo[4,3-m]dipyrrrolo[3,2-f:3',4'-i][l,4]diazacyclopentadeca ine-3,8(2H,5H)-dione (172)

[1060]

[1061]

[1062] Step 1. To a solution of dimethyl malonate (4.11 g, 31.0 mmol, 1.2 eq) in THF (80 mL) was added NaH (1.24 g, 31.09 mmol, 60% purity, 1.2 eq) in small portions at 0 °C and the mixture was stirred for 1.0 h before adding 2,4-dichloro-5-nitro-pyridine (5.0 g, 25.9 mmol, 1.0 eq) in portions. 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 in vacuo. The residue was purified by silica gel column (PE:EA = 100:0 to 100:30) to give 172-2 as a yellow oil (3.6 g, 11.2 mmol, 43.3% yield). 1 H NMR (400 MHz, 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. 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 Na2C03 (2 M, 3.12 mL, 3.0 eq) in dioxane (8.0 mL) was added Pd(dppf)C12 (152 mg, 0.207 mmol, 0.1 eq). The mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. After completion, the mixture was concentrated in vacuo and purified by silica gel column (DCM:MeOH = 100:2) to give 172-3 (800 mg, 1.50 mmol, 71.9% yield) as a red-brown gum. LCMS: m / z 535.4 (M+1) + .

[1064] Step 3. To a solution of 172-3 (350 mg, 654 pmol, 1.0 eq) in DCM (10 mL) was added HC1 / dioxane (4 M, 1.64 mL, 10 eq). The mixture was stirred at 20 °C for 1 h. After completion, the mixture was concentrated in vacuo to give 172-4 (300 mg, 0.621 mmol, 94.9% yield) as an off-white solid. LCMS: m / z 435.3 (M+1) + .

[1065] Step 4. To a solution of 2-formyl-5-methyl-lH-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 DCM (10 mL) was added EDCI (191 mg, 1.00 mmol, 1.5 eq) at 20 °C and the mixture was stirred for 0.5 h before adding 172-4 (290 mg, 0.667 mmol, 1.0 eq). The mixture was stirred for 0.5 h. After completion, the mixture was concentrated in vacuo 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. To a solution of 172-5 (250 mg, 0.438 mmol, 1.0 eq) in DMSO (5.0 mL) and H20 (1.0 mL) was added LiCl (55.8 mg, 1.32 mmol, 3.0 eq). The mixture was stirred at 100 °C for 7 h. After completion, the mixture was diluted with EtOAc (100 mL) and washed with brine (2 x 40 mL). The organic layer was dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column (DCM:MeOH = 20:1) to give 172-6 (180 mg, 0.334 mmol, 76.1% yield) as a brown gum. LCMS: m / z 512.1 (M+1) + .

[1068] Step 6. To a solution of 172-6 (150 mg, 0.293 mmol, 1.0 eq) in AcOH (40.0 mL) was added Fe (163 mg, 2.93 mmol, 10.0 eq). The mixture was stirred at 90 °C for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was re-dissolved in MeOH (20.0 mL), and saturated NaHC03(20.0 mL) was added dropwise and stirred at 20 °C for 2 h. The mixture was concentrated in vacuo to give a gum. The gum was re-dissolved in DCM / MeOH (ratio = 10:1, 100 mL), filtered and the filtrate was concentrated in vacuo to give a crude material. The crude material was purified by silica gel column (DCM:MeOH = 100:5) to give 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, startin...

Claims

1. A compound of formula IV or a pharmaceutically acceptable salt thereof, 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 Excludes -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 and R 8 Each independently is 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 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; the limiting condition is that R 7 or R 8 One of them is the Z-bond; 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 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... 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 according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is 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 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 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 group consisting of: 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.

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 select 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-2H,13H-16,1-(nitromethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclic tetradecyne-3,8(5H,9H)-dione; [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; [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 pentadecylyn-3,8(2H,5H)-dione; [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]oxazonide-pentadecanyne-3,8(2H,5H)-dione; [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; [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; [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-pentadecanyne-3,8(2H,5H)-dione; [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]oxazonidedecadeyn-3,8(2H,5H)-dione; [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 pentadecylyn-3,8(2H,5H)-dione; [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; [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; [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; [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; [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; [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]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione; [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]oxadiazacyclic pentadecylyn-3,8(2H,5H)-dione; [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; [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; [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; [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; [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; [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]triazacyclic tetradecanyne-3,8(2H,5H)-dione; [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 tetradecynyl-3,8(2H,5H)-dione; [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; [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; [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; [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; [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; [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; [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(nitromethamine)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecyne-4,19(5H,18H)-dione; [19a(20)Z]-2-methyl-5,6,7,8,9,10-hexahydro-15,17-(ethylenediamide)pyrazolo[1,5-g]dipyrrolo[3,4-k:2',3'-n][1,4,7]triazacyclohexadecyne-4,19(1H,18H)-dione; [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; [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; [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]oxazonide-pentadecanyne-3,8(5H,9H)-dione; [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; [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]oxazonidecyclopentadecanyne-3,8(5H,9H)-dione; [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]oxazonidecyclopentadecanyne-3,8(5H,9H)-dione; [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 pentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenediamide)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclic pentadecyne-3,8(2H,5H)-dione; [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 pentadecyne-3,8(2H,5H)-dione; [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 pentadecyne-3,8(2H,5H)-dione; [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; [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 pentadecyne-3,8(2H,5H)-dione; [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 pentadecyne-3,8(2H,5H)-dione; [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 pentadecyne-3,8(2H,5H)-dione; [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 pentadecyne-3,8(2H,5H)-dione; [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; [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]triazacyclic pentadecylyn-3,8(2H,5H)-dione; [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 pentadecyne-3,8(2H,5H)-dione; [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 pentadecyne-3,8(2H,5H)-dione; [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; [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]triazacyclic pentadecylyn-3,8(2H,5H)-dione; [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; [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; [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; [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; [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 pentadecyne-3,8(2H,5H)-dione; [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; [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 pentadecyne-3,8(2H,5H)-dione; [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; [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; [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; [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; [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]oxazonidedecadeyn-3,8(5H,9H)-dione; [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]oxazonidecyclopentadecanyne-3,8(2H,5H)-dione; [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]oxazonidedecadeyn-3,8(5H,9H)-dione; [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 pentadecyne-3,8(2H,5H)-dione; [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 pentadecyne-3,8(2H,5H)-dione; [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; [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 pentadecyne-3,8(2H,5H)-dione; [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; [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; [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]oxazonidecyclopentadecanyne-3,8(2H,5H)-dione; [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]oxazonide-pentadecanyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-17,1-(nitromethyl)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclic pentadecyne-3,8(2H,5H)-dione; [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; [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethylenediamide)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclic pentadecyne-3,8(2H,5H)-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]triazacyclopentadenyne-3,8(2H,5H)-dione.

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]benzoxazadiazepine-3,8(2H,5H)-dione; [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; [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; [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; [3a(4)Z]-15-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethylenediamide)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxazadiazetadecylene-3,8(5H,9H)-dione; [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; [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 [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-pentadecanyne-3,8(5H,9H)-dione.

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-2H-1,17-(ethylenedimethyl)pyrido[3,2-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclic tetradetyne-3,8(5H,9H)-dione; [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; [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 tetradecyne-3,8(5H,9H)-dione; [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,18-(ethylenediamide)pyrido[2,1-c]dipyrrolo[3,2-j:3',4'-m][1,4,8]triazacyclic tetradecanyne-3,8,14(2H,5H)-trione; and [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; 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,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; [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; [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]oxazazacyclic pentadecadeyn-4,16(5H,15H)-dione; [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; [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; [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; [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; [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 pentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(ethylenediamide)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecanyne-4,16(5H,15H)-dione; [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; [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; [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; [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 pentadecyne-4,16(5H,15H)-dione; [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 pentadecyne-4,16(5H,15H)-dione; [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; [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]oxazazacyclic pentadecadeyn-4,16(5H,15H)-dione; [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]dioxazonide-4,16(5H,15H)-dione; [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]dioxadiazazepinedecadecanyne-4,16(5H,15H)-dione; [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; [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; [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethylenediamide)dipyrrolo[3,4-d:2',3'-g][1,3,10,13]oxatriazacyclopentadecanyne-4,16(1H,15H)-dione; [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 pentadecylyn-4,16(1H,15H)-dione; [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]dioxadiazazepinedecadecanyne-4,16(5H,15H)-dione; [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; [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; [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenediamide)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione; [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]dioxazonidedecadeyn-4,16(5H,15H)-dione; [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; [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]oxadiazacyclic pentadecylyn-4,16(1H,15H)-dione; [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; [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]dioxazonidedecadeyn-4,16(5H,15H)-dione; [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-13,15-(ethylenediamide)dipyrrolo[3,2-f:3',4'-i][1,13,4]oxasulfurazine-pentadecanyne-4,17(5H,16H)-dione; [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H-13,15-(ethylenedimethyl)-12λ 6 -Dipyrrolo[3,2-f:3',4'-i][1,13,4]oxasulfurazine-4,12,12,17(5H,9H,16H)-tetraone; [17a(18)Z]-2-methyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenediamide)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazonhexadecyne-4,17(5H,16H)-dione; [12R,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenediamide)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazonhexadecyne-4,17(5H,16H)-dione; [12S,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenediamide)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazonhexadecyne-4,17(5H,16H)-dione; [12S,17a(18)Z]-2,5,12-trimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethylenediamide)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazonohexadecyne-4,17(5H,16H)-dione; [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenediamide)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione; [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; [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 hexadecyne-4,10,17(5H,9H,16H)-trione; [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenediamide)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione; [12S,17a(18)Z]-2,5,12-trimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenediamide)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione; [17a(18)Z]-2-methyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenediamide)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione; [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenediamide)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecyne-4,10,17(5H,9H,16H)-trione; [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethylenediamide)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione; [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; [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; [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenediamide)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacyclic heptadecylyn-4,12,18(5H,13H,17H)-trione; [18a(19)Z]-2,5-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenediamide)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacyclic heptadecylyn-4,12,18(5H,13H,17H)-trione; [18a(19)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenediamide)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacyclic heptadecylene-4,12,18(5H,13H,17H)-trione; [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenediamide)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacyclic heptadecylene-4,12,18(5H,13H,17H)-trione; [13R,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenediamide)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacyclic heptadecylene-4,12,18(5H,13H,17H)-trione; [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; [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenediamide)dipyrrolo[3,4-i:2',3'-l][1,4,8,15]oxatriazacycloheptadecyne-4,12,18(5H,13H,17H)-trione; [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 heptadecylyn-4,12,18(5H,13H,17H)-trione; [13S,18a(19)Z]-13-hydroxy-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethylenediamide)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacyclic heptadecylyn-4,12,18(5H,13H,17H)-trione; [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; [16a(17)Z]-19-chloro-2-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenediamide)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione; [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; [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-7-carboxylic acid methyl ester; [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; [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; [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; [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; [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; [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]dioxazonidecyclopentadecanyne-4,16(5H,15H)-dione; [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]dioxazonidedecadeyn-4,16(5H,15H)-dione; [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenediamide)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazonidedecadeyn-4,16(5H,15H)-dione; [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; [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; [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]oxasulfurazine-pentadecanyne-4,8,8,16(1H,5H,15H)-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]oxasulfurazine-4,8,16(1H,5H,15H)-trione; [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethylenediamide)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxasulfurazine-pentadecanyne-4,16(5H,15H)-dione; [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; [16a(17)Z]-2,5-dimethyl-6,7-dihydro-1H,9H-12,14-(ethylenedimethyl)-11λ 6 -Dipyrrolo[3,4-g:2',3'-j][1,4,13]oxasulfurazine-pentadecanyne-4,11,11,16(5H,10H,15H)-tetraone; [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; [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; [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; [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; [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]oxadiazacyclic pentadecylyn-4,16(1H,15H)-dione; [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; [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; [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 [16a(17)Z]-19-chloro-5-methyl-6,7-dihydro-1H,9H-12,14-(ethylenedimethyl)-11λ 6 -Dipyrrolo[3,4-g:2',3'-j][1,4,13]oxasulfurazine-4,11,11,16(5H,10H,15H)-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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