Macrocycles and their use

Abstract

To provide macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat disease, such as cancer.SOLUTION: For example, a compound (41) below is shown.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 USC § 119(e) to U.S. Provisional Application No. 63 / 050,559, filed July 10, 2020, U.S. Provisional Application No. 63 / 143,569, filed January 29, 2021, and U.S. Provisional Application No. 63 / 217,950, filed July 2, 2021, the disclosures of all of which applications are incorporated herein by reference in their entireties.

[0002] Technical Field This application relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds in the treatment of diseases such as cancer. [Background technology]

[0003] background Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signal transduction cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G, et al. The protein kinase complement of the human genome. Science. 2002, 298:1912-34). Dysregulation of kinase activity is associated with many diseases, including cancer and 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- and loss-of-function mutations, gene amplifications and deletions, splicing alterations, and translocations (Wilson LJ, et al. New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res. 2018, 78:15-29). The important role of kinases in cancer and other diseases makes them attractive targets for drug discovery, with 52 small molecule kinase inhibitors approved, 46 of which are for targeted cancer therapy (Roskoski R Jr. Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2020 Update. Pharmacol Res 2020, 152:104609). While kinase inhibitors have achieved dramatic success in targeted cancer therapy, the development of treatment resistance remains a barrier for small molecule kinase inhibitors.Acquired secondary mutations within the kinase domain during treatment often lead to treatment 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, there is a need to invent kinase inhibitors that not only target kinase oncogenic drivers for better efficacy and long-term disease control, but also overcome the most frequent resistance mutations.

[0004] Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide (World Health Organization. Cancer Fact Sheet 2017). Activating EGFR mutations have been reported in approximately 10%–15% of adenocarcinoma cases in Caucasian patients and 50% of cases in Asian patients (Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res 2015;4:36-54). The two most frequent EGFR alterations found in NSCLC tumors are a short in-frame deletion (del19) in exon 19 of the EGFR gene 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 patients with advanced EGFR mutation-positive (Del19 or L858R) NSCLC and are used as first-line standard of care in this setting. However, most patients acquire resistance to gefitinib or erlotinib over the course of treatment, with 50%–70% of tumors harboring the EGFR T790M gatekeeper mutation (Sequist LV, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26).

[0005] The second-generation EGFR inhibitors, afatinib and dacomitinib, are covalent, irreversible EGFR inhibitors that also inhibit the ERB family of 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). Afatinib and dacomitinib are more potent EGFR inhibitors approved for first-line treatment of advanced EGFR mutation-positive (Del19 or L858R) NSCLC than gefitinib and erlotinib, and are associated with longer progression-free survival (PFS). However, EGFR T790M mutations are acquired over time with afatinib treatment (Tanaka K, et al. Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Onco-target 2017; 8:68123-30). EGFR T790M contributes to 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).

[0006] The third-generation EGFR inhibitor osimertinib is also an irreversible inhibitor that targets both EGFR activating mutations (Del19 and L858R) and the T790M resistance double mutation, demonstrating 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 patients with metastatic EGFR T790M mutation-positive NSCLC after first-line EGFR inhibitor therapy and subsequently approved in the first-line setting for patients with EGFR mutation-positive NSCLC in a head-to-head trial with erlotinib or gefitinib in the phase III FLAURA trial (Soria JC, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113-25). The C797S mutation at the EGFR covalent binding residue to the irreversible EGFR inhibitor osimertinib has been detected in patients resistant to osimertinib (Ramalingam SS, et al. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Presented at the ESMO 2018).

[0007] Genetic alterations of the rearranged upon transfection (RET) gene occur in a variety of 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). The multikinase inhibitors lenvatinib, sorafenib, and cabozantinib have been approved for certain thyroid cancers. Recently, the highly selective RET inhibitors selpercatinib and pralsetinib have been approved for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced / metastatic RET-altered medullary thyroid cancer (MTC), and papillary thyroid cancer (PTC). Acquired resistance to RET mutations after treatment with multikinase inhibitors or selective RET inhibitors has been reported in RET-mutated patients or cell lines, including gatekeeper mutations V804M and V804L, hinge mutations Y806N and Y806C, solvent-tip 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). With sequential treatment with multiple RET inhibitors, acquired compound mutations, such as RET M918T / V804M, M918T / V804M / G810C, V804M / G810C, or other combinations, may render the disease refractory to current multikinase and selective RET inhibitors in exogenous settings. Therefore, there is a need to develop new generation RET inhibitors that can target both primary and secondary RET mutations in RET-mutated patients with or without treatment with approved RET inhibitors.

[0008] Chronic myeloid leukemia (CML) is characterized by the Philadelphia (Ph) chromosome, resulting from the balanced reciprocal translocation t(9;22)(q34;q11), which results in the production of the BCR-ABL oncogene, encoding the chimeric BCR-ABL1 oncoprotein (Salesse S, Verfaillie CM. BCR / ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Oncogene. 2002, 21(56):8547-59). Imatinib, a selective BCR-ABL1 kinase inhibitor, was the first approved tyrosine kinase inhibitor and has revolutionized the treatment and outcomes of patients with CML. However, mutations in the BCR-ABL1 kinase domain confer resistance to imatinib treatment. More than 50 mutation sites and more than 70 individual mutations conferring various levels of resistance have been identified in CML patients (Apperley J: Part I: Mechanisms of resistance to imatinib in chronic myeloid leukemia. Lancet Oncol 2007, 8:1018-1029). More potent second-generation BCR-ABL1 inhibitors have been approved, but none are effective against all imatinib-resistant mutations. Y253H, E255V, F359V, and Q252H confer intermediate resistance to nilotinib, and E255V, F317L, and Q252H confer intermediate resistance to dasatinib, whereas T315I confers 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, but not against T315L and T315M.The diverse and complex mutations observed after sequential treatment with multiple BCR-ABL1 inhibitors pose 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 completely safe, and widespread use of second- or third-generation BCR-ABL1 inhibitors is hindered by toxicity. Therefore, there is a need to develop new generation BCR-ABL1 inhibitors that can target both the BCR-ABL1 fusion protein and acquired mutations and have a favorable safety profile.

[0009] FLT3-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase normally expressed in hematopoietic stem or progenitor cells and plays a critical role in the early development of both myeloid and lymphoid lineages. Mutations in FLT3 are found in approximately 30% of newly diagnosed AML cases, occurring as internal tandem duplications (ITDs) (approximately 25%) or point mutations in the tyrosine kinase domain (TKDs) (7–10%) (Daver N, et al. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 2019, 33(2):299–312). Both FLT3-ITD and FLT3-TKD mutations constitutively activate FLT3 kinase activity, leading to AML proliferation and survival. The multikinase inhibitor midostaurin has been approved for the on-site treatment of patients with FLT3-mutated (ITD or TKD) AML in combination with induction chemotherapy, and the second-generation selective FLT3 inhibitor gilteritinib has been approved as a single agent for patients with relapsed or refractory FLT3-mutated AML. While results with FLT3 inhibitor-based treatments are encouraging, many patients still do not respond to or subsequently relapse after FLT3 inhibitor therapy. One mechanism of resistance is the acquisition of secondary mutations in the FLT3 kinase domain, including mutations in activating residues (e.g., D835, I836, 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). Therefore, there is a need to develop new generation FLT3 inhibitors that can target both primary and secondary RET mutations in patients with FLT3-mutated cancers who have or have not been treated with approved FLT3 inhibitors.

[0010] Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract, accounting 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 GISTs (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 is approved as first-line treatment for patients with unresectable, recurrent, or metastatic GISTs, except those with the PDGFRA D842V mutation. The majority of patients who initially receive clinical benefit from imatinib ultimately progress after 20 to 24 months of treatment (Blanke, CD 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).Oncogenically activated KIT remains a key driver of GIST growth and survival after imatinib failure in up to 90% of patients due to reactivation of KIT signaling by tumor subclones harboring heterogeneous secondary KIT mutations (Serrano C, et al. Complementary activity of tyrosine kinase inhibitors against secondary KIT mutations in imatinib-resistant gastrointestinal stromal tumors. British Journal of Cancer, 2019, 120: 612-620). Sunitinib and regorafenib inhibit only specific secondary mutations, limiting their efficacy as second- and third-line treatments, respectively. Therefore, there is a need to develop new generation KIT and / or PDGFR inhibitors that can target both primary and a wide range of secondary mutations in GIST patients with or without prior treatment with approved KIT and / or PDGFR inhibitors. Summary of the Invention [Problem to be solved by the invention]

[0011] Overall, there is an urgent need to develop next-generation kinase inhibitors that can target both primary and clinically emerging secondary mutations to achieve good efficacy and long-term treatment as first-line therapy or to overcome resistance mutations in refractory patients. For example, there is a need to develop new-generation reversible EGFR inhibitors that are effective against oncogenic driver EGFR mutations such as L858R, Del19, L858R / T790M, Del19 / T790M, L858R / C979S, and Del19 / C979S, as well as other emerging and established resistance mutations, while maintaining good selectivity over wild-type EGFR. [Means for solving the problem]

[0012] Summary of the Invention In one embodiment, the present invention provides a compound of formula I [ka]

[0013] [During the ceremony,

[0014] A is 5-10 membered heteroarylene or C6-C 10 is arylene;

[0015] 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 -OO-, -OS- or -ON(R 5 )-not including bonds;

[0016] X is N or C(R 6 ) and;

[0017] X 1 is N or C(R 7 ) and;

[0018] X 2 is N or C(R 8 ) and;

[0019] X 3 is N or C(R 9 ) and;

[0020] X 4 is N or C(R 10 ) and;

[0021] Y and Y 1 are each independently O or S;

[0022] Y 2 is -O-, -N(R 11 )- or -S-;

[0023] Z is 3-7 membered heterocycloalkylene, C3-C6 cycloalkylene, C6-C 10Arylene, 5- to 10-membered heteroarylene, -C(R 12 )(R 13 )-, -C(O)-, -O-, -N(R 14 )-, -S-, -S(O)- or -S(O)2-, where 3- to 7-membered heterocycloalkylene, C3-C6 cycloalkylene, C6-C 10 Each hydrogen atom in the arylene and 5- to 10-membered heteroarylene is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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)NR 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)NR 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 , substituted with -CN or -NO2;

[0024] Z 1 Ha-NR 2 C(Y 1 )-, -C(Y 1 )NR 2 -, -O-, -N(R 2 )-, -S-, -S(O)- or -S(O)2-;

[0025] Each R 1 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NR 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 , -NRa 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)NR 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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from 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)NR 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)NR 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 , substituted with -CN or -NO2;

[0026] R 2 , R 5 , R 11 or R 14 each independently represents H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe , -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)NR 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)NR 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’ , substituted with -CN or -NO2;

[0027] Each R 3, R 4 , R 12 and R 13 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NR 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)NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c Rd , -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 these together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocycloalkyl is independently optionally selected from 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)NR 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)NR 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 , substituted with -CN or -NO2;

[0028] R 6 is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -CN;

[0029] R 7 and R 8 each independently represents a bond to Z, H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NRa R b , -S(O)NR 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)NR 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-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)Re , -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)NR 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)NR 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; provided that R 7 or R 8 is a bond to Z;

[0030] R 9 and R 10each independently represents H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NR 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)NR 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 atom to which they are attached, form a C4-C6 cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a C6-C 10 aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently optionally selected from 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)NR 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)NRe 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 , substituted with -CN or -NO2;

[0031] Each R a , R b , R c , R d , R e and R f are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkyl-C6-C 10 selected from the group consisting of aryl and 5-10 membered heteroaryl;

[0032] m is 0, 1, 2, 3, or 4; and

[0033] n is 2, 3, 4, 5, 6, 7, or 8. or a pharmaceutically acceptable salt thereof.

[0034] In one embodiment, the present invention provides a compound of formula II [ka]

[0035] [In the formula, 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 defined herein. or a pharmaceutically acceptable salt thereof.

[0036] In one embodiment, the present invention provides a compound of formula III [ka]

[0037] [In the formula, R 1 , A, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 2 , Z, Z 1 , m and n are as defined herein. or a pharmaceutically acceptable salt thereof.

[0038] In one embodiment, the present invention provides a compound of formula IV [ka]

[0039] [In the formula, 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 defined herein. or a pharmaceutically acceptable salt thereof.

[0040] In one embodiment, the present invention provides a compound of formula V [ka]

[0041] [In the formula, R 1 , A, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 1 , Z, Z 1 , m and n are as defined herein. or a pharmaceutically acceptable salt thereof.

[0042] In one embodiment, the present invention provides a compound of formula VI [ka]

[0043] [In the formula, 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 defined herein. or a pharmaceutically acceptable salt thereof.

[0044] In one embodiment, the present invention provides a compound of formula VII [ka] [In the formula, 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 defined herein. or a pharmaceutically acceptable salt thereof.

[0045] In one embodiment, the present invention provides a compound of formula VIII [ka]

[0046] [In the formula, 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 defined herein. or a pharmaceutically acceptable salt thereof.

[0047] In certain aspects of each of the above embodiments, ring B(Z) is [ka] In some embodiments, ring B(Z) is [ka] isn't it.

[0048] 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.

[0049] In some aspects of the embodiments herein, the compounds are those in which ring B(Z) is [ka] and R 9 and / or R 10 is not H. In some embodiments, the compound is one in which ring B(Z) is [ka] and R 9 and / or R 10is not H. In some aspects of the embodiments herein, the compound is 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and / or R 10 is not H, and the ring B(Z) is [ka] In some aspects of the embodiments herein, the compound is not a compound where X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and / or R 10 is not H, and the ring B(Z) is [ka] In some aspects of the embodiments herein, the compound is not a compound where X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and / or R 10 is -Cl and ring B(Z) is [ka] In some aspects of the embodiments herein, the compound is not a compound where X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and / or R 10 is -Cl and ring B(Z) is [ka] In some aspects of the embodiments herein, X 1 is C(R 7 ) and X 3 is C(R 9 ) and 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 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and / or R 10 is not -Cl, and ring B(Z) is [ka] In some aspects of the embodiments herein, X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and / or R 10 is not -Cl, and ring B(Z) is [ka] isn't it.

[0050] In certain embodiments of the above aspects, the compound of Formulae (I)-(VIII) is a compound selected from those described or exemplified in the detailed description below.

[0051] In a further aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of Formula (I) to (VIII) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable excipient.

[0052] In a further aspect, the present invention relates to a compound of formula (I) to (VIII) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0053] In a further aspect, the present invention relates to a method for treating a disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formulae (I)-(VIII) or a pharmaceutically acceptable salt thereof.

[0054] In a further aspect, the present invention relates to the use of a compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof for the preparation 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 a disease.

[0055] In a further aspect, the present invention relates to a method for inhibiting a tyrosine kinase, such as EGFR, comprising contacting a cell containing one or more of the kinases with an effective amount of at least one compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof and / or at least one pharmaceutical composition of the present invention, wherein the contacting is in vitro, ex vivo or in vivo.

[0056] Further embodiments, features, and advantages of the present invention will become apparent from the following detailed description and through the practice of the invention. The compounds of the present invention can be described as embodiments in any of the following numbered paragraphs. It is understood that any embodiment described herein can be used in combination with any other embodiment described herein, unless the embodiments are mutually inconsistent.

[0057] 1. Formula I [ka]

[0058] [During the ceremony,

[0059] A is 5-10 membered heteroarylene or C6-C 10 is arylene;

[0060] 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 -OO-, -OS- or -ON(R 5 )-not including bonds;

[0061] X is N or C(R 6 ) and;

[0062] X 1 is N or C(R 7 ) and;

[0063] X 2 is N or C(R 8 ) and;

[0064] X 3 is N or C(R 9 ) and;

[0065] X 4 is N or C(R 10 ) and;

[0066] Y and Y 1 are each independently O or S;

[0067] Y 2 is -O-, -N(R 11 )- or -S-;

[0068] Z is 3-7 membered heterocycloalkylene, C3-C6 cycloalkylene, 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-, where 3- to 7-membered heterocycloalkylene, C3-C6 cycloalkylene, C6-C 10 Each hydrogen atom in the arylene and 5- to 10-membered heteroarylene is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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)NR 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)NR 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 eR f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0069] Z 1 Ha-NR 2 C(Y 1 )-, -C(Y 1 )NR 2 -, -O-, -N(R 2 )-, -S-, -S(O)- or -S(O)2-;

[0070] Each R 1 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NR 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 , -NRa S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)NR 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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from 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)NR 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)NR 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 , substituted with -CN or -NO2;

[0071] R 2 , R 5 , R 11 or R 14 each independently represents H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from 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)NR 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)NR 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’ , substituted with -CN or -NO2;

[0072] Each R 3 , R 4 , R 12 and R 13are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NR 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)NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PRc 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 these together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocycloalkyl is independently optionally selected from 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)NR 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 eS(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)NR 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 , substituted with -CN or -NO2;

[0073] R 6 is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -CN;

[0074] R 7 and R 8 each independently represents a bond to Z, H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NR 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)NR 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-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from 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 eR 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)NR 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)NR 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; provided that R 7 or R 8 is a bond to Z;

[0075] R 9 and R 10each independently represents H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NR 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)NR 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 atom to which they are attached, form a C4-C6 cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a C6-C 10 aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently optionally selected from 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)NR 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)NRe 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 , substituted with -CN or -NO2;

[0076] Each R a , R b , R c , R d , R e and R f are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkyl-C6-C 10 selected from the group consisting of aryl and 5-10 membered heteroaryl;

[0077] m is 0, 1, 2, 3, or 4; and

[0078] n is 2, 3, 4, 5, 6, 7, or 8. or a pharmaceutically acceptable salt thereof.

[0079] 2. Formula IV [ka]

[0080] Item 1. The compound of item 1, or a pharmaceutically acceptable salt thereof, having the formula:

[0081] 3. Formula VI [ka]

[0082] Item 1. The compound of item 1, or a pharmaceutically acceptable salt thereof, having the formula:

[0083] 4. The compound according to any one of items 1 to 3, wherein A is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, or a pharmaceutically acceptable salt thereof.

[0084] 5. A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein A is pyrrolylene.

[0085] 6. A [ka] where R 1a is C1-C6 alkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b or -P(O)OR, wherein each hydrogen atom in the C-C alkyl is independently optionally selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e Rf , -S(O)NR 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)NR 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, or a pharmaceutically acceptable salt thereof.

[0086] 7. A [ka] 2. The compound of any of the preceding claims, wherein:

[0087] 8. Each R 1 is —CN or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORe , -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)NR 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)NR 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, or a pharmaceutically acceptable salt thereof.

[0088] 9. Each R 1 A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein is -CN or methyl.

[0089] 10. R 1a 4. A compound according to any preceding clause, or a pharmaceutically acceptable salt thereof, wherein is methyl.

[0090] 11. R 2 is H or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is independently optionally selected from 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)NR 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)NR e R f , -C(O)R e , -C(O)OR e , -C(O)NRe 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, or a pharmaceutically acceptable salt thereof.

[0091] 12. R 2 A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein is H or methyl.

[0092] 13. Z is a 5- or 6-membered heteroarylene, wherein each hydrogen atom in the 5- or 6-membered heteroarylene is independently optionally selected from 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)NR 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 eS(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)NR 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, or a pharmaceutically acceptable salt thereof.

[0093] 14. Z is pyrazolylene, oxazolylene, thiazolylene, pyridinylene, pyrimidinylene, or pyridine-2-onylene, wherein each hydrogen atom in the pyrazolylene, oxazolylene, thiazolylene, pyridinylene, pyrimidinylene, and pyridine-2-onylene is independently optionally selected from 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)NR e Rf , -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)NR 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, or a pharmaceutically acceptable salt thereof.

[0094] 15. Z [ka] or Z is [ka] or Z is [ka] A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, which is not:

[0095] 16. Z is C6-C 10 arylene, wherein C-C 10 Each hydrogen atom in the arylene is independently optionally selected from 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)NR 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)NR 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 13. The compound of any one of items 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with -CN or -NO2.

[0096] 17. Z is phenylene, wherein each hydrogen atom in the phenylene is independently optionally selected from 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)NR 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)NR 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 17. The compound of any one of items 1 to 12 or 16, or a pharmaceutically acceptable salt thereof, which is substituted with -CN or -NO2.

[0097] 18. Z [ka] 18. The compound of any one of items 1 to 12, 16 or 17, or a pharmaceutically acceptable salt thereof.

[0098] 19. Z is a 3- to 7-membered heterocycloalkylene, wherein each hydrogen atom in the 3- to 7-membered heterocycloalkylene is independently optionally selected from 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)NR 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 , -NRe S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)NR 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 13. The compound of any one of items 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with -CN or -NO2.

[0099] 20. Z is pyrrolidonylene or azetidinylene, wherein each hydrogen atom in the pyrrolidonylene and azetidinylene is independently optionally selected from 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)NR e R f , -NR e R f , -NR e C(O)R f , -NRe 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)NR 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 20. The compound of any one of items 1 to 12 or 19, or a pharmaceutically acceptable salt thereof, which is substituted with -CN or -NO2.

[0100] 21. Z is -C(R 12 )(R 13 )-, -O-, -N(R 14 13. The compound of any one of items 1 to 12, wherein the group is —S—, —S(O)—, or —S(O)2—, or a pharmaceutically acceptable salt thereof.

[0101] 22. Z is -C(R 12 )(R 13 22. The compound of any one of items 1 to 12 or 21, or a pharmaceutically acceptable salt thereof, wherein:

[0102] 23. R 12 and R 13 H, deuterium, fluoro, chloro, bromo, -OR eand C1-C6 alkyl; or R 12 and R 13 together with the carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl is independently optionally selected from 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)NR 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)NR 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 A compound of any of the preceding paragraphs substituted with -CN or -NO2.

[0103] 24. R 12 is H and R 13 A compound of any of the preceding paragraphs in which is methyl.

[0104] 25. R 12 is methyl and R 13 A compound of any of the preceding paragraphs in which is H.

[0105] 26. R 12 and R 13 A compound of any of the preceding paragraphs in which is H.

[0106] 27. R 12 is methyl and R 13 A compound according to any of the preceding clauses, wherein is -OH.

[0107] 28. R 12 is -OH and R 13 A compound of any of the preceding paragraphs in which is methyl.

[0108] 29. The compound of any one of paragraphs 1 to 12 or 21, or a pharmaceutically acceptable salt thereof, wherein Z is —O—.

[0109] 30. Z is -N(R 14 22. The compound of any one of items 1 to 12 or 21, or a pharmaceutically acceptable salt thereof, wherein:

[0110] 31. R 14 A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein is H, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl.

[0111] 32. R 14 A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein is H, methyl or cyclopropyl.

[0112] 33. The compound of any one of paragraphs 1 to 12 or 21, or a pharmaceutically acceptable salt thereof, wherein Z is -S-.

[0113] 34. The compound of any one of paragraphs 1 to 12 or 21, or a pharmaceutically acceptable salt thereof, wherein Z is -S(O)2-.

[0114] 35. A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 3.

[0115] 36. A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 4.

[0116] 37. A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 5.

[0117] 38. A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 6.

[0118] 39. A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 7.

[0119] 40. Each L is independently -C(O)-, -O-, -CH2-, -C(H)(CH3)-, -C(H)(OH)-, -C(H)(C(O)OR c )-, -C(H)(C(O)NR c R d 2. The compound of any of the preceding clauses, wherein the aryl group is selected from the group consisting of —NH—, and —NCH3—, or a pharmaceutically acceptable salt thereof.

[0120] 41. X is C(R 6 ) or a pharmaceutically acceptable salt thereof.

[0121] 42. R 6A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein is H.

[0122] 43. A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Y is O.

[0123] 44. Y 1 A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein:

[0124] 45. Y 2 -N(R 11 )-, or a pharmaceutically acceptable salt thereof.

[0125] 46. ​​X 1 exists, and X 3 A compound according to any of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein is N.

[0126] 47. X 1 exists, and X 4 46. ​​The compound of any one of items 1 to 45, wherein is N, or a pharmaceutically acceptable salt thereof.

[0127] 48. X 3 and X 4 46. ​​The compound of any one of items 1 to 45, wherein is N, or a pharmaceutically acceptable salt thereof.

[0128] 49. X 1 46. ​​The compound of any one of items 1 to 45, or a pharmaceutically acceptable salt thereof, wherein, when present, is N.

[0129] 50. X 2 46. ​​The compound of any one of items 1 to 45, or a pharmaceutically acceptable salt thereof, wherein, when present, is N.

[0130] 51. X 3 46. ​​The compound of any one of items 1 to 45, wherein is N, or a pharmaceutically acceptable salt thereof.

[0131] 52. X 446. ​​The compound of any one of items 1 to 45, wherein is N, or a pharmaceutically acceptable salt thereof.

[0132] 53. X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 46. ​​The compound of any one of items 1 to 45, or a pharmaceutically acceptable salt thereof, wherein

[0133] 54. C(R 7 ) when present, is independently H, deuterium, fluoro, chloro, —CN or methyl, or a pharmaceutically acceptable salt thereof.

[0134] 55. C(R 8 ) when present, is independently H, deuterium, fluoro, chloro, —CN or methyl, or a pharmaceutically acceptable salt thereof.

[0135] 56. C(R 9 ) when present, is independently H, deuterium, fluoro, chloro, —CN or methyl, or a pharmaceutically acceptable salt thereof.

[0136] 57. C(R 10 ) when present is H, or a pharmaceutically acceptable salt thereof.

[0137] 58. -(L) n<h2 style=";text-align:left;direction:ltr">-(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(C H2)2-、-O(CH2)2SO(CH2)2-、-(CH2)2O(C(H)(C(O)N(H)(アゼチジン-3-イル))-CH 2-、-(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)(ピペリジン-4-イル))-CH2-、-(CH2)2O(C(H)(C) (O)N(H)(ピロリジン-3-イル))-CH2-、-(CH2)2O(C(H)(C(O)N(H)(4-メチルピペラジン-1-イ(i))-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-、The compound of any of the preceding claims, wherein the compound is -CHN(CH(CH))-(CH)-, -(CH)N(CH)-(CH)-, -CHCH(CH)-N(CH)-(CH)-, or -O-CH(CH)-CHN(CH)-(CH)-.

[0138] 59. A compound of item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of: [3a(4)Z]-10,11-dihydro-2H,13H-16,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0139] [3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(azenometheno)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0140] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(azenometheno)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0141] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(diazandiylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0142] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0143] [3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(azenometheno)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0144] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(azenometheno)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0145] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0146] [3a(4)Z,11S]-11-hydroxy-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0147] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H,12H-15,17-(ethanediylidene)pyrazolo[4,3-p]dipyrrolo[3,2-i:3',4'-l][1,4,7,14]dioxadiazacycloheptadecin-4,19(5H,18H)-dione;

[0148] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0149] [3a(4)Z]-3,8-dioxo-2,3,5,8,9,10,11,12-octahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecine-6-carbonitrile;

[0150] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)imidazo[4,5-i]pyrazolo[3,4-b]pyrrolo[3,4-f][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0151] [3a(4)Z]-6,15-dimethyl-9,10,11,12-tetrahydro-15H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0152] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0153] [3a(4)Z]-6,16-dimethyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0154] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)dipyrrolo[3,4-f:2',3'-i][1,2]thiazolo[3,4-b][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0155] [3a(4)Z]-6,9-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0156] [3a(4)Z]-6,9-dimethyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0157] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0158] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0159] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)pyrazolo[5,1-c]dipyrrolo[3,2-j:3',4'-m][1,4,8]triazacyclotetradecine-3,8(2H,5H)-dione;

[0160] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-17,1-(azenometheno)pyrazolo[1,5-e]dipyrrolo[3,4-i:2',3'-l][1,5]diazacyclotetradecine-3,8(2H,5H)-dione;

[0161] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,19(5H,18H)-dione;

[0162] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(azenometheno)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecin-4,19(5H,18H)-dione;

[0163] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(azenometheno)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,19(5H,18H)-dione;

[0164] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecin-4,19(5H,18H)-dione;

[0165] [10R,19a(20)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecyne-4,19(5H,18H)-dione;

[0166] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecyne-4,19(5H,18H)-dione;

[0167] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(azenometheno)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,19(5H,18H)-dione;

[0168] [19a(20)Z]-2-methyl-5,6,7,8,9,10-hexahydro-15,17-(ethanediylidene)pyrazolo[1,5-g]dipyrrolo[3,4-k:2',3'-n][1,4,7]triazacyclohexadecin-4,19(1H,18H)-dione;

[0169] [19a(20)Z]-2,5-dimethyl-5,6,7,8,9,10-hexahydro-15,17-(ethanediylidene)pyrazolo[1,5-g]dipyrrolo[3,4-k:2',3'-n][1,4,7]triazacyclohexadecin-4,19(1H,18H)-dione;

[0170] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclopentadecyne-3,8(5H,9H)-dione;

[0171] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0172] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0173] [3a(4)Z]-6,9-dimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0174] [3a(4)Z]-6,9,16-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0175] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione;

[0176] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione;

[0177] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0178] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione;

[0179] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione;

[0180] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0181] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0182] [3a(4)Z]-20-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0183] [3a(4)Z]-19-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0184] [3a(4)Z]-6,9,20-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0185] [3a(4)Z]-9,20-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione;

[0186] [3a(4)Z]-6,16-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0187] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0188] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0189] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecyne-3,8(2H,5H)-dione;

[0190] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-17,1-(azenometheno)[1,2]oxazolo[4,5-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(5H,9H)-dione;

[0191] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-17,1-(azenometheno)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(5H,9H)-dione;

[0192] [3a(4)Z]-6,14-dimethyl-10,11,13,14-tetrahydro-2H-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0193] [3a(4)Z]-6,9,14-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0194] [3a(4)Z]-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0195] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0196] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0197] [3a(4)Z]-6,9,16-trimethyl-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0198] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(5H,9H)-dione;

[0199] [3a(4)Z]-6,9,12,14,16-pentamethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0200] [3a(4)Z]-6,9,14,16-tetramethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0201] [3a(4)Z]-6,9,14,16-tetramethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0202] [3a(4)Z]-9,14,16-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0203] [3a(4)Z]-9,14,16-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0204] [3a(4)Z]-12-ethyl-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0205] [3a(4)Z]-6,9,14-trimethyl-12-(propan-2-yl)-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0206] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0207] [3a(4)Z]-9,14-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0208] [3a(4)Z]-6,9-dimethyl-16-(propan-2-yl)-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0209] [3a(4)Z]-9-methyl-16-(propan-2-yl)-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0210] [3a(4)Z]-6,9,14-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0211] [3a(4)Z]-9,14-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0212] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0213] [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0214] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione; and

[0215] [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecyne-3,8(2H,5H)-dione.

[0216] 60. A compound of item 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-(ethanediylidene)dipyrrolo[3,2-g:3',4'-j][1,5,12]benzoxadiazacyclopentadecin-3,8(2H,5H)-dione;

[0217] [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0218] [3a(4)Z]-6-methyl-10,11-dihydro-2H-17,1-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4]benzoxazacyclotetradecine-3,8(5H,9H)-dione;

[0219] [3a(4)Z]-16-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0220] [3a(4)Z]-15-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0221] [3a(4)Z]-14-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0222] [3a(4)Z]-13-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione; and

[0223] [3a(4)Z]-6,9,12-trimethyl-10,11,12,13-tetrahydro-2H-1,18-(ethanediylidene)dipyrrolo[3,2-g:3',4'-j][2,5]benzodiazacyclopentadecin-3,8(5H,9H)-dione.

[0224] 61. A compound of item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of: [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)pyrido[3,2-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0225] [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)pyrimido[5,4-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0226] [3a(4)Z]-6,16-dimethyl-10,11-dihydro-2H-1,17-(ethanediylidene)pyrido[3,4-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0227] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,18-(ethanediylidene)pyrido[2,1-c]dipyrrolo[3,2-j:3',4'-m][1,4,8]triazacyclotetradecine-3,8,14(2H,5H)-trione;

[0228] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-18,1-(azenometheno)pyrido[1,2-e]dipyrrolo[3,4-i:2',3'-l][1,5]diazacyclotetradecine-3,8,14(2H,5H)-trione;

[0229] or a pharmaceutically acceptable salt thereof.

[0230] 62. A compound of item 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-(azenometheno)tripyrrolo[1,2-a:3',2'-i:3'',4''-l][1,4,7]triazacyclopentadecin-3,8(5H,9H)-dione;

[0231] [3a(4)Z,13aR]-6-methyl-9,10,11,12,13,13a,14,15-octahydro-17,1-(azenometheno)azeto[1,2-a]dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecin-3,8(2H,5H)-dione;

[0232] [16a(17)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenometheno)dipyrrolo[3,4-g:2',3'-j][1,4,6,13]oxatriazacyclopentadecine-4,16(5H,15H)-dione;

[0233] [16a(17)Z]-2,5,11-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclopentadecyne-4,16(5H,15H)-dione;

[0234] [17a(18)Z]-2,12-dimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclohexadecyne-4,17(5H,16H)-dione;

[0235] [17a(18)Z]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclohexadecyne-4,17(5H,16H)-dione;

[0236] [17a(18)Z]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,11,13]oxatriazacyclohexadecin-4,17(5H,16H)-dione;

[0237] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecin-4,16(5H,15H)-dione;

[0238] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione;

[0239] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione;

[0240] [16a(17)Z]-11-cyclopropyl-2,5-dimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione;

[0241] [16a(17)Z]-11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione;

[0242] [10R,16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecin-4,16(5H,15H)-dione;

[0243] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecin-4,16(5H,15H)-dione;

[0244] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclopentadecyne-4,16(5H,15H)-dione;

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

[0246] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0247] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione;

[0248] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione;

[0249] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,3,10,13]oxatriazacyclopentadecin-4,16(1H,15H)-dione;

[0250] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,4-d:2',3'-g][1,3,10,13]oxatriazacyclopentadecin-4,16(1H,15H)-dione;

[0251] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione;

[0252] [9R,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione;

[0253] [9S,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione;

[0254] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0255] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0256] [10R,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0257] [10S,16a(17)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0258] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione;

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

[0260] [9S,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0261] [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-13,15-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,13,4]oxathiazacyclohexadecin-4,17(5H,16H)-dione;

[0262] [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H-13,15-(ethanediylidene)-12λ 6 -dipyrrolo[3,2-f:3',4'-i][1,13,4]oxathiazacyclohexadecyne-4,12,12,17(5H,9H,16H)-tetrone;

[0263] [17a(18)Z]-2-methyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecin-4,17(5H,16H)-dione;

[0264] [12R,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecin-4,17(5H,16H)-dione;

[0265] [12S,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecin-4,17(5H,16H)-dione;

[0266] [12S,17a(18)Z]-2,5,12-trimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecin-4,17(5H,16H)-dione;

[0267] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0268] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azenometheno)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0269] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0270] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0271] [12S,17a(18)Z]-2,5,12-trimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0272] [17a(18)Z]-2-methyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0273] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0274] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0275] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azenometheno)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0276] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0277] [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione;

[0278] [18a(19)Z]-2,5-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione;

[0279] [18a(19)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione;

[0280] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione;

[0281] [13R,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione;

[0282] [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(azenometheno)dipyrrolo[3,4-i:2',3'-l][1,4,8,15]oxatriazacycloheptadecin-4,12,18(5H,13H,17H)-trione;

[0283] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,4-i:2',3'-l][1,4,8,15]oxatriazacycloheptadecin-4,12,18(5H,13H,17H)-trione;

[0284] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecin-4,12,18(5H,13H,17H)-trione;

[0285] [13S,18a(19)Z]-13-hydroxy-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecin-4,12,18(5H,13H,17H)-trione;

[0286] [16a(17)Z]-2-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0287] [16a(17)Z]-19-chloro-2-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0288] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0289] Methyl [7R,16a(17)Z]-19-chloro-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxylate;

[0290] [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-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

[0291] [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-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

[0292] [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-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

[0293] [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-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

[0294] [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-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

[0295] [7R,16a(17)Z]-19-chloro-2,5-dimethyl-7-(4-methylpiperazine-1-carbonyl)-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-4,16(5H,15H)-dione;

[0296] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0297] [10S,16a(17)Z]-19-chloro-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0298] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0299] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,16(5H,15H)-dione;

[0300] [16a(17)Z]-19-chloro-2,5-dimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione;

[0301] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14-(ethanediylidene)-8λ 6 -dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,8,8,16(1H,5H,15H)-tetrone;

[0302] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14-(ethanediylidene)-8λ 4 -dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,8,16(1H,5H,15H)-trione;

[0303] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,16(5H,15H)-dione;

[0304] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,16(5H,15H)-dione;

[0305] [16a(17)Z]-2,5-dimethyl-6,7-dihydro-1H,9H-12,14-(ethanediylidene)-11λ 6 -dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,11,11,16(5H,10H,15H)-tetrone;

[0306] [16a(17)Z]-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,16(5H,15H)-dione;

[0307] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)pyrazolo[4,3-i]pyrrolo[3,4-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0308] [16a(17)Z]-19-chloro-5-methyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione;

[0309] [16a(17)Z]-19-chloro-2,5,8-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione;

[0310] [16a(17)Z]-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-19-carbonitrile;

[0311] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecine-4,16(5H,15H)-dione;

[0312] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,16(5H,15H)-dione; and

[0313] [16a(17)Z]-19-chloro-5-methyl-6,7-dihydro-1H,9H-12,14-(ethanediylidene)-11λ 6 -dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,11,11,16(5H,10H,15H)-tetrone.

[0314] 63. A pharmaceutical composition comprising at least one compound according to any one of items 1 to 62 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable additives.

[0315] 64. A method for treating a disease such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any of items 1 to 62 or a pharmaceutically acceptable salt thereof.

[0316] 65. A compound of any of paragraphs 1 to 62 or a pharmaceutically acceptable salt thereof for use in a method for treating cancer in a subject.

[0317] 66. A compound of any one of paragraphs 1 to 62 or a pharmaceutically acceptable salt thereof for treating cancer in a subject.

[0318] 67. Use of a compound of any of paragraphs 1 to 62, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject. DETAILED DESCRIPTION OF THE INVENTION

[0319] Detailed Description Before further describing the present invention, it is to be understood that the invention is not limited to the particular described embodiments, as such may, of course, vary. It is also to be understood that the terminology used herein is used merely for the purpose of describing particular embodiments, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0320] For the sake of brevity, the descriptions of publications, including patents, cited herein are incorporated herein by reference. Unless defined differently, 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 invention belongs. All patents, applications, published applications, and other publications mentioned herein are incorporated herein by reference in their entirety. If a definition defined in this section contradicts or is inconsistent with a definition set forth in a patent, application, or other publication incorporated herein by reference, the definition in this section shall take precedence over the definition incorporated by reference.

[0321] As used herein and in the appended claims, the singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Moreover, the claims may be drafted to exclude any optional element. That is, this statement is intended to serve as a predicate for the use of exclusive terminology such as "solely," "only," and the like or the use of a "negative" limitation in connection with the recitation of claim elements.

[0322] As used herein, the terms "comprise," "include," and "contain" are used in their open, non-limiting sense.

[0323] To provide a more concise description, quantitative terms used herein are not qualified with the term "about." Whether or not the term "about" is explicitly used, all numbers used herein are meant to refer to actual measured values, as well as approximations of such values ​​that can be reasonably estimated based on common general knowledge in the art, including equivalents and approximations of such values ​​based on experimental and / or measurement conditions. When yields are described as percentages, such yields refer to the mass of the substance for which the yield is stated relative to the maximum amount of that substance that should be obtained under specific stoichiometric conditions. Concentrations expressed as percentages refer to mass ratios unless otherwise indicated.

[0324] 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 invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are described herein. All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0325] Unless otherwise specified, the methods and techniques of the present embodiments are generally carried out according to conventional methods well known in the art and as described in the various general and more specific references cited and described herein. See, for example, 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.

[0326] Chemical names of compounds described herein generally follow commercially available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0327] It is also recognized that certain features of the invention, which, for clarity, are described in separate embodiments, may also be provided in combination in a single embodiment. Conversely, it is also recognized that various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of embodiments involving chemical groups represented by variables, so long as such combinations provide compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), are specifically embraced by the present disclosure and are specifically disclosed by the present disclosure as if each and every combination were individually and explicitly disclosed herein. Furthermore, all subcombinations of such chemical groups listed in embodiments describing variables are also specifically embraced by the present disclosure and are specifically disclosed herein as if each and every such subcombination of chemical groups were individually and explicitly disclosed herein.

[0328] chemistry definition The term "alkyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group. The term "alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon group. In some embodiments, C-C 20 Alkyl or C1-C 20 Alkylene, C1-C 12 Alkyl or C1-C 12 It may be advantageous to limit the number of atoms in an "alkyl" or "alkylene," such as alkylene or C1-C6 alkyl or C1-C6 alkylene, to a particular range of atoms. 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 that would be considered equivalent to any of the foregoing examples based on the common general knowledge in the 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 the like. It is recognized that alkyl or alkylene groups can be unsubstituted or substituted as described herein. The alkyl or alkylene groups may be substituted with one or more of any of the substituents in the various embodiments described.

[0329] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical having one or more double bonds. The term "alkenylene" refers to a straight or branched chain divalent hydrocarbon radical having one or more double bonds. In certain embodiments, C2-C 20 Alkenyl or C2-C 20 Alkenylene, C2-C 12 Alkenyl or C2-C 12It may be advantageous to limit the number of atoms in an "alkenyl" or "alkenylene," such as alkenylene or C2-C6 alkenyl or C2-C6 alkenylene, to a particular range of atoms. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Examples of alkenylene groups include ethenylene (or vinylene) (-CH=CH-), n-propenylene (-CH=CHCH2-), iso-propenylene (-CH=CH(CH3)-), and the like. The term includes cis- and trans-isomers and mixtures thereof. It is recognized that an alkenyl or alkenylene group can be unsubstituted or substituted as described herein. An alkenyl or alkenylene group can contain one or more of any of the substituents in the various embodiments described, and can be substituted.

[0330] The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical having one or more triple bonds. The term "alkynylene" refers to a straight or branched chain divalent hydrocarbon radical having one or more triple bonds. In certain embodiments, C2-C 20 Alkynyl or C2-C 20 Alkynylene, C2-C 12 Alkynyl or C2-C 12 It may be advantageous to limit the number of atoms in an "alkynyl" or "alkynylene" to a particular range of atoms, such as alkynylene or C2-C6 alkynyl or C2-C6 alkynylene. Examples of alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), and the like. It is recognized that an alkynyl or alkynylene group can be unsubstituted or substituted as described herein. An alkynyl or alkynylene group can be substituted, including one or more of any of the substituents in the various embodiments described.

[0331] 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 certain embodiments, it may be advantageous to limit the number of atoms in a "cycloalkyl" or "cycloalkylene" to a specific range of atoms, such as 3 to 12 ring atoms. Polycyclic carbocyclic rings include fused, bridged, and spiropolycyclic ring systems. Illustrative examples of cycloalkyl groups include monovalent radicals of the following, while cycloalkylene groups, in the form of appropriately bonded moieties, include divalent radicals of the following: [ka] In particular, the cyclopropyl moiety has the structure [ka] In particular, the cyclopropylene moiety can be represented by the structural formula [ka] It is recognized that the cycloalkyl or cycloalkylene group can be unsubstituted or substituted as described herein. The cycloalkyl or cycloalkylene group can be substituted with one or more of any of the substituents in the various embodiments described.

[0332] The term "halogen" or "halo" refers to chlorine, fluorine, bromine or iodine.

[0333] The term "haloalkyl" refers to an alkyl group having one or more halo substituents. Examples of haloalkyl groups include -CF, -(CH)F, -CHF, -CHBr, -CHCF, and -CHCHF. The term "haloalkylene" refers to an alkyl group having one or more halo substituents. Examples of haloalkyl groups include -CF-, -C(H)(F)-, -C(H)(Br)-, -CHCF-, and -CHC(H)(F)-.

[0334] The term "aryl" refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. The term "arylene" refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. In certain embodiments, a monovalent all-carbon monocyclic or fused-ring polycyclic group of 6 to 14 carbon atoms (C6-C8) is 14 aryl), monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-C 10 aryl), a divalent all-carbon monocyclic or fused-ring polycyclic group of 6 to 14 carbon atoms (C6-C 14 arylene), a divalent all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C 10 It may be advantageous to limit the number of atoms in an "aryl" or "arylene" (e.g., arylene) to a particular range of atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, and anthracenyl. Examples of aryl groups include, but are not limited to, phenylene, naphthalenylene, and anthracenylene. It is recognized that an aryl or arylene group can be unsubstituted or substituted as described herein. An aryl or arylene group can be substituted, including one or more of any of the substituents in the various embodiments described.

[0335] The term "heterocycloalkyl" refers to a monovalent monocyclic or polycyclic ring system that is saturated or partially saturated and has one or more non-carbon ring atoms. The term "heterocycloalkylene" refers to a monovalent monocyclic or polycyclic ring system that is saturated or partially saturated and has one or more non-carbon ring atoms. In certain embodiments, it may be advantageous to limit the number of atoms in a "heterocycloalkyl" or "heterocycloalkylene" to a particular range of ring atoms, such as 3 to 12 ring atoms (3 to 12 members), or 3 to 7 ring atoms (3 to 7 members), or 3 to 6 ring atoms (3 to 6 members), or 4 to 6 ring atoms (4 to 6 members), or 5 to 7 ring atoms (5 to 7 members). In certain embodiments, it may be advantageous to limit the number and type of ring heteroatoms in a "heterocycloalkyl" or "heterocycloalkylene" to a particular range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Polycyclic ring systems include fused, bridged, and spiro systems. The ring structure may optionally contain an oxo group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following, while heterocycloalkylene groups, in the form of appropriately bonded moieties, include divalent radicals of the following: [ka]

[0336] A three-membered heterocycle may contain at least one heteroatom ring atom that is sulfur, oxygen, or nitrogen. Non-limiting examples of three-membered heterocyclic groups include the monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom that is sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocyclic groups include the monovalent and divalent radicals of azetidine, oxetane, and thietane. A five-membered heterocycle may 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 5-membered heterocyclic groups include monovalent and divalent radicals of pyrrolidine, tetrahydrofuran, 2,5-dihydro-1H-pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2-one, and oxazolidin-2-one. 6-membered heterocycles 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 6-membered heterocyclic groups include the monovalent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A "heterobicycle" is a fused bicyclic ring system containing one heterocycle fused to a cycloalkyl or one other heterocycle.

[0337] It is recognized that a heterocycloalkyl or heterocycloalkylene group can be unsubstituted or substituted as described herein, and the heterocycloalkyl or heterocycloalkylene group can be substituted with one or more of any of the substituents in the various embodiments described.

[0338] The term "heteroaryl" refers to a monovalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (a ring structure having carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and has 3 to 12 ring atoms per heterocycle. The term "heteroarylene" refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (a ring structure having carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that has 3 to 12 ring atoms per heterocycle. In certain embodiments, it may be advantageous to limit the number of ring atoms in a "heteroaryl" or "heteroarylene," such as a 5- to 10-membered heteroaryl or a 5- to 10-membered heteroarylene, to a specific range of atom members. In some cases, a 5- to 10-membered heteroaryl can be a monocyclic or fused bicyclic ring having 5 to 10 ring atoms, where at least one ring atom is a heteroatom, such as N, O, or S. In certain cases, a 5- to 10-membered heteroarylene may be a monocyclic ring or a 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 groups include monovalent radicals of the following, while examples of 5- to 10-membered heteroarylene groups, in the form of appropriately bonded moieties, include divalent radicals of the following: [ka]

[0339] In some embodiments, a "monocyclic" heteroaryl can be an aromatic 5- or 6-membered heterocycle. A 5-membered heteroaryl or heteroarylene 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 5-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 5-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 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 containing one heteroaryl ring fused to phenyl or one other heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.Non-limiting examples of bicyclic heteroarylene groups include the divalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole. In particular, the pyrrolyl moiety has the structural formula [ka] In particular, the pyrrolylene moiety can be represented by the structural formula [ka] It can be represented by:

[0340] It is recognized that a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein, and can be substituted with one or more of any of the substituents in the various embodiments described.

[0341] The term "oxo" refers to a carbonyl oxygen. For example, cyclopentyl substituted with oxo is cyclopentanone.

[0342] The term "substituted" means that a particular group or moiety bears one or more substituents. The term "unsubstituted" means that a particular group bears no substituents. When the term "substituted" is used to describe a structural system, it means that substitution occurs anywhere in the system allowed by valence. In some embodiments, "substituted" means that a particular group or moiety bears one, two, or three substituents. In other embodiments, "substituted" means that a particular group or moiety bears one or two substituents. In yet other embodiments, "substituted" means that a particular group or moiety bears one substituent.

[0343] Any formula given herein is intended to represent a compound of that structural formula and certain variants or forms. For example, any formula given herein is intended to include a racemate or one or more enantiomers, diastereomers, or geometric isomers, or mixtures thereof. Furthermore, any formula given herein is also intended to refer to a hydrate, solvate, or polymorph of such a compound, or mixtures thereof.

[0344] Any formula given herein is also intended to represent unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have structures represented by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 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 Such isotopically labeled compounds are useful for metabolic studies, preferably 14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques including drug or substrate tissue distribution assays [e.g., positron emission tomography (PET) or single photon emission computed tomography (SPECT)] or radioactive treatment of patients. 2Substitution with heavy isotopes, such as H, may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the invention and prodrugs thereof may generally be prepared by converting non-isotopically labeled reactants into readily available isotopically labeled reactants by practice of the methods disclosed in the schemes below or in the Examples and Preparations.

[0345] Nomenclature “(atom) i-j " where j>i, as used herein, when applied to a group of substituents, is meant to refer to an embodiment of the invention in which each and every atom number from i to j, inclusive, is independently realized. For example, the term C 1-3 refers independently to embodiments having one carbon member (C1), two carbon members (C2), and three carbon members (C3).

[0346] Any di-substituent described herein is intended to encompass various possible attachment positions, if more than one is possible. For example, the di-substituent -AB- (where A≠B) herein refers to a di-substituent having A attached to a first substituent and B attached to a second substituent, and also refers to a di-substituent having A attached to a second substituent and B attached to the first substituent. For example, in certain embodiments, a compound moiety -(L) having the formula -CH(CH)-CHNH-(CH)-, connecting the two groups A and B, if applicable, is provided. n It is understood that -CH(CH3)-CH2NH-(CH2)2- can include both the embodiment A-CH(CH3)-CH2NH-(CH2)2-B and B-CH(CH3)-CH2NH-(CH2)2-A. More specifically, in this example, the groups -Z- and -NR 2 - the compound part of the formula -CH(CH3)-CH2NH-(CH2)2- that connects -(L) n The compounds of formulas (I) to (VIII) having -Z-CH(CH3)-CH2NH-(CH2)2-NR 2 - and -NR 2It is understood that both embodiments, -CH(CH3)-CH2NH-(CH2)2-A, are included.

[0347] The present invention also relates to pharmaceutically acceptable salts of the compounds of formulas (I)-(VIII), preferably the specific compounds described above and exemplified herein, as well as pharmaceutical compositions containing such salts and methods of using such salts.

[0348] "Pharmaceutically acceptable salt" is intended to mean a free acid or base salt of a compound described herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally, SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with subject tissues without undue toxicity, irritation, or allergic response. The compounds described herein may have sufficiently acidic groups, sufficiently basic groups, both types of functional groups, or more than one of each type, and thus react with several inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0349] Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate, hexylate ... Suitable pharmaceutically acceptable salts include 1,6-diacidal acid salts, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0350] For compounds of formula (I)-(VIII) containing a basic nitrogen, pharmaceutically acceptable salts may be prepared by any suitable method available in the art, for example, by rinsing with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, or with an 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, pyranosidic acid, e.g., glucuronic acid or galacturonic acid, alpha- hydroxy acids such as mandelic acid, citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, sulfonic acids such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or any compatible mixture of acids such as those mentioned herein by way of example, and any other acid and mixtures thereof which are considered equivalent or acceptable substitutes in the light of the ordinary level of skill in the art.

[0351] The present invention also relates to pharmaceutically acceptable prodrugs of compounds of Formulas (I)-(VIII) and methods of treatment using such pharmaceutically acceptable prodrugs. The term "prodrug" refers to a precursor of a specified compound that, after administration to a subject, yields the compound in vivo through a chemical or physiological process, such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., at physiological pH, the prodrug is converted to a compound of Formulas (I)-(VIII)). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. Illustrative methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

[0352] The present invention also relates to pharmaceutically active metabolites of compounds of Formulas (I)-(VIII) and the use of such metabolites in the methods of the present invention. "Pharmaceutically active metabolite" means a pharmacologically active metabolic product in the body of a compound of Formulas (I)-(VIII) or a salt thereof. Prodrugs and active metabolites of a compound can be determined using routine techniques known or available in the art. For example, 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; see Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

[0353] As used herein, the term "protecting group" or "PG" refers to any group commonly known to those skilled in the art that is introduced into a molecule by chemical modification of a functional group, such as an amine or hydroxyl, to obtain chemoselectivity in a subsequent chemical reaction. It is recognized that such a protecting group can then be removed from the functional group at a later point in the synthesis to provide additional opportunities for reaction at such a functional group or to unmask such a functional group in the final product. Protecting groups are described, for example, in Wuts, PGM, Greene, TW, Greene, TW, & John Wiley & Sons. (2006). Greene's protective groups in organic synthesis. Hoboken, NJ: Wiley-Interscience. Those skilled in the art will readily recognize the chemical process conditions under which such a protecting group can be introduced onto a functional group. Suitable amine protecting groups useful in connection with the present invention include, but are not limited to, 9-fluorenylmethyl-carbonyl (FMOC), t-butylcarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl (Ac), trifluoroacetyl, phthalimide, benzyl (Bn), triphenylmethyl (trityl, Tr), benzylidene, and p-toluenesulfonyl (tosylamide, Ts).

[0354] Representative Embodiments In one embodiment, the present invention provides a compound of formula I [ka]

[0355] [In the formula, R 1 , A, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 2 , Z, Z 1 , m and n are as defined herein. or a pharmaceutically acceptable salt thereof.

[0356] In one embodiment, the present invention provides a compound of formula II [ka]

[0357] [In the formula, 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 defined herein. or a pharmaceutically acceptable salt thereof.

[0358] In one embodiment, the present invention provides a compound of formula III [ka]

[0359] [In the formula, R 1 , A, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 2 , Z, Z 1 , m and n are as defined herein. or a pharmaceutically acceptable salt thereof.

[0360] In one embodiment, the present invention provides a compound of formula IV [ka]

[0361] [In the formula, 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 defined herein. or a pharmaceutically acceptable salt thereof.

[0362] In one embodiment, the present invention provides a compound of formula V [ka]

[0363] [In the formula, R 1 , A, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 1 , Z, Z 1 , m and n are as defined herein. or a pharmaceutically acceptable salt thereof.

[0364] In one embodiment, the present invention provides a compound of formula VI [ka]

[0365] [In the formula, 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 defined herein. or a pharmaceutically acceptable salt thereof.

[0366] In one embodiment, the present invention provides a compound of formula VII [ka] [In the formula, 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 defined herein. or a pharmaceutically acceptable salt thereof.

[0367] In one embodiment, the present invention provides a compound of formula VIII [ka]

[0368] [In the formula, 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 defined herein. or a pharmaceutically acceptable salt thereof.

[0369] In some embodiments, ring A is a 5- to 10-membered heteroarylene and Z is a 3- to 7-membered heterocycloalkylene, C-C cycloalkylene, C-C 10 arylene or 5- to 10-membered heteroarylene (also known as ring B). In some embodiments, ring A is a 5- to 10-membered heteroarylene, and ring B is a 5- to 10-membered heteroarylene. In some embodiments, ring A is a 5- to 10-membered heteroarylene, and ring B is a 3- to 7-membered heterocycloalkylene. In some embodiments, ring A is a 5- to 10-membered heteroarylene, and ring B is a C3-C6 cycloalkylene. In some embodiments, ring A is a 5- to 10-membered heteroarylene, and ring B is a C6-C 10 It is an arylene.

[0370] In some embodiments, ring A is C6-C 10 arylene, Z is 3-7 membered heterocycloalkylene, C3-C6 cycloalkylene, C6-C 10 In some embodiments, ring A is C6-C 10In some embodiments, ring A is C6-C arylene and ring B is 5-10 membered heteroarylene. 10 In some embodiments, ring A is C6-C arylene and ring B is 3- to 7-membered heterocycloalkylene. 10 In some embodiments, ring A is C-C arylene and ring B is C-C cycloalkylene. 10 arylene, and ring B is C6-C 10 It is an arylene.

[0371] In some embodiments, ring A is a 5- or 6-membered heteroarylene, and Z is a 3- to 7-membered heterocycloalkylene, C-C cycloalkylene, C-C 10 It is arylene or 5- to 10-membered heteroarylene (also known as ring B). In some embodiments, ring A is 5- to 6-membered heteroarylene, and ring B is 5- to 10-membered heteroarylene. In some embodiments, ring A is 5- to 6-membered heteroarylene, and ring B is 3- to 7-membered heterocycloalkylene. In some embodiments, ring A is 5- to 6-membered heteroarylene, and ring B is C3-C6 cycloalkylene. In some embodiments, ring A is 5- to 6-membered heteroarylene, and ring B is C6-C6 cycloalkylene. 10 It is an arylene.

[0372] In some embodiments, ring A is a 5- or 6-membered heteroarylene containing 1, 2, or 3 nitrogen ring atoms. In some embodiments, ring A is furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene. In some embodiments, ring A is pyrrolylene. In some embodiments, ring B is a 5- or 6-membered heteroarylene containing 1 or 2 nitrogen ring atoms. In some embodiments, ring B is pyrazolylene, oxazolylene, thiazolylene, pyridinylene, pyrimidinylene, or pyridin-2-onylene. In some embodiments, ring A is pyrrolylene and ring B is pyrazolylene, oxazolylene, thiazolylene, pyridinylene, pyrimidinylene, and pyridin-2-onylene.

[0373] In certain embodiments, ring A has the formula [ka] It is of

[0374] where R 1a is C1-C6 alkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b or -P(O)OR, wherein each hydrogen atom in the C-C alkyl is independently optionally selected from deuterium, halogen, C-C alkyl, C-C 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)NR 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)NR 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.

[0375] In certain embodiments, ring A has the formula [ka] It is of the type.

[0376] In some embodiments, ring B(Z) has the formula [ka] It is of the type.

[0377] In some embodiments, ring B(Z) has the formula [ka] It is of the type.

[0378] In some embodiments, ring B(Z) has the formula [ka] It is of the type.

[0379] In some embodiments, ring B(Z) is [ka] In some embodiments, ring B(Z) is [ka] isn't it.

[0380] In some embodiments, ring B(Z) is C6-C 10 arylene, wherein C-C 10 Each hydrogen atom in an aryl is independently optionally selected from 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)NR e R f , -NR e R f , -NR e C(O)Rf , -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)NR 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.

[0381] In certain embodiments, Ring B is phenylene, wherein each hydrogen atom in the phenylene is independently optionally selected from 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)NRe 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)NR 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.

[0382] In certain embodiments, ring B has the formula [ka] It is of the type.

[0383] In certain embodiments, ring B(Z) is a 3- to 7-membered heterocycloalkylene, wherein each hydrogen atom in the 3- to 7-membered heterocycloalkylene is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e Rf , -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)NR 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)NR 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.

[0384] In certain embodiments, Ring B is pyrrolidonylene or azetidinylene, wherein each hydrogen atom in pyrrolidonylene and azetidinylene is independently optionally selected from 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)NR 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)NR 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.

[0385] In certain embodiments, ring A is a 5- or 6-membered heteroarylene and Z is —C(R 12 )(R 13 )-, -O-, -N(R 14 )-, -S-, -S(O)- or -S(O)2-.

[0386] In certain embodiments, each R 1 when present, independently represent deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NR 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 , -NRa S(O)NR 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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from 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)NR 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)NR 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.

[0387] In some embodiments, R 1 is, when present, —CN or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is independently optionally selected from 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)NR e R f , -NR e R f , -NR e C(O)R f , -NRe 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)NR 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 -NO. In some embodiments, R 1 When present, R 1 is -CN or methyl.

[0388] In some embodiments, R 1a when present, 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 the C1-C6 alkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NRe R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR 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)NR 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 -NO. In some embodiments, R 1a When present, is methyl.

[0389] In some embodiments, R 2are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from 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)NR 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)NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e Rf , -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.

[0390] In some embodiments, R 2 is H or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is independently optionally selected from 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)NR 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)NR 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 -NO. In some embodiments, R 2 is H or methyl.

[0391] In certain embodiments, 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 -OO-, -OS- or -ON(R 5 )-bonds are not included.

[0392] In certain embodiments, each R 3 , R 4 , R 12 and R 13 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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 Rd , -SR c , -S(O)R c , -S(O)2R c , -S(O)NR c R d , -S(O)NR 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)NR 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 13two of them, together with one or more carbons to which they are attached, form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocycloalkyl is independently optionally selected from 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)NR 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)NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e Rf , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2.

[0393] In some embodiments, R 12 and R 13 when present, independently represent H, deuterium, fluoro, chloro, bromo, -OR e and C1-C6 alkyl; or R 12 and R 13 together with the carbon to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl is independently optionally selected from 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)NR 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)NR 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.

[0394] In certain embodiments, when present, R 12 is H and R 13 is methyl. In certain embodiments, when present, R 12 is methyl and R 13 is H. In some embodiments, when present, R 12 and R 13 is 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.

[0395] In certain embodiments, each L is independently selected from the group consisting of -C(O)-, -O-, -CH2-, -C(H)(CH3)-, -C(H)(OH)-, -NH-, and -NCH3-. n<h2 style=";text-align:left;direction:ltr">-(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(C H2)2-、-O(CH2)2SO(CH2)2-、-(CH2)2O(C(H)(C(O)N(H)(アゼチジン-3-イル))-CH 2-、-(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)(ピペリジン-4-イル))-CH2-、-(CH2)2O(C(H)(C) (O)N(H)(ピロリジン-3-イル))-CH2-、-(CH2)2O(C(H)(C(O)N(H)(4-メチルピペラジン-1-イ(i))-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-、In some embodiments, -Z-(L), -Z-(L), -Z-(L)-(CH)-, ... n -Z 1 - is -OO-, -OS- or -ON(R x )-bonds are not included.

[0396] In some embodiments, R 5 is H or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is independently optionally selected from 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)NR 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)NR 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 -NO. In some embodiments, R 5 is H or methyl.

[0397] In some embodiments, X is -N-. In some embodiments, X is C(R 6 In some embodiments, R 6 When present, R is H, deuterium, halogen, C-C alkyl, C-C alkenyl, C-C alkynyl, or -CN. 6 is H, when it exists.

[0398] In some embodiments, X 1 is N or C(R 7 ) and X 2 is N or C(R 8 ) where R 7 or R 8 One of X 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 8In 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(R 10 In some embodiments, X 1 and X 3 is N. In some embodiments, X 1 and X 4 is N. In some embodiments, X 3 and X 4 is N. In some embodiments, X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 In some embodiments, the compound is X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 10 is not a compound where X is not H. In some embodiments, the compound 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 is not a compound where X is not H. In some embodiments, the compound 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and R 10 is not a compound that is not H.

[0399] In some embodiments, R 7 and R 8 each independently represents a bond to Z, H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NR 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)NR 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 aR 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-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from 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)NR 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)NR 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; provided that R 7 or R 8 is a bond to Z;

[0400] In some embodiments, R 9 and R 10 each independently represents H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NR 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 , -NRa S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)NR 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 They, together with the carbon atom to which they are attached, are C4-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-C 10 aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2Re , -S(O)NR e R f , -S(O)NR 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)NR 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.

[0401] In some embodiments, R 9 and R 10 each of which is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 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)NR 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)NR 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 They, together with the carbon atom to which they are attached, are C4-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or C6-C 10aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently optionally selected from 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)NR 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)NR 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 Rf , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2.

[0402] 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.

[0403] In some embodiments, the compound is [ka] and R 9 and / or R 10 is not H. In some embodiments, the compound is [ka] and R 9 and / or R 10 is not H. In some embodiments, the compound is 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10) and R 9 and / or R 10 is not H, and the ring B(Z) is [ka] In some embodiments, the compound is not a compound where X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and / or R 10 is not H, and the ring B(Z) is [ka] In some embodiments, the compound is not a compound where X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and / or R 10 is -Cl, and ring B(Z) is [ka] In some embodiments, the compound is not a compound where X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and / or R 10 is -Cl, and ring B(Z) is [ka] In some embodiments, X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R10 ) and R 9 and / or R 10 is not —Cl. In some embodiments, X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and / or R 10 is not -Cl, and ring B(Z) is [ka] In some embodiments, X 1 is C(R 7 ) and X 3 is C(R 9 ) and X 4 is C(R 10 ) and R 9 and / or R 10 is not -Cl, and ring B(Z) is [ka] isn't it.

[0404] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0405] 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.

[0406] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: [3a(4)Z]-10,11-dihydro-2H,13H-16,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0407] [3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(azenometheno)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0408] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(azenometheno)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0409] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(diazandiylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0410] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0411] [3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(azenometheno)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0412] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(azenometheno)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0413] [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0414] [3a(4)Z,11S]-11-hydroxy-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0415] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H,12H-15,17-(ethanediylidene)pyrazolo[4,3-p]dipyrrolo[3,2-i:3',4'-l][1,4,7,14]dioxadiazacycloheptadecin-4,19(5H,18H)-dione;

[0416] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0417] [3a(4)Z]-3,8-dioxo-2,3,5,8,9,10,11,12-octahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecine-6-carbonitrile;

[0418] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)imidazo[4,5-i]pyrazolo[3,4-b]pyrrolo[3,4-f][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0419] [3a(4)Z]-6,15-dimethyl-9,10,11,12-tetrahydro-15H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0420] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0421] [3a(4)Z]-6,16-dimethyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0422] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)dipyrrolo[3,4-f:2',3'-i][1,2]thiazolo[3,4-b][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0423] [3a(4)Z]-6,9-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0424] [3a(4)Z]-6,9-dimethyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0425] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0426] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione;

[0427] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)pyrazolo[5,1-c]dipyrrolo[3,2-j:3',4'-m][1,4,8]triazacyclotetradecine-3,8(2H,5H)-dione;

[0428] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-17,1-(azenometheno)pyrazolo[1,5-e]dipyrrolo[3,4-i:2',3'-l][1,5]diazacyclotetradecine-3,8(2H,5H)-dione;

[0429] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,19(5H,18H)-dione;

[0430] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(azenometheno)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecin-4,19(5H,18H)-dione;

[0431] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(azenometheno)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,19(5H,18H)-dione;

[0432] [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecin-4,19(5H,18H)-dione;

[0433] [10R,19a(20)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecyne-4,19(5H,18H)-dione;

[0434] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecyne-4,19(5H,18H)-dione;

[0435] [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(azenometheno)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,19(5H,18H)-dione;

[0436] [19a(20)Z]-2-methyl-5,6,7,8,9,10-hexahydro-15,17-(ethanediylidene)pyrazolo[1,5-g]dipyrrolo[3,4-k:2',3'-n][1,4,7]triazacyclohexadecin-4,19(1H,18H)-dione;

[0437] [19a(20)Z]-2,5-dimethyl-5,6,7,8,9,10-hexahydro-15,17-(ethanediylidene)pyrazolo[1,5-g]dipyrrolo[3,4-k:2',3'-n][1,4,7]triazacyclohexadecin-4,19(1H,18H)-dione;

[0438] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclopentadecyne-3,8(5H,9H)-dione;

[0439] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0440] [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0441] [3a(4)Z]-6,9-dimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0442] [3a(4)Z]-6,9,16-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0443] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione;

[0444] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione;

[0445] [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0446] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione;

[0447] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione;

[0448] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0449] [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0450] [3a(4)Z]-20-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0451] [3a(4)Z]-19-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0452] [3a(4)Z]-6,9,20-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0453] [3a(4)Z]-9,20-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione;

[0454] [3a(4)Z]-6,16-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0455] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0456] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0457] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecyne-3,8(2H,5H)-dione;

[0458] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-17,1-(azenometheno)[1,2]oxazolo[4,5-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(5H,9H)-dione;

[0459] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-17,1-(azenometheno)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(5H,9H)-dione;

[0460] [3a(4)Z]-6,14-dimethyl-10,11,13,14-tetrahydro-2H-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0461] [3a(4)Z]-6,9,14-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0462] [3a(4)Z]-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0463] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0464] [3a(4)Z]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0465] [3a(4)Z]-6,9,16-trimethyl-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0466] [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(5H,9H)-dione;

[0467] [3a(4)Z]-6,9,12,14,16-pentamethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0468] [3a(4)Z]-6,9,14,16-tetramethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0469] [3a(4)Z]-6,9,14,16-tetramethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0470] [3a(4)Z]-9,14,16-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0471] [3a(4)Z]-9,14,16-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0472] [3a(4)Z]-12-ethyl-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0473] [3a(4)Z]-6,9,14-trimethyl-12-(propan-2-yl)-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0474] [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0475] [3a(4)Z]-9,14-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0476] [3a(4)Z]-6,9-dimethyl-16-(propan-2-yl)-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0477] [3a(4)Z]-9-methyl-16-(propan-2-yl)-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione;

[0478] [3a(4)Z]-6,9,14-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0479] [3a(4)Z]-9,14-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione;

[0480] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0481] [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione;

[0482] [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione; and

[0483] [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-3,8(2H,5H)-dione;

[0484] or a pharmaceutically acceptable salt thereof.

[0485] In another embodiment, the present invention provides [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,18-(ethanediylidene)dipyrrolo[3,2-g:3',4'-j][1,5,12]benzoxadiazacyclopentadecin-3,8(2H,5H)-dione;

[0486] [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0487] [3a(4)Z]-6-methyl-10,11-dihydro-2H-17,1-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4]benzoxazacyclotetradecine-3,8(5H,9H)-dione;

[0488] [3a(4)Z]-16-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0489] [3a(4)Z]-15-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0490] [3a(4)Z]-14-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0491] [3a(4)Z]-13-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione; and

[0492] [3a(4)Z]-6,9,12-trimethyl-10,11,12,13-tetrahydro-2H-1,18-(ethanediylidene)dipyrrolo[3,2-g:3',4'-j][2,5]benzodiazacyclopentadecyne-3,8(5H,9H)-dione or a pharmaceutically acceptable salt thereof.

[0493] In another embodiment, the present invention provides [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)pyrido[3,2-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0494] [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)pyrimido[5,4-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0495] [3a(4)Z]-6,16-dimethyl-10,11-dihydro-2H-1,17-(ethanediylidene)pyrido[3,4-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione;

[0496] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,18-(ethanediylidene)pyrido[2,1-c]dipyrrolo[3,2-j:3',4'-m][1,4,8]triazacyclotetradecine-3,8,14(2H,5H)-trione;

[0497] [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-18,1-(azenometheno)pyrido[1,2-e]dipyrrolo[3,4-i:2',3'-l][1,5]diazacyclotetradecine-3,8,14(2H,5H)-trione;

[0498] or a pharmaceutically acceptable salt thereof.

[0499] In another embodiment, the present invention provides [3a(4)Z,13aR]-6-methyl-10,11,12,13,13a,14,15,16-octahydro-2H-18,1-(azenometheno)tripyrrolo[1,2-a:3',2'-i:3'',4''-l][1,4,7]triazacyclopentadecin-3,8(5H,9H)-dione;

[0500] [3a(4)Z,13aR]-6-methyl-9,10,11,12,13,13a,14,15-octahydro-17,1-(azenometheno)azeto[1,2-a]dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecin-3,8(2H,5H)-dione;

[0501] [16a(17)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenometheno)dipyrrolo[3,4-g:2',3'-j][1,4,6,13]oxatriazacyclopentadecine-4,16(5H,15H)-dione;

[0502] [16a(17)Z]-2,5,11-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclopentadecyne-4,16(5H,15H)-dione;

[0503] [17a(18)Z]-2,12-dimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclohexadecyne-4,17(5H,16H)-dione;

[0504] [17a(18)Z]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclohexadecyne-4,17(5H,16H)-dione;

[0505] [17a(18)Z]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,11,13]oxatriazacyclohexadecin-4,17(5H,16H)-dione;

[0506] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecin-4,16(5H,15H)-dione;

[0507] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione;

[0508] [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione;

[0509] [16a(17)Z]-11-cyclopropyl-2,5-dimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione;

[0510] [16a(17)Z]-11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione;

[0511] [10R,16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecin-4,16(5H,15H)-dione;

[0512] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecin-4,16(5H,15H)-dione;

[0513] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclopentadecyne-4,16(5H,15H)-dione;

[0514] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenometheno)dipyrrolo[3,4-g:2',3'-j][1,4,6,13]oxatriazacyclopentadecin-4,16(5H,15H)-dione;

[0515] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0516] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione;

[0517] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione;

[0518] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,3,10,13]oxatriazacyclopentadecin-4,16(1H,15H)-dione;

[0519] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,4-d:2',3'-g][1,3,10,13]oxatriazacyclopentadecin-4,16(1H,15H)-dione;

[0520] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione;

[0521] [9R,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione;

[0522] [9S,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione;

[0523] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0524] [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0525] [10R,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0526] [10S,16a(17)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0527] [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione;

[0528] [9R,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0529] [9S,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0530] [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-13,15-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,13,4]oxathiazacyclohexadecin-4,17(5H,16H)-dione;

[0531] [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H-13,15-(ethanediylidene)-12λ 6 -dipyrrolo[3,2-f:3',4'-i][1,13,4]oxathiazacyclohexadecyne-4,12,12,17(5H,9H,16H)-tetrone;

[0532] [17a(18)Z]-2-methyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecin-4,17(5H,16H)-dione;

[0533] [12R,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecin-4,17(5H,16H)-dione;

[0534] [12S,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecin-4,17(5H,16H)-dione;

[0535] [12S,17a(18)Z]-2,5,12-trimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecin-4,17(5H,16H)-dione;

[0536] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0537] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azenometheno)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0538] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0539] [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0540] [12S,17a(18)Z]-2,5,12-trimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0541] [17a(18)Z]-2-methyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0542] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0543] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0544] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azenometheno)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0545] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione;

[0546] [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione;

[0547] [18a(19)Z]-2,5-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione;

[0548] [18a(19)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione;

[0549] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione;

[0550] [13R,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione;

[0551] [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(azenometheno)dipyrrolo[3,4-i:2',3'-l][1,4,8,15]oxatriazacycloheptadecin-4,12,18(5H,13H,17H)-trione;

[0552] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,4-i:2',3'-l][1,4,8,15]oxatriazacycloheptadecin-4,12,18(5H,13H,17H)-trione;

[0553] [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecin-4,12,18(5H,13H,17H)-trione;

[0554] [13S,18a(19)Z]-13-hydroxy-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecin-4,12,18(5H,13H,17H)-trione;

[0555] [16a(17)Z]-2-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0556] [16a(17)Z]-19-chloro-2-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0557] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0558] Methyl [7R,16a(17)Z]-19-chloro-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxylate;

[0559] [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-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

[0560] [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-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

[0561] [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-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

[0562] [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-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

[0563] [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-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide;

[0564] [7R,16a(17)Z]-19-chloro-2,5-dimethyl-7-(4-methylpiperazine-1-carbonyl)-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-4,16(5H,15H)-dione;

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

[0566] [10S,16a(17)Z]-19-chloro-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0567] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0568] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,16(5H,15H)-dione;

[0569] [16a(17)Z]-19-chloro-2,5-dimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione;

[0570] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14-(ethanediylidene)-8λ 6 -dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,8,8,16(1H,5H,15H)-tetrone;

[0571] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14-(ethanediylidene)-8λ 4 -dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,8,16(1H,5H,15H)-trione;

[0572] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,16(5H,15H)-dione;

[0573] [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,16(5H,15H)-dione;

[0574] [16a(17)Z]-2,5-dimethyl-6,7-dihydro-1H,9H-12,14-(ethanediylidene)-11λ 6 -dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,11,11,16(5H,10H,15H)-tetrone;

[0575] [16a(17)Z]-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,16(5H,15H)-dione;

[0576] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)pyrazolo[4,3-i]pyrrolo[3,4-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione;

[0577] [16a(17)Z]-19-chloro-5-methyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione;

[0578] [16a(17)Z]-19-chloro-2,5,8-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione;

[0579] [16a(17)Z]-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-19-carbonitrile;

[0580] [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecine-4,16(5H,15H)-dione;

[0581] [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,16(5H,15H)-dione; and

[0582] [16a(17)Z]-19-chloro-5-methyl-6,7-dihydro-1H,9H-12,14-(ethanediylidene)-11λ 6 -dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,11,11,16(5H,10H,15H)-tetrone

[0583] or a pharmaceutically acceptable salt thereof.

[0584] The following are representative examples of embodiments of compounds of formula (I): [Table 1] [Table 2] [Table 3] [Table 4]

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 17

[0585] Those skilled in the art will recognize that the compound species listed or described herein are not exhaustive and that additional species within these defined ranges may be selected.

[0586] Pharmaceutical Composition For therapeutic purposes, pharmaceutical compositions containing the compounds described herein may further contain one or more pharmaceutically acceptable additives. Pharmaceutically acceptable additives are non-toxic and otherwise biologically suitable substances for administration to a subject. Such additives facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable additives include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, bulking agents, emulsifiers, or taste modifiers. In a preferred embodiment, the pharmaceutical composition of the present invention is a sterile composition. Pharmaceutical compositions can be prepared using known or available mixing techniques to those skilled in the art.

[0587] Sterile compositions are also contemplated by the present invention, including compositions that comply with national and local regulations governing such compositions.

[0588] The pharmaceutical compositions and compounds described herein can be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or with solid carriers as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules, by conventional methods known in the art for preparing various dosage forms. The pharmaceutical compositions of the present invention can be administered by any suitable delivery route, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0589] For oral administration, the compounds of the present invention may be provided as solids, such as tablets or capsules, or as solutions, emulsions, or suspensions. To prepare oral compositions, the compounds of the present invention may be formulated to provide a daily dosage of, for example, about 0.1 mg to 1 g, or about 1 mg to 50 mg, or about 50 to 250 mg, or about 250 mg to 1 g. Oral tablets may contain the active ingredient mixed with compatible pharmaceutically acceptable additives, such as diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Examples of liquid oral additives include ethanol, glycerol, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are examples of disintegrants. Binders may include starch and gelatin. Lubricants, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0590] Oral capsules include hard and soft gelatin capsules.To prepare hard gelatin capsules, the active ingredient can be mixed with a solid, semi-solid or liquid diluent.Soft gelatin capsules can be prepared by mixing the active ingredient with water, oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono- and diglycerides of short-chain fatty acids, polyethylene glycol 400 or propylene glycol.

[0591] Oral administration liquids can be in the form of suspension, solution, emulsion or syrup, or can be freeze-dried or presented as a dry product for reconstitution with water or other suitable medium before use.Such liquid compositions can optionally contain suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous media such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, pharmaceutically acceptable additives such as flavorings or colorings.

[0592] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the present invention are provided in sterile aqueous solutions or suspensions buffered to an appropriate pH and isotonic, or in parenterally acceptable oils. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be provided in unit-dose forms, such as ampoules or disposable injection devices, in multi-dose forms, such as vials from which the appropriate dose can be withdrawn, or in solid or pre-concentrate forms that can be used to prepare injectable formulations. Exemplary infusion doses range from about 1 to 1,000 μg / kg / min of solution mixed with a pharmaceutical carrier over periods ranging from several minutes to several days.

[0593] For nasal, inhaled, or oral administration, the pharmaceutical compositions of the present invention may be administered, for example, using a spray formulation, similarly containing suitable carriers. The compositions of the present invention may also be formulated for rectal administration as suppositories.

[0594] For topical application, the compounds of the present invention are preferably formulated into creams, ointments, or similar vehicles suitable for topical administration. For topical administration, the compounds of the present invention are mixed with a pharmaceutical carrier at a drug concentration of about 0.1% to about 10% of the vehicle. Another method of administering the drugs of the present invention may utilize a patch formulation for transdermal delivery.

[0595] As used herein, the term "treat" or "treatment" encompasses both "prophylactic" and "curative" treatment. "Prophylactic" treatment is meant to refer to postponing the development of a disease, disease symptom, or medical condition, suppressing symptoms that may appear, or reducing the risk of development or recurrence of a disease or symptom. "Curative" treatment includes reducing the severity or inhibiting worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing worsening of existing disease symptoms, preventing the onset of further symptoms, ameliorating or preventing the underlying systemic cause of a symptom, intercepting a disorder or disease, for example, halting the progression of a disorder or disease, alleviating a disorder or disease, inducing regression of a disorder or disease, alleviating a condition caused by a disease or disorder, or arresting the symptoms of a disease or disorder.

[0596] The term "subject" refers to a mammalian patient in need of such treatment, such as a human.

[0597] Examples of diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation. As used herein, the term "cancer" includes ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER cancer, and the like. +These include, but are not limited to, breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian carcinoma, gastric adenocarcinoma, colorectal carcinoma, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, spitzoid tumor, sarcoma, astrocytoma, brain low-grade glioma, breast secretory carcinoma, breast analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, cutaneous melanoma, head and neck squamous cell carcinoma, childhood glioma CML, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin's lymphoma, and serous and clear cell endometrial carcinoma. In some embodiments, cancers include lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophageal cancer, glioblastoma, head and neck cancer, inflammatory myofibroblastic tumor, and anaplastic large cell lymphoma. Pain includes pain of any origin or etiology, including, for example, cancer pain, pain from chemotherapy treatment, nerve pain, pain from injury or other origin. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren's syndrome, type I diabetes, and lupus. Examples of neurological diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Examples of inflammatory diseases include atherosclerosis, allergies, and inflammation from infection or wounds.

[0598] In some embodiments, the compounds and pharmaceutical compositions of the present invention specifically target tyrosine receptor kinases, particularly EGFR. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow down, or inhibit the activity of one or more of these kinases. In a preferred embodiment, the treatment method targets cancer. In other embodiments, the method is for the treatment of lung cancer or non-small cell lung cancer.

[0599] In the inhibitory methods of the present invention, an "effective amount" refers to an amount sufficient to inhibit the target protein. Measurement of such target modification can be performed by routine analytical methods, such as those described below. Such modification is useful in a variety of settings, including in vitro assays. In such methods, the cells are preferably cancer cells with aberrant signaling due to upregulation of EGFR.

[0600] In the treatment methods of the present invention, an "effective amount" generally refers to an amount or dosage sufficient to provide the desired therapeutic benefit to a subject in need of such treatment. Effective amounts or dosages of the compounds of the present invention can be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, such as the method or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject's health, condition, and weight, and the judgment of the treating physician. Exemplary dosages range from approximately 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 dosage can be given in single or divided dose units (e.g., BID, TID, QID).

[0601] Once the patient's disease is improved, dosage can be adjusted for preventive or maintenance treatment.For example, dosage or administration frequency or both can be reduced according to symptoms to the level that maintains desired therapeutic or preventive effect.Of course, once symptoms are alleviated to an appropriate level, treatment can be stopped.However, patients may need intermittent treatment on a long-term basis due to any recurrence of symptoms.Patient may also need chronic treatment on a long-term basis.

[0602] Drug combinations The compounds of the invention described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Additionally, the additional active ingredients include other therapies or drugs that reduce the adverse effects of the treatment on the intended disease target. Such combinations may serve to increase efficacy, improve other disease symptoms, reduce one or more side effects, or reduce the required dosage of the compounds of the invention. The additional active ingredients may be administered in a separate pharmaceutical composition from the compounds of the invention, or may be included in a single pharmaceutical composition with the compounds of the invention. The additional active ingredients may be administered simultaneously with, before, or after the administration of the compounds of the invention.

[0603] The combination agents include additional active ingredients known or discovered to be effective in treating the diseases and disorders described herein, including those active against other targets associated with the disease. For example, the compositions and formulations and treatment methods of the present invention may further include other drugs or pharmaceuticals, such as other active agents useful in treating the target disease or related symptoms or conditions or that are palliative. For cancer indications, such additional 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 chemotherapeutic agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum agents, mitotic inhibitors, antibodies, hormone therapy, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory agents, such as NSAIDs. The pharmaceutical compositions of the present invention may further include one or more such active agents, and the treatment methods may further include the administration of an effective amount of one or more such active agents.

[0604] Chemical synthesis method The following examples are offered by way of illustration, but not limitation, of the present invention. Those skilled in the art will recognize that the following synthetic reactions and schemes may be modified by the selection of appropriate starting materials and reactants to provide other compounds of Formulas (I)-(VIII).

[0605] In one embodiment, the present invention provides a compound of formula (IX): [ka]

[0606] [Wherein A' optionally represents deuterium, halogen, -OC1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)Ra , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)NR 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)NR 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, or a 5- to 10-membered heteroaryl or C6-C 10aryl, where -OC1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from 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)NR 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)NR 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)NRe R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0607] Z' is a 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 , -NR a R b , -SR a , -S(O)R a or -S(O)2R a wherein 3-7 membered heterocycloalkyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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)NR 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)NR 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 , substituted with -CN or -NO2;

[0608] X is -N- or -C(R 6 )-and;

[0609] X 1 -N-, -C(R 7 )- or bond to Z'; X 2 -N-, -C(R 8 )- or a bond to Z'; provided that X 1 or X 2 is a bond to Z';

[0610] X 3 is -N- or -C(R 9 )-and;

[0611] X 4 is -N- or -C(R 10 )-and;

[0612] Y is -O- or -S-;

[0613] Y 2 is -O-, -N(R 11 )- or -S-;

[0614] R 6 is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -CN;

[0615] R 7 , R 8 , R 9 and R 10 each independently represents H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -OC1-C6 alkyl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)NR 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 Rb , -NR a S(O)NR 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 atom to which they are attached, form a C4-C6 cycloalkyl, a 4- to 7-membered heterocycloalkyl, or a C6-C 10 aryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently optionally selected from 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)NR e Rf , -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)NR 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 , substituted with -CN or -NO2;

[0616] R 11 are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from 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)NR 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)NR 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’ , substituted with -CN or -NO2;

[0617] Each R a , R b , R c , Rd , R e and R f are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkyl-C6-C 10 aryl and 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkyl-C6-C 10Aryl and 5-10 membered heteroaryl are independently optionally selected from -OH, -OPG, -CN, -OCi-C6 alkyl, -NH, -NHPG, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-C6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NHCi-C6 alkyl, -N(Ci-C6 alkyl)C(O)NH2, -N(Ci-C6 alkyl)C(O)NHCi-C6 alkyl, -NHC(O)N(Ci-C6 alkyl)2, -N( C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, -NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O )NH(C1-C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -COOPG, -C(O)OC1-C6 alkyl, -C(O)NH2 , -C(O)NHPG, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl; and

[0618] PG is a protecting group. The present invention provides a compound of the formula:

[0619] Abbreviations: The examples described herein make use of materials designated by the following abbreviations known to those of skill in the art, including, but not limited to: [Table 32] [Table 33]

[0620] General law A [ka]

[0621] A mixture of oxindole A1-1 (1.0 equivalent (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 suction 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.

[0622] Intermediates A-1 to A-26 can be prepared by general method A using the corresponding starting materials A1 and A2 shown in the table below: [Table 34] [Table 35] [Table 36] [Table 37] [Table 38] [Table 39]

[0623] General law BI [ka]

[0624] Step 1. To a solution of B1-1 (1.0 eq.) and B2-1 (1.5 eq.) in DMF (0.25 M), Cs2CO3 (2.0 eq.) was added, and the mixture was stirred under nitrogen at 60-80 °C until the reaction was complete. Water (5 equivalent volumes of DMF) was added to the cooled DMF solution, and the product was extracted three times with ethyl acetate (1 equivalent volume of water). The combined extracts were washed with water, aqueous HCl (1N), brine, and dried over magnesium sulfate. After filtration and concentration, the crude product was purified on a silica gel column to give the pure product B3-1.

[0625] Alternative Step 1: B1-1 (1.0 eq.) was added to a suspension of NaH (60% in mineral oil, 1.1 eq.) in THF (0.5 M) at ambient temperature. After 30 min, B2-1 (1.0 eq.) was added to the above suspension. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and purified on a silica gel column to give B3-1.

[0626] Step 2. To a solution of B3-1 (1.0 eq.) in dry acetonitrile (0.25 M) was added N-bromosuccinimide (1.05 eq.), and the solution was stirred at ambient temperature until the reaction was complete. The reaction was quenched with aqueous sodium thiosulfate (0.1 N), and then the acetonitrile was removed under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The combined extracts were washed with water and brine, and then dried over magnesium sulfate. After filtration and concentration, the crude product was purified on a silica gel column to give the pure product B4-1.

[0627] Step 3. A mixture of B4-1 (1.0 eq), bis(pinacolato)diborane (1.2 eq), KOAc (3.0 eq), and catalyst Pd(dppf)Cl / CHCl (0.05 eq) in anhydrous DMF (0.5 M) was purged with nitrogen gas. The mixture was heated under nitrogen at about 95°C for about 15 hours. The reaction solution was cooled, diluted with ethyl acetate (5 volumes of DMF), filtered through a silica gel column, and concentrated. The residue was further purified by silica gel flash chromatography to give the pure product BI-1.

[0628] The following pinacol boronic acids BI-1 to BI-16 were prepared from general method BI using the corresponding starting materials B1 and B2: [Table 40] [Table 41] [Table 42]

[0629] General Law B-II [ka]

[0630] Step 1. To a solution of B5-1 (1.0 eq.) and B2-2 (1.5 eq.) in DMF (0.25 M), Cs2CO3 (2 eq.) was added, and the mixture was stirred under nitrogen at 60-80 °C until the reaction was complete. Water (5 volumes of DMF) was added to the cooled DMF solution, and the product was extracted three times with ethyl acetate (1 volume of water). The combined extracts were washed with water, aqueous HCl (1N), brine, and dried over magnesium sulfate. After filtration and concentration, the crude product was purified on a silica gel column to give the pure product B6-1.

[0631] Step 2. A mixture of B6-1 (1.0 eq), bis(pinacolato)diborane (1.2 eq), KOAc (3.0 eq), and catalyst Pd(dppf)Cl / CHCl (0.05 eq) in anhydrous DMF (0.5 M) was purged with nitrogen gas. The mixture was heated under nitrogen at about 95 °C for about 15 hours. The reaction solution was cooled, diluted with ethyl acetate (5 volumes of DMF), 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.

[0632] The following pinacol boronic acids B-II-1 to B-II-10 were prepared from general method B-II using the corresponding starting materials B5 and B2 as shown in the table below: [Table 43] [Table 44]

[0633] General Law B-III [ka]

[0634] Step 1. B7-1 pyrazole (1.0 eq.) was added to a suspension of NaH (60% in mineral oil, 1.1 eq.) in THF (0.5 M) at ambient temperature. After 30 min, 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 three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and purified on a silica gel column to give B9-1.

[0635] Step 2. To a solution of B9-1 (1.0 eq.) in anhydrous THF (0.2 M) was added n-BuLi (2.5 M in hexane, 1.1 eq.) at 0 °C. The reaction solution was stirred at ambient temperature for 1 h and 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 warmed to 0 °C over 1 h. The reaction was diluted with saturated NH4Cl solution and extracted with DCM. The organic layer was dried over Na2SO4, concentrated, and purified on a silica gel column to give B-III-1.

[0636] The following pinacol boronic acids B-III-1 to B-III-6 were prepared from general method B-III using the corresponding starting materials B7 and B8 as shown in the table below: [Table 45]

[0637] General Law B-IV [ka]

[0638] 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 hour and partitioned between water and ethyl acetate. The organic layer was separated, washed successively with saturated NaHCO3 and brine, concentrated, and dried under reduced pressure. The residue was dissolved in CHCl2 (0.2 M), and the solution was cooled to 0 °C. To the solution was added di(tert-butyl)dicarbonate (1.2 eq.) in portions. The ice bath was removed, and the mixture was stirred overnight at ambient temperature. The reaction solution was diluted with dichloromethane, washed with water, and dried over magnesium sulfate. After filtration and concentration, the residue was purified on a silica gel column to give B12-1.

[0639] Steps 2 and 3 were the same as steps 2 and 3 in B-IV-1 to obtain B-IV-1.

[0640] The following pinacol boronic acids B-IV-1 to B-IV-7 were prepared from general method B-IV using the corresponding starting materials B10 and B11 as shown in the table below: [Table 46] [Table 47]

[0641] General law C [ka]

[0642] To a solution of A-1 (1.0 eq.), B-1 (1.2 eq.), and CsCO (3 eq.) in DME / HO (5:1, 0.2 M) was added Pd(PPh)Cl (0.05 eq.) under N. The mixture was stirred at 85 °C overnight, cooled to ambient temperature, and quenched with HO. The resulting mixture was extracted three times with EtOAc. The combined extracts were washed with brine and dried over anhydrous NaSO. After filtration and concentration, the resulting residue was purified by silica gel column chromatography to give the desired product C-1.

[0643] The following intermediates C-1 to C-66 were prepared from general procedure C using the corresponding two starting materials A and B as shown in the table below: [Table 48] [Table 49] [Table 50] [Table 51] [Table 52] Table 53 Table 54 Table 55 Table 56 Table 57 Table 58 Table 59 Table 60 Table 61 Table 62 Table 63 Table 64

[0644] General method D

change

[0645] To a stirring solution of A-9 (1.0 eq.) in toluene (0.2 M) under nitrogen, D1-1 (1.5 eq.), sodium tert-butoxide (3 eq.), BINAP (0.05 eq.), and Pd(OAc) (0.05) were added. 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 NaSO. After filtration and concentration, the residue was purified on a silica gel column to give D-1.

[0646] The following intermediates D-1 to D-16 were prepared from general method D using the corresponding two starting materials A and D1 as shown in the table below: [Table 65] [Table 66] [Table 67] [Table 68]

[0647] General Law E [ka]

[0648] 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 stirred under nitrogen at 60-80 °C until the reaction was complete. Water (5 volumes of DMF) was added to the cooled DMF solution, and the product was extracted three times with ethyl acetate (1 volume of water). The combined extracts were washed with water, aqueous HCl (1N), brine, and dried over magnesium sulfate. After filtration and concentration, the crude product was purified on a silica gel column to give the pure product E-1.

[0649] The following intermediates E-1 to E-16 were prepared from general method E using the corresponding two starting materials A and E1 as shown in the table below: [Table 69] [Table 70] [Table 71] [Table 72]

[0650] General law F [ka]

[0651] To a solution of E-16 (1.0 eq.) in DCM (0.2 M) was added m-chloroperbenzoic acid (m-CPBA) (3 eq.) at 0 °C. The reaction mixture was warmed 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 concentration, the residue was purified by flash column silica gel chromatography to give F-1.

[0652] General Law G [ka]

[0653] Step 1. To a solution of A1-19 (1.0 eq.) in DCM (0.2 M) and EtN (4 eq.) in an ice bath, MsCl (3 eq.) was added, and the mixture was stirred overnight at 0 °C to ambient temperature. The reaction was diluted with DCM, washed with ice water and brine, and dried over Na SO . After filtration and concentration, the residue was dried under reduced pressure to give G1-1, which was used without further purification.

[0654] Step 2. 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) at ambient temperature. After 30 minutes, G1-1 (1.0 eq.) was added to the above suspension. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride and extracted three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and dried under reduced pressure. The residue was dissolved in THF / water (1:1, 0.5 M), and aqueous NaOH (6 M, 3 eq.) was added to the mixture. The resulting mixture was stirred at 60 °C until hydrolysis was complete. The reaction solution was cooled to ambient temperature, diluted with EtOAc, washed with brine, and dried over Na2SO4. After filtration and concentration, the residue was purified on a silica gel column to give G3-1.

[0655] Step 3. G3-1 was reacted with A2-2 according to general method A to give G-1.

[0656] The following intermediates G-1 to G-4 were prepared from general method G using the corresponding two starting materials A1 and G2 as shown in the table below: [Table 73]

[0657] General law H [ka]

[0658] 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 pentafluorophenyl diphenylphosphinate (FDPP) (1.1 eq.). The solution was stirred at ambient temperature until amide formation was complete. The mixture was diluted with water and extracted three times with EtOAc. The combined extracts were washed three times with water, aqueous HCl (1N), saturated aqueous Na2CO3, and brine, dried over Na2SO4, and concentrated. The resulting residue was purified on a silica gel column to give H2-1.

[0659] Step 2. H2-1 was reacted with A2-2 according to general method A to give H-1.

[0660] The following intermediates H-1 to H-10 were prepared from general method H using the corresponding two starting materials A1 and H1 as shown in the table below: [Table 74] [Table 75] [Table 76]

[0661] General Law I [ka]

[0662] 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 pentafluorophenyl diphenylphosphinate (FDPP) (1.1 eq.). The solution was stirred at ambient temperature until amide formation was complete. The mixture was diluted with water and extracted three times with EtOAc. The combined extracts were washed three times with water, aqueous HCl (1N), saturated aqueous Na2CO3, and brine, dried over Na2SO4, and concentrated. The resulting residue was purified on a silica gel column to give I1-1.

[0663] Step 2. I1-1 was reacted with A2-2 according to general method A to give I-1.

[0664] The following intermediates I-1 to I-5 were prepared from general method I using the corresponding two starting materials A1 and D1 as shown in the table below: [Table 77] [Table 78] [Table 79]

[0665] General law J [ka]

[0666] Step 1. To a solution of C-1 (1.0 eq.) in MeOH (0.2 M) was added a solution of LiOH (3 eq.) in HO (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 HCl (1 N) to a pH of approximately 4-5, and then extracted with CHCl. ​​The combined extracts were dried over NaSO, concentrated, and dried under reduced pressure. The resulting crude solid was dissolved in CHCl (0.2 M), and to the solution was added a solution of HCl in dioxane (4 eq. HCl). The solution was stirred at 40 °C until the removal of Boc was complete. The solvent was removed by rotary evaporation, and the residue was dried under reduced pressure to give crude J-1, which was used in the next step without further purification.

[0667] Step 2. To a solution of J-1 (1 eq.) in DMF (0.2 M) was added DIPEA (3 eq.) and pentafluorophenyl diphenylphosphinate (FDPP) (1.1 eq.). The solution was stirred at ambient temperature until amide formation was complete. The mixture was diluted with water and extracted three times with EtOAc. The combined extracts were washed three times with water, HCl aqueous solution (1N), saturated Na2CO3 aqueous solution and brine, dried over Na2SO4, and concentrated. The resulting residue was purified on a silica gel column to give compound 1.

[0668] By general method J, compounds 1-66 were prepared from the corresponding C-1-C-66, compounds 67-82 from D-1-D-16, compounds 83-98 from E-1-E-16, compound 99 from F-1, compounds 100-103 from G-1-G-4, compounds 104-113 from H-1-H-10, and compounds 114-122 from I-1-I-9.

[0669] General law K [ka]

[0670] 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 CsCO (3 eq) in dioxane and HO was added Pd(PPh)Cl (0.1 eq) under nitrogen. The mixture was stirred at 100 °C under N for 16 h, then cooled and concentrated under reduced pressure. The residue was purified by column chromatography (SiO) to give tert-butyl N-methyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate (K-1).

[0671] General law L [ka]

[0672] 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) under nitrogen, Pd(dppf)Cl (0.1 eq) and aqueous NaCO (2 M, 3.0 eq) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. Upon completion, the mixture was concentrated under reduced pressure to give the crude title compound. The residue was purified on a 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).

[0673] General law M [ka]

[0674] 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 under reduced pressure. The residue was purified on a silica gel column to give tert-butyl N-methyl-N-[2-[2-(2-oxoindolin-5-yl)oxyethoxy]ethyl]carbamate (M-1).

[0675] General law N [ka]

[0676] Step 1. To a solution of tert-butyl N-methyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate (1 eq) in DCM was added HCl / dioxane (4 M, 10 eq), and the resulting mixture was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure to give 5-[2-[2-[2-(methylamino)ethoxy]ethyl]pyrazol-3-yl]indolin-2-one HCl salt.

[0677] Step 2. To a solution of 5-[2-[2-[2-(methylamino)ethoxy]ethyl]pyrazol-3-yl]indolin-2-one HCl salt (0.34 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (1 eq) in acetonitrile, 1-methylimidazole (3 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium hexafluorophosphate (1.5 eq) were added, and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and purified by column silica gel chromatography. The crude product was triturated with MeOH at 25 °C for 10 min, then filtered to give 2-formyl-N,5-dimethyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]-1H-pyrrole-3-carboxamide (N-1).

[0678] General law O [ka]

[0679] To a solution of N-1 (1 eq) in EtOH was added piperidine (2 eq). The mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure. The crude product was triturated with MeOH at 25° C. for 10 minutes to give the title compound (41).

[0680] Example 1

[0681] Preparation of methyl 2-[(Z)-(5-chloro-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene)methyl]-1H-pyrrole-3-carboxylate (A-27) by general method A [ka]

[0682] A mixture of 5-chloro-1,3-dihydropyrrolo[2,3-c]pyridin-2-one (1.0 g, 5.93 mmol, 1 eq), methyl 2-formyl-1H-pyrrole-3-carboxylate (908 mg, 5.93 mmol, 1 eq), and piperidine (1.01 g, 11.86 mmol, 1.17 mL, 2.0 eq) in EtOH (100 mL) was stirred at 80 °C for 1 h. After completion, the mixture was cooled to ambient temperature and the product precipitated. The solid was filtered, washed with EtOH (30 mL), and dried under reduced pressure to give methyl 2-[(Z)-(5-chloro-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene)methyl]-1H-pyrrole-3-carboxylate (1.6 g, 4.21 mmol, 71% yield) as a yellow powder. 1 H NMR (400 MHz, DMSO-d6) δ (ppm)

[0683] A-28 to A-31 were prepared according to a method similar to A-27. [Table 80]

[0684] Example 2

[0685] Preparation of tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (BI-2) by General Method BI [ka]

[0686] Step 1: To a solution of 1,2-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)O (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. After completion, the mixture was diluted with DCM (200 mL) and washed with brine (100 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (9.0 g, 47.4 mmol, 79.7% yield, 97% purity) as a pale yellow powder. 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.81 (d, J = 3.2 Hz, 1H), 5.90 (d, J = 3.2 Hz, 1H), 1.63 (s, 9H)

[0687] Step 2. To a solution of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (7.0 g, 38.0 mmol, 1 eq) and tert-butyl N-(3-bromopropyl)carbamate (9.95 g, 41.80 mmol, 1.1 eq) in DMF (21 mL) was added K2CO3 (7.88 g, 57.0 mmol, 1.5 eq). The mixture was stirred at 80 °C for 16 h. After completion, the mixture was diluted with EtOAc (100 mL) and washed with brine (2 × 40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by Combiflash (40 g silica column, eluting with 0–40% EtOAc in PE, ca. 10%) to give tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]pyrazole-1-carboxylate (8.2 g, 22.8 mmol, 60% yield, 95% purity) as a white oil. 1H NMR (400 MHz, DMSO-d6) δ (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)

[0688] Step 3. To a solution of tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]pyrazole-1-carboxylate (1.50 g, 4.39 mmol, 1 eq) and Pin2B2 (2.23 g, 8.7 mmol, 2.0 eq) in THF (30 mL) was added (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (291.2 mg, 439 μmol, 0.1 eq) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (235 mg, 878 μmol, 0.2 eq) under a nitrogen atmosphere. The mixture was stirred at 70 °C for 16 h. After completion, the mixture was diluted with EtOAc (50 mL) and washed with brine (2 × 20 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified on a silica gel column (40 g, 0–100% EA in PE, eluted at approximately 35%) to give tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (BI-2, 2.3 g, 2.9 mmol, 67.2% yield) as a white oil. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.10 (s, 1H), 6.81 (t, J = 5.2 Hz, 1H), 3.80 - 3.76 (m, 2H), 3.06 (q, J = 6.4 Hz, 2H), 1.84 - 1.82 (m, 1 H), 1.55 (s, 9H), 1.37 (s, 9H), 1.25 (s, 12H)

[0689] Example 3

[0690] Preparation of tert-butyl N-[3-[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]oxypropyl]carbamate (BI-5) by General Method BI [ka]

[0691] 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), and extracted with EA (3 × 60 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (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 a colorless gum. 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.10 (d, J = 2.4 Hz, 1H), 5.58 (d, J = 2.4 Hz, 1H), 4.95 - 4.92 (m, 1H), 4.18 - 4.15 (m, 2 H), 3.71(s, 3H), 3.30 - 3.25 (m, 2H), 1.94 - 1.90 (m, 2H), 1.43 (s, 9H)

[0692] Step 2. To a solution of tert-butyl N-[3-(1-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 column chromatography on silica gel (PE:EA = 25:1 to 2:1) to afford tert-butyl N-[3-(4-bromo-1-methyl-pyrazol-3-yl)oxypropyl]carbamate (7.3 g, 21.84 mmol, 79.6% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.18 (s, 1H), 5.04 - 5.02 (m, 1H), 4.28 - 4.25 (m, 2 H), 3.72 (s, 3H), 3.32 - 3.27 (m, 2H), 1.97 - 1.94 (m, 2H), 1.44 (s, 9H)

[0693] Step 3. To a mixture of tert-butyl N-[3-(4-bromo-1-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 μmol, 0.1 eq) under nitrogen. The mixture was stirred at 60° C. under a nitrogen atmosphere for 16 hours. Upon completion, the mixture was cooled to ambient temperature, diluted with PE (200 mL), and filtered. The organic layer was concentrated under reduced pressure to give a grass-green oil. The crude material was purified on a silica gel column (20 g, eluted with 0-100% EtOAc in PE for 15 min at approximately 60%) to give tert-butyl N-[3-[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]oxypropyl]carbamate (BI-5, 2.9 g, 6.08 mmol, 68% yield) as a brown gum. LCMS: m / z 381.9 (M+1) +

[0694] Example 4

[0695] Preparation of tert-butyl N-[3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propyl]carbamate (B-II-1) by General Method B-II [ka]

[0696] To a mixture of 2-(4,4,5,5-tetramethyl-1,3,2-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. After completion, the mixture was cooled, diluted with ethyl acetate (200 mL), washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, eluted with 0–100% EtOAc in PE, 25%) to give tert-butyl N-[3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propyl]carbamate (B-II-1, 10 g, 22.5 mmol, 49.5% yield, 85% purity) as a colorless gum. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.70 - 7.76 (m, 1 H), 7.37 - 7.44 (m, 1 H), 6.95 - 7.01 (m, 1 H), 6.86 - 6.92 (m, 1 H), 5.46 - 5.62 (m, 1 H), 4.05 - 4.12 (m, 2 H), 3.36 - 3.49 (m, 2 H), 1.96 - 2.05 (m, 2 H), 1.44 (s, 10 H), 1.37 (s, 12 H)

[0697] Example 5

[0698] Preparation of tert-butyl N-[3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate (B-II-2) by General Method B-II

[0699] B-II-2 was prepared using a method similar to B-II-1.

[0700] Example 6

[0701] Preparation of [2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl]pyrazol-3-yl]boronic acid (B-III-7) via general method B-III [ka]

[0702] 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. After completion, the mixture was quenched with water (300 mL), and the combined organic layers were washed with saturated NaHCO (80 mL), brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl methanesulfonate (25.0 g, 75.0 mmol, 76.9% yield) as a pale 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)

[0703] Step 2. To a solution of 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl methanesulfonate (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. After completion, the mixture was quenched with water (200 mL) and diluted with EA (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO, DCM:MeOH=20:1) to give tert-butyl N-[2-(2-pyrazol-1-ylethoxy)ethyl]carbamate (13.0 g, 48.3 mmol, 85.6% yield) as a colorless oil. LCMS: m / z 256.0 (M+1) +

[0704] Step 3. To a solution of tert-butyl N-[2-(2-pyrazol-1-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, followed by the addition of a solution of 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. After completion, the mixture was quenched with MeOH (50 mL), concentrated under reduced pressure, and purified by reverse-phase HPLC to afford [2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl]pyrazol-3-yl]boronic acid (B-III-7, 500 mg, 18.1% yield) as a white powder. 1H 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+1) +

[0705] Example 7

[0706] Preparation of [2-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]ethyl]pyrazol-3-yl]boronic acid (B-III-8) via general method B-III

[0707] B-III-8 was prepared using a method similar to B-III-7. LCMS: m / z 314.1 (M+1) +

[0708] Preparation of [2-[2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino]ethyl]pyrazol-3-yl]boronic acid (B-III-9) [ka]

[0709] 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. After completion, the mixture was quenched with water (10 mL) and diluted with DCM (20 mL). The organic layer was washed with saturated NaHCO (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (2-(tert-butoxycarbonylamino)ethyl methanesulfonate (1.20 g, 4.51 mmol, 72% yield, 90% purity) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) 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)

[0710] Step 2. 2-(tert-Butoxycarbonylamino)ethyl methanesulfonate (9.00 g, 37.0 mmol, 1.0 eq.) and 2-aminoethanol (22.9 g, 376 mmol, 10 eq.) were heated at 80° C. for 16 h. The mixture was quenched with water (200 mL) and diluted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (tert-butyl N-[2-(2-hydroxyethylamino)ethyl]carbamate (10.0 g, 36.7 mmol, 97.6% yield) as a pale yellow solid. 1 H NMR (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)

[0711] 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 HO (12 mL) was added NaHCO (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. After completion, the mixture was quenched with water (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by flash chromatography (40 g silica gel column, 0% to 100% EtOAc in 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) δ = 7.44 - 7.27 (m, 5H), 6.94 - 6.80 (m, 1H), 5.07 (s, 2H), 4.78 - 4.68 (m, 1H), 3.48 (d, J = 3.5 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) +

[0712] 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. After completion, the mixture was quenched with water (150 mL) and diluted with DCM (3 x 150 mL). The combined organic layers were washed with saturated NaHCO3 (100 mL), brine (80 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude (2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino]ethyl methanesulfonate, 4.00 g, 9.60 mmol, 95% yield) which was obtained as a pale yellow gum. LCMS: m / z 317.1 (M+1-100). +

[0713] Step 5. To a solution of 2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino]ethyl methanesulfonate (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 CsCO (6.91 g, 21.2 mmol, 2 eq.). The mixture was stirred at 50 °C for 3 h. After completion, the mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (12 g silica gel column, 0% to 100% EtOAc in PE) to afford benzyl N-[2-(tert-butoxycarbonylamino)ethyl]-N-(2-pyrazol-1-ylethyl)carbamate (3.60 g, 7.88 mmol, 74.2% yield) as a pale yellow gum. LCMS: m / z 389.4 (M+1) +

[0714] 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 a N atmosphere. 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 a N atmosphere for 1.5 h. Upon completion, the mixture was quenched with MeOH (10 mL) and extracted with EtOAc (3×60 mL). The combined organic layers were washed with purified 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) +

[0715] Example 8

[0716] Preparation of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]carbamate (BV-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) [ka]

[0717] 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 LiAlH (1.65 g, 43.4 mmol, 1 eq). The mixture was stirred at 0 °C for 15 min, then slowly quenched with water (0.086 mL), followed by the addition of saturated sodium hydroxide (1.65 mL) and water (4.8 mL). The reaction mixture was filtered and concentrated under reduced pressure to give (4-bromo-2-methyl-pyrazol-3-yl)methanol (7.75 g, 40.6 mmol, 93.5% yield) as a colorless oil. LCMS: 190.9 (M+1) +

[0718] 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), followed by the dropwise addition of a solution of PPh3 (12.8 g, 48.7 mmol, 1.2 eq) in DCM (2 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was slowly quenched with water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column silica gel 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 a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 7.56 (s, 1H), 4.75 (s, 2H), 3.87 (s, 3H)

[0719] Step 3. To a solution of 4-bromo-5-(bromomethyl)-1-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 under N at 25 °C for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, 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 (BV-1, 1.2 g, 3.12 mmol, 79.3% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 7.42 (s, 1H), 4.80 (s, 1H), 4.55 (s, 2H), 3.91 (s, 3H), 3.52 - 3.48 (m, 2H), 3.32 (d, J = 5.2 Hz, 2H), 1.44 (s, 9H)

[0720] 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), [2-(2-aminophenyl)phenyl]chloropalladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (235 mg, 0.299 mmol, 0.1 eq) was added at 25 °C under nitrogen. The mixture was stirred at 60 °C under N for 12 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column silica gel chromatography (PE:EA = 25:1 to 3:1) to give 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, 1.55 g, 2.64 mmol, 88.3% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) 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)

[0721] Example 9

[0722] Preparation of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (BV-2) [ka]

[0723] To a solution of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]carbamate (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, followed by the addition of CHI (407.71 mg, 2.87 mmol, 1.5 eq). 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), and washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (PE:EA=100:0 to 100:35) to give tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (630 mg, 1.81 mmol, 94% yield) as a colorless oil. LCMS: m / z 370.2 (M+Na). +

[0724] Example 10

[0725] Preparation of tert-butyl N-[2-[benzyloxycarbonyl-[(4-bromo-2-methyl-pyrazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate (BV-3) [ka]

[0726] Step 1. To a solution of 4-bromo-2-methyl-pyrazole-3-carbaldehyde (4.55 g, 24.1 mmol, 1 eq) and tert-butyl N-(2-aminoethyl)-N-methyl-carbamate (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) (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 × 40 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1:0 to 4:0) to give tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methylamino]ethyl]-N-methyl-carbamate (3.40 g, 8.52 mmol, 35.3% yield) as a yellow oil. LCMS: m / z 348.9 (M+1) +

[0727] Step 2. To a mixture of a solution of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methylamino]ethyl]-N-methyl-carbamate (2.74 g, 7.89 mmol, 1 eq)) in THF (80 mL) and a solution of NaHCO (1.99 g, 23.7 mmol, 3 eq) in HO (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 hours, quenched with water (80 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1:0 to 4:0) to give tert-butyl N-[2-[benzyloxycarbonyl-[(4-bromo-2-methyl-pyrazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate (BV-3, 2.89 g, 5.83 mmol, 73.9% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.42 (s, 1H), 7.36 (s, 5H), 5.18 (s, 2H), 4.67 (s, 2H), 3.84 (s, 2H), 3.70 - 3.23 (m, 6H), 2.79 - 2.67 (m, 2H), 1.45 (s, 9H)

[0728] Example 11

[0729] Preparation of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (BV-4) and tert-butyl 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]carbamate (B-IV-4) [ka]

[0730] tert-Butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methylamino]ethyl]-N-methyl-carbamate (3.30 g, 9.50 mmol, 1 eq), (CHO) n To a solution of (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 NaBHCN (716 mg, 11.4 mmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. After completion, the mixture was quenched with saturated NH Cl (10 mL), concentrated under reduced pressure, diluted with EtOAc (100 mL), and washed with brine (2 × 70 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (PE:EA = 1:0 to 100:40) to give tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (BV-4, 3 g, 8.30 mmol, 87% yield) as a colorless gum.1 H NMR (400 MHz, CDCl3) δ (ppm) 7.37 (s, 1H), 3.87 (s, 3H), 3.51 (s, 2H), 3.39 - 3.21 (m, 2H), 2.73 (s, 3H), 2.54 - 2.43 (m, 2H), 2.24 (s, 3H), 1.42 (s, 9H)

[0731] [ka] To a solution of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (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 μL, 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 NH4Cl (50.0 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (2×25.0 mL), dried over sodium sulfate, and concentrated under reduced pressure to give tert-butyl 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]carbamate (1.6 g, 2.35 mmol, 77.2% yield).

[0732] Preparation of tert-butyl-N-[2-[benzyloxycarbonyl-[(4-bromo-3-methyl-1H-pyrazol-5-yl)methyl]amino]ethyl]-N-methyl-carbamate (BV-5) [ka]

[0733] BV-5 was prepared using a method similar to BV-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) +

[0734] Preparation of tert-butyl N-[2-[(4-bromo-5-methyl-isoxazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (BV-6) [ka]

[0735] BV-6 was prepared using a method analogous to BV-2, starting from (5-methylisoxazol-3-yl)methanol. 1 H NMR (400 MHz, CDCl3) 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)

[0736] Preparation of tert-butyl N-[2-[benzyloxycarbonyl-[(4-bromo-5-methyl-isoxazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate (BV-7) [ka]

[0737] 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 MnO (38.4 g, 442 mmol, 5 eq.). The mixture was stirred at 25 °C for 16 h and filtered. The filtrate was concentrated under reduced pressure to give 5-methylisoxazole-3-carbaldehyde (6.50 g, 35.0 mmol, 39.71% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 10.12 (s, 1H), 6.40 (s, 1H)2.53 (s, 3H)

[0738] Step 2. To a solution of 5-methylisoxazole-3-carbaldehyde (6.50 g, 58.0 mmol, 1 eq.), tert-butyl N-(2-aminoethyl)-N-methyl-carbamate (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) (24.8 g, 117 mmol, 2 eq.). The mixture was stirred at 25 °C for 16 h. Upon completion, 50 mL water was added and the reaction was extracted with EtOAc (3 x 50 mL). The combined extracts were concentrated under reduced pressure. The residue was purified by column chromatography (SiO, DCM / MeOH, 100:0 to 100:10) to give tert-butyl N-methyl-N-[2-[(5-methylisoxazol-3-yl)methylamino]ethyl]carbamate (1.30 g, 4.20 mmol, 7.18% yield) as a colorless oil. LC-MS: m / z 270.2 (M+1) +

[0739] 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 HO (10 mL) was added NaHCO (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 × 10 mL) and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO, 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 a colorless oil. 1 H NMR (400 MHz, CDCl3) δ = 7.28 (s, 5H), 5.91 (s, 1H), 5.09 (s, 2H), 4.47 - 4.41 (m, 2H), 3.38 - 3.22 (m, 4H), 2.80 (s, 3H), 2.32 (s, 3H), 1.36 (s, 9H); LC-MS: m / z 304.5 (M+1) +

[0740] 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 (4×40 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified on a 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 (BV-7, 320 mg, 630 μmol, 36.4% yield) as a colorless gum. 1 H NMR (400 MHz, CDCl3) δ = 7.38 - 7.33 (m, 5H), 5.18 (s, 2H), 4.61 - 4.50 (m, 2H), 3.60 - 3.28 (m, 4H), 2.77 - 2.66 (m, 3H), 2.40 (s, 3H), 1.44 (s, 9H); LC-MS: m / z 384.3 (M-99) +

[0741] Preparation of tert-butyl N-[2-[(4-bromo-2,5-dimethyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (BV-8) [ka]

[0742] Step 1. To a mixture of 2,5-dimethylpyrazole-3-carbaldehyde (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) (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 and then extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 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, CDCl3) 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) +

[0743] 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 N for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on 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 (MV-8, 1.3 g, 3.38 mmol, 58.9% yield, 97.5% purity) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 3.80 (s, 3H), 3.46 (s, 2H), 3.36 - 3.21 (m, 2H), 2.85 - 2.84 (m, 3H), 2.74 (s, 2H), 2.17 (s, 3H), 2.01 (s, 3H), 1.40 (s, 9H)

[0744] Preparation of tert-butyl N-[2-[(2-bromophenyl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (BV-9) [ka]

[0745] 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) (3.44 g, 16.2 mmol, 1.5 eq). The mixture was stirred at 25 °C for 16 h. After completion, the mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, concentrated under reduced pressure, and purified by flash silica gel chromatography (40 g silica gel column, 0% to 100% DCM in MeOH) to give tert-butyl N-[2-[(2-bromophenyl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (MV-9, 3.50 g, 8.82 mmol, 81.5% yield) as a colorless gum. LC-MS: m / z 357.9 (M+1) +

[0746] Preparation of tert-butyl N-[3-(4-bromo-2,5-dimethyl-pyrazol-3-yl)oxypropyl]-N-methyl-carbamate (BV-10) [ka]

[0747] 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. 1,4-Dioxane (300 mL) was added to the residue, and the mixture was filtered and washed with petroleum ether (30 mL × 3). The filtrate was washed with brine (15 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl N-(3-chloropropyl)-N-methyl-carbamate (24.5 g, crude). 1H NMR (400 MHz, DMSO-d6) δ = 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)

[0748] 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 N was added NaH (1.11 g, 27.8 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred for 0.5 h, followed by the addition of MeI (3.95 g, 27.8 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h, quenched by slow addition of water, and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure 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) δ = 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)

[0749] Step 3. To a solution of tert-butyl N-[3-(2,5-dimethylpyrazol-3-yl)oxypropyl]-N-methylcarbamate (6 g, 21.2 mmol, 1 eq) in ACN (30 mL), NBS (3.77 g, 21.2 mmol, 1 eq) was added at 25 °C and stirred for 16 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA = 25:1 to 2:1) to give tert-butyl N-[3-(4-bromo-2,5-dimethylpyrazol-3-yl)oxypropyl]-N-methylcarbamate (BV-10, 6.8 g, 18.2 mmol, 86% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 4.20 (s, 2H), 3.56 (s, 3H), 3.33 (s, 2H), 2.82 (s, 3H), 2.03 (s, 3H), 1.97-1.88 (m, 2H), 1.38 (s, 9H). LCMS: m / z 384.1(M+Na) +

[0750] Preparation of tert-butyl N-[2-[(4-bromo-2,5-dimethyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (BV-11) [ka]

[0751] 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 hours. 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 ethyl 4-bromo-2,5-dimethyl-pyrazole-3-carboxylate (12 g, 45.2 mmol, 75.9% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 4.35 - 4.29 (m, 2H), 4.02 (s, 3H), 2.17 (s, 3H), 1.34-1.32 (m, 3H)

[0752] 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 LiAlH (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 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 a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ = 5.31 (s, 1H), 4.44 - 4.40 (m, 2H), 3.79 (s, 3H), 2.22 (s, 3H)

[0753] 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 EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (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). +

[0754] 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 under N2 at 25 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 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 (BV-11, 5.5 g, 14.6 mmol, 97.6% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 4.50 - 4.46 (m, 2H), 3.83 (s, 3H), 3.63 - 3.31 (m, 4H), 2.87 (s, 3H), 2.22 (s, 3H), 1.44 (s, 9H)

[0755] Preparation of tert-butyl N-[2-[(4-bromo-5-cyclopropyl-isoxazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (BV-12) [ka]

[0756] BV-12 was prepared using a method similar to that for BV-1, starting from 5-cyclopropylisoxazole-3-carboxylic acid. The bromination procedure is similar to that for BV-7. 1H NMR (400 MHz, CDCl3) δ = 4.53 (s, 2H), 3.60 (s, 2H), 3.40 (s, 2H), 2.91 (s, 3H), 2.10 - 2.07 (m, 1H), 1.17 (s, 9H), 1.16 - 1.12 (m, 2H), 1.11 - 1.10 (m, 2H). LCMS: m / z 277.1 (M-Boc) +

[0757] Preparation of tert-butyl N-[2-[(4-bromo-5-isopropyl-isoxazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (BV-13) [ka]

[0758] BV-13 was prepared using a method similar to that for BV-1, starting from ethyl 5-isopropylisoxazole-3-carboxylate. The bromination procedure is similar to that for BV-7. 1 H NMR (400 MHz, CDCl3) δ = 4.55 (s, 2H), 3.63 (s, 2H), 3.41 (s, 2H), 2.91 (s, 3H), 1.45 (s, 9H), 1.34 (d, J = 7.2 Hz, 6H). LCMS: m / z 277.1 (M-Boc) +

[0759] Preparation of tert-butyl N-[3-(4-bromo-2-methyl-pyrazol-3-yl)oxypropyl]-N-methyl-carbamate (BV-14) [ka]

[0760] BV-14 was prepared using a method analogous to BV-10, starting from 2-methylpyrazol-3-ol. 1H NMR (400 MHz, CDCl3) δ = 7.20 (s, 1H), 4.25 (s, 2H), 3.61 (s, 3H), 3.43 - 3.28 (m, 2H), 2.82 (s, 3H), 1.96 - 1.89 (m, 2H), 1.38 (s, 9H). LCMS: m / z 350.2 (M+1) +

[0761] Preparation of tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-[(3Z)-3-[(3-methoxycarbonyl-1H-pyrrol-2-yl)methylene]-2-oxo-1H-pyrrolo[2,3-c]pyridin-5-yl]pyrazole-1-carboxylate (C-6a) by general method C [ka]

[0762] To a solution of methyl 2-[(Z)-(5-chloro-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene)methyl]-1H-pyrrole-3-carboxylate (500 mg, 1.65 mmol, 1 eq) and tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (3.85 g, 8.23 ​​mmol, 5 eq) in dioxane (10 mL) and HO (1 mL) was added CsCO (1.61 g, 4.94 mmol, 3 eq) and Pd(PPh)Cl (115 mg, 0.165 mmol, 0.1 eq). The resulting mixture was stirred at 90 °C under N atmosphere for 14 h. After completion, the reaction mixture was concentrated under reduced pressure, and 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.

[0763] C-67 to C73 were prepared according to a method similar to that of C-6a. [Table 81] [Table 82]

[0764] Preparation of 3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(azenometheno)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione (6) by general method J [ka]

[0765] Step 1. To a solution of tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-[(3Z)-3-[(3-methoxycarbonyl-1H-pyrrol-2-yl)methylene]-2-oxo-1H-pyrrolo[2,3-c]pyridin-5-yl]pyrazole-1-carboxylate (200 mg, 0.329 mmol, 1 eq) in MeOH (4 mL) and HO (0.4 mL) was added LiOH·HO (206 mg, 4.93 mmol, 15 eq). The resulting mixture was stirred at 50 °C for 15 h. Upon completion, the mixture was concentrated under reduced pressure, dissolved in water (300 mL), and the pH of the aqueous phase was adjusted to 5–6 with 1 M aqueous HCl to precipitate the product. The solid was filtered and triturated with MeOH (15 mL) at 25° C. for 5 min 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-pyrrole-3-carboxylic acid (154 mg, 0.311 mmol, 95% yield) as an orange solid. LCMS m / z 495.2 (M+1) +

[0766] 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-pyrrole-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 for 2 hours at 25° C. After completion, the mixture was concentrated under reduced pressure to give 2-[(Z)-[5-[3-(3-aminopropoxy)-1H-pyrazol-4-yl]-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene]methyl]-1H-pyrrole-3-carboxylic acid HCl salt (130 mg) as a red solid. 1 H 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)

[0767] Step 3. To a solution of 2-[(Z)-[5-[3-(3-aminopropoxy)-1H-pyrazol-4-yl]-2-oxo-1H-pyrrolo[2,3-c]pyridin-3-ylidene]methyl]-1H-pyrrole-3-carboxylic acid (70 mg, HCl) 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 HO (30 mL) and filtered. The filter cake was concentrated under reduced pressure to give the crude product, which was then triturated with MeOH (2 mL), filtered, and dried under reduced pressure to give 6 as a yellow solid (23.4 mg, 32.5% yield). 1H 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, LCMS m / z 377.4 (M+1) +

[0768] Examples 7, 11, 14, 22, 24, 39 and 123 were prepared following methods analogous to 6. [Table 83] [Table 84]

[0769] Preparation of tert-butyl N-methyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate (K-1) by general method K [ka]

[0770] 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 CsCO (1.84 g, 5.63 mmol, 3 eq) in dioxane (10 mL) and HO (2 mL) was added Pd(PPh)Cl (131 mg, 0.187 mmol, 0.1 eq) under nitrogen. The mixture was stirred at 100 °C under N for 16 h, then cooled and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, 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, CDCl3) 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) +

[0771] K-2 was prepared according to a similar method to K-1. [Table 85]

[0772] Preparation of tert-butyl N-methyl-N-[2-[[2-methyl-4-(2-oxoindolin-5-yl)pyrazol-3-yl]methoxy]ethyl]carbamate (L-1) by general method L [ka]

[0773] 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-1,3,2-dioxaborolan-2-yl)indolin-2-one (668 mg, 2.58 mmol, 1.5 eq) in dioxane (17 mL) was added Pd(dppf)Cl (125 mg, 0.172 mmol, 0.1 eq) and aqueous NaCO (2 M, 2.58 mL, 3.0 eq) under nitrogen. The mixture was stirred at 100 °C under nitrogen atmosphere for 2 hours. After completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (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) +

[0774] L-2 to L-13 were produced according to a method similar to that of L-1. [Table 86] [Table 87] [Table 88]

[0775] Preparation of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (M1) [ka]

[0776] 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) (315 mg, 1.43 mmol, 0.05 eq) in DCM (80 mL) was added dropwise a solution of ethyl 2-diazoacetate (9.77, 85.6 mmol, 3 eq) in DCM (50 mL). The mixture was stirred at 25 °C for 16 h, and then HO (5 mL) was added and partitioned. The organic phase was separated, washed with HO (10 mL × 3), dried over NaSO, 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. 1 H NMR (400 MHz, CDCl3) 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)

[0777] 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 LiAlH (1.31 g, 34.4 mmol, 1.5 eq) at 0 °C under N. 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 H0 (3 mL). NaSO was added to the combined mixture, followed by stirring for 10 min. The mixture was filtered and concentrated under reduced pressure. 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 pale yellow oil. 1H NMR (400 MHz, CDCl3) 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)

[0778] Preparation of tert-butyl N-[2-[(2R)-2-hydroxypropoxy]ethyl]-N-methyl-carbamate (M5) [ka]

[0779] Step 1. To a mixture of methyl (2R)-2-hydroxypropanoate (20.0 g, 192 mmol, 1 eq.) and benzyl 2,2,2-trichloroethaneimidate (51.0 g, 202 mmol, 1.05 eq.) in DCM (66.5 mL) and hexane (133 mL), trifluoromethanesulfonic acid (1.11 mL) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 50 h and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified on a 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. 1 H NMR (400 MHz, CDCl3) 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 = 6.8Hz, 3H)

[0780] 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 slowly added LAH (2.30 g, 62.0 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. After completion, the mixture was slowly quenched with water (2.3 mL) at 0 °C, followed by 15% aqueous NaOH (2.3 mL) and water (7.0 mL). After filtration, the filtrate was concentrated under reduced pressure and purified on a silica gel column (petroleum ether: EtOAc, 100:0 to 100:40) to afford (2R)-2-benzyloxypropan-1-ol (7.00 g, 34.0 mmol, 81.79% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ = 7.41 - 7.29 (m, 5H), 4.67 (d, J = 11.6 Hz, 1H), 4.52 (d, J = 11.6 Hz, 1H), 3.74 - 3.67 (m, 1H), 3.66 - 3.60 (m, 1H), 3.58 - 3.51 (m, 1H), 1.21 (d, J = 6.0 Hz, 3H)

[0781] 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. After completion, the mixture was diluted with EtOAc (80 mL) and washed with water (30 mL), saturated NH4Cl (30 mL), and brine (30 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified on a 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 a colorless oil.

[0782] 1H NMR (400 MHz, CDCl3) 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) +

[0783] 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 hours. After completion, water (1 mL) was slowly added to the mixture, followed by 15% aqueous NaOH (1 mL) and water (3 mL) at 0° C. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2-[(2R)-2-benzyloxypropoxy]-N-methyl-ethanamine (4.00 g, 11.6 mmol, 69.1% yield).

[0784] Step 5. A mixture of 2-[(2R)-2-benzyloxypropoxy]-N-methyl-ethanamine (3.77 g, 16.9 mmol, 1.0 eq.), DMAP (206 mg, 1.69 mmol, 0.1 eq.), (Boc)O (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 for 16 h at 20° C. The mixture was concentrated under reduced pressure to give the crude product, which was purified on a silica gel column (petroleum ether:EtOAc, 100:0 to 100:10) to give tert-butyl N-[2-[(2R)-2-benzyloxypropoxy]ethyl]-N-methyl-carbamate (4.00 g, 10.51 mmol, 62.28% yield) as a colorless oil. LCMS: m / z 234.3 (M+1) +

[0785] Step 6. To a mixture of tert-butyl N-[2-[(2R)-2-benzyloxypropoxy]ethyl]-N-methyl-carbamate (3.80 g, 11.7 mmol, 1.0 eq.) in MeOH (40 mL) was added Pd(OH) (825 mg, 1.17 mmol, 20% purity, 0.1 eq.) under a nitrogen atmosphere. The mixture was stirred at 25 °C under 50 Psi H for 16 h. Upon completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified on a silica gel column (petroleum ether: EtOAc, 100:0 to 100:30) to afford tert-butyl N-[2-[(2R)-2-hydroxypropoxy]ethyl]-N-methyl-carbamate (M5, 2.10 g, 9.00 mmol, 76.6% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ = 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)

[0786] Preparation of methyl (2R)-3-[tert-butoxycarbonyl(methyl)amino]-2-(2-hydroxyethoxy)propanoate (M6) [ka]

[0787] Step 1. A solution of methyl (2R)-oxirane-2-carboxylate (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 the main peak was the desired MS. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (220 g silica gel column, 0% to 100% EtOAc in PE) to give methyl (2R)-3-[benzyl(methyl)amino]-2-hydroxy-propanoate (15.3 g, 68.5 mmol, 99.9% yield) as a brown oil. 1 H NMR (400 MHz, CDCl3) δ = 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) +

[0788] Step 2. To a solution of methyl (2R)-3-[benzyl(methyl)amino]-2-hydroxy-propanoate (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 dropwise a solution of tert-butyl 2-diazoacetate (24.2 g, 170 mmol, 2 eq.) in DCM (50 mL) and the mixture was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (330 g silica gel column, 0% to 100% EtOAc in PE) to give methyl (2R)-3-[benzyl(methyl)amino]-2-(2-tert-butoxy-2-oxo-ethoxy)propanoate (9.80 g, 29.0 mmol, 34.1% yield) as a brown oil. 1 H NMR (400 MHz, CDCl3) 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) +

[0789] Step 3. To a solution of methyl (2R)-3-[benzyl(methyl)amino]-2-(2-tert-butoxy-2-oxo-ethoxy)propanoate (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 under reduced pressure, and the residue was purified by Combiflash (120 g silica gel column, 0% to 30% MeOH in DCM) 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, CDCl3) 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 LC-MS: m / z 282.4 (M+1) +

[0790] 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 under reduced pressure. The residue was purified by Combiflash (80 g silica gel column, 0% to 100% EtOAc in PE, 0% to 100% MeOH in EtOAc) to give methyl (2R)-3-[benzyl(methyl)amino]-2-(2-hydroxyethoxy)propanoate (4.60 g, 10.8 mmol, 36.7% yield) as a brown oil. LC-MS: m / z 238.1 (M+1) +

[0791] 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 H (15 Psi) for 3 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give methyl (2R)-2-(2-hydroxyethoxy)-3-(methylamino)propanoate (1.3 g) as a colorless oil. LC-MS: m / z 178.1 (M+1) +

[0792] Step 6. To a solution of methyl (2R)-2-(2-hydroxyethoxy)-3-(methylamino)propanoate (2.70 g, 15.2 mmol, 1 eq.) and EtN (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 BocO (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 under reduced pressure, and the residue was purified by Combiflash (20 g silica gel column, 0% to 100% EtOAc in PE) to give methyl (2R)-3-[tert-butoxycarbonyl(methyl)amino]-2-(2-hydroxyethoxy)propanoate (1.15 g, 4.15 mmol, 27.22% yield) as a colorless oil. LC-MS: m / z 278.1 (M+1) +

[0793] Preparation of tert-butyl N-[2-(2-hydroxyethylsulfanyl)ethyl]-N-methyl-carbamate (M8) [ka]

[0794] 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 × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 30 / 1 to 20 / 1) to give tert-butyl N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfanyl]ethyl]carbamate (5.5 g, 16.39 mmol, 78.5% yield) as a pale yellow solid product. 1 H NMR (400 MHz, DMSO-d6) δ = 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) +

[0795] 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) at 0 °C was added NaH (983 mg, 24.6 mmol, 60% purity, 1.5 eq). The reaction was stirred under N at 0 °C for 15 min, followed by the dropwise addition of CHI (3.49 g, 24.6 mmol, 1.5 eq). The reaction was stirred under N at 25 °C for 6 h. Upon completion, the mixture was quenched with water (10 mL), then diluted with HO (90 mL) and extracted with 90 mL of EtOAc (30 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO, 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 pale yellow solid product. 1 H NMR (400 MHz, DMSO-d6) δ = 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)

[0796] 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 HO (50 mL) and extracted with EtOAc (100 mL × 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 pale yellow solid product. 1 H NMR (400 MHz, DMSO-d6) δ = 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)

[0797] Preparation of tert-butyl N-[2-[benzyloxycarbonyl(2-hydroxyethyl)amino]ethyl]-N-methyl-carbamate (M9) [ka]

[0798] Step 1. To a solution of tert-butyl N-(2-aminoethyl)-N-methyl-carbamate (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. After 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 under reduced pressure. The residue was purified by flash silica gel chromatography (120 g silica gel column, 0% to 100% DCM in MeOH) to give tert-butyl N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]ethyl]-N-methyl-carbamate (7.50 g, 18.0 mmol, 31.4% yield) as a colorless gum. LC-MS: m / z 333.8 (M+1) +

[0799] Step 2. To a solution of tert-butyl N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]ethyl]-N-methyl-carbamate (2.70 g, 8.12 mmol, 1 eq) in THF (80 mL) and HO (20 mL) was added CbzCl (1.80 g, 10.5 mmol, 1.50 mL, 1.3 eq) and NaHCO (2.05 g, 24.3 mmol, 947 μL, 3 eq). The mixture was stirred at 25 °C for 16 h. After completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40.0 g silica gel column, 0% to 100% PE in EA) to give tert-butyl N-[2-[benzyloxycarbonyl-[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]ethyl]-N-methyl-carbamate (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) +

[0800] 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. After completion, the mixture was quenched with NH4Cl (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 under reduced pressure. The residue was purified by flash silica gel chromatography (12 g silica gel column, 0% to 100% DCM in MeOH) to afford 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) +

[0801] Preparation of tert-butyl N-[2-[2-(6-chloro-2-oxo-indolin-5-yl)oxyethyl-methyl-amino]ethyl]-N-methyl-carbamate (M10) [ka]

[0802] 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. After 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 under reduced pressure. The residue was purified by flash silica gel chromatography (220 g silica gel column, 0% to 100% DCM in MeOH) 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) δ = 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)

[0803] 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. After completion, the mixture was diluted with water (200 mL) and extracted with DCM (3 x 180 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (180 g silica gel column, 0% to 100% DCM in MeOH) 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) δ = 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)

[0804] Preparation of tert-butyl N-methyl-N-[2-[2-(2-oxoindolin-5-yl)oxyethoxy]ethyl]carbamate (M-1) by general method M [ka]

[0805] 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 tert-butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (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 under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 100:3) to give tert-butyl N-methyl-N-[2-[2-(2-oxoindolin-5-yl)oxyethoxy]ethyl]carbamate (M-1, 400 mg, 0.719 mmol, 26.8% yield) as a light brown gum. LCMS: m / z 251.3 (M+1) +

[0806] M-2 to M-10 were prepared according to a method similar to that for M-1. [Table 89] [Table 90]

[0807] Preparation of tert-butyl N-methyl-N-[2-[2-(2-oxoindolin-5-yl)sulfanylethoxy]ethyl]carbamate (M-1s) [ka]

[0808] Step 1. To a mixture of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (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 HO (5 mL). The organic phase was separated, washed with HO (5 mL × 2), dried over NaSO, 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 pale yellow oil. LCMS: m / z 275 (M-Boc) +

[0809] Step 2. To a solution of 5-sulfanylindolin-2-one (330 mg, 2.00 mmol, 1 eq) in DMF (5 mL) was added KCO (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 for 2 h under a N atmosphere and partitioned between HO (10 mL) and EtOAc (10 mL). The organic phase was separated, washed with brine (5 mL × 3), dried over NaSO, 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)sulfanylethoxy]ethyl]carbamate (M-1s, 450 mg, 1.06 mmol, 52.8% yield) as a yellow oil. LCMS: m / z 267.4 (M-Boc). +

[0810] Preparation of tert-butyl N-[2-[2-(6-chloro-2-oxo-indolin-5-yl)sulfanylethoxy]ethyl]-N-methyl-carbamate (M-2s) [ka]

[0811] M-2s was prepared using a method analogous to M-1s using 6-chloro-5-sulfanylindolin-2-one. 1 H NMR (400 MHz, DMSO-d6) δ = 10.50 (s, 1H), 7.38 (s, 1H), 6.88 (s, 1H), 3.56 (t, J = 6.4 Hz, 2H), 3.48 (s, 3H), 3.46 (s, 1H), 3.31 (s, 1H), 3.29 - 3.26 (m, 2H), 3.06 (t, J = 6.4 Hz, 2H), 2.78 (d, J = 9.2 Hz, 2H), 1.37 (s, 9H). LCMS: m / z 301.0 (M-Boc) +

[0812] Preparation of 2-formyl-N,5-dimethyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]-1H-pyrrole-3-carboxamide (N-1) by general method N [ka]

[0813] Step 1. To a solution of tert-butyl N-methyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate (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 reduced pressure to give 5-[2-[2-[2-(methylamino)ethoxy]ethyl]pyrazol-3-yl]indolin-2-one HCl salt (123 mg, 0.34 mmol, 90% yield) as a white solid. LCMS: m / z 301.3 (M+1) +

[0814] Step 2. 5-[2-[2-[2-(methylamino)ethoxy]ethyl]pyrazol-3-yl]indolin-2-one HCl salt (113 mg, 0.34 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (51.4 mg, 0.34 mmol, 1 eq) in acetonitrile (1 mL) 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 hours. The reaction mixture was concentrated under reduced pressure and purified by column silica gel 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-1-yl]ethoxy]ethyl]-1H-pyrrole-3-carboxamide (N-1, 110 mg, 0.21 mmol, 62% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.06 (s, 1H), 10.50 (s, 1H), 9.43 - 9.20 (m, 1H), 8.57 (s, 2H), 7.49 (d, J = 1.6 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+1) +

[0815] N-2 to N-39 were prepared by a method analogous to N-1 using the corresponding intermediates K-2, L-1-L-13, M-1-M-10, M-1s and M-2s and the corresponding pyrrole aldehydes. [Table 91] [Table 92] [Table 93] [Table 94] [Table 95] [Table 96] [Table 97]

[0816] Preparation of [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecin-4,19(5H,18H)-dione (41) by general method O [ka]

[0817] To a solution of N-1 (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 under reduced pressure. The crude product was triturated with MeOH (5 mL) at 25 °C for 10 min to give 41 (42.2 mg, 0.100 mmol, 40% yield) as an orange solid. 1H NMR (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+1) +

[0818] Examples 42, 91, 92, 124-158 and 160-171 were prepared from starting materials N2-N39, respectively, by methods analogous to 41. For 42, 125, 127, 139, 145, 160 and 163, the Cbz protecting group was removed after the cyclization step as follows: [ka]

[0819] 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 under reduced pressure. The residue was dissolved in saturated NaHCO3 (30 mL aqueous solution) and lyophilized to give a solid. The solid was suspended in DCM / MeOH (10:1), filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (DCM:MeOH = 1:0 to 100:7) to give 125 (3.3 mg, 6.4% yield) as an orange powder.

[0820] For 133-138, the amides were synthesized after hydrolysis of ester 132 followed by amide coupling with the corresponding amine and, if not necessary, deprotection of the Boc protecting group, as follows: [ka]

[0821] Step 1. To a solution of 132 (100 mg, 0.217 mmol, 1 eq.) in THF (1 mL), MeOH (1 mL), and HO (0.5 mL) was added LiOH HO (27.4 mg, 0.652 mmol, 3 eq.). The mixture was stirred at 15 °C for 3 h. The mixture was concentrated under reduced pressure to give 132-1 (115 mg, crude) as a yellow solid. LC-MS: m / z 446.0 (M+1) +

[0822] Step 2. To a solution of 132-1 (50.0 mg, 0.112 mmol, 1 eq.), tert-butyl 3-aminoazetidine-1-carboxylate (23.2 mg, 0.134 mmol, 1.2 eq.), and 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×3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 133-1 (19.0 mg, 30% yield) as a yellow solid. LC-MS: m / z 600.5 (M+1) +

[0823] 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 under reduced pressure, and the residue was purified by Combiflash (4 g silica gel column, 0% to 20% MeOH in DCM) to give 133 (7.99 mg) as a yellow solid.

[0824] 144 was oxidized to give 148 and 149, respectively, as follows: [ka] To a solution of 144 (20 mg, 47.9 μmol, 1 eq) in DMF (2 mL), MeOH (2 mL), and HO (2 mL) was added oxone (588 mg, 0.957 mmol, 20 eq). The mixture was stirred at 25 °C for 16 h. After completion, the mixture was filtered and the solid was triturated with HO and MeOH to give 148 (1.2 mg) as a pale yellow solid product. The filtrate was evaporated and purified by preparative HPLC to give 149 (2.3 mg) as a pale yellow solid product.

[0825] 125 was converted to 152 or 156 by reductive amination using acetaldehyde or acetone as follows for 152: [ka] 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 NaBHCN (296 mg, 4.71 mmol, 5 eq), followed by 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, 0% to 100% DCM in MeOH) to give 152 (5.89 mg, 12.7 μmol, 1.35% yield) as an orange solid.

[0826] 154 and 170 were oxidized to 155 and 171, respectively, using the following method: [ka]

[0827] 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 adding saturated NaHCO (1 mL), and then extracted with DCM (5 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, 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. [Table 98] [Table 99] [Table 100] [Table 101] [Table 102] [Table 103] [Table 104] [Table 105] [Table 106]

[0828] Preparation of [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)pyrazolo[4,3-i]pyrrolo[3,4-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione (159) [ka]

[0829] Step 1. To a mixture of ethyl 1H-pyrazole-4-carboxylate (20.0 g, 142 mmol, 1.0 eq) and KCO (39.4 g, 285 mmol, 2.0 eq) in MeCN (250 mL) was added MOMCl (18.1 g, 225 mmol, 1.5 eq) at 0 °C. The mixture was heated to 40 °C and stirred for 2 h. After completion, the mixture was quenched with water (30 mL) and concentrated under reduced pressure to give a mixture (50 mL), which was diluted with brine (100 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified on a silica gel column (PE:EA = 2:1) to give ethyl 1-(methoxymethyl)pyrazole-4-carboxylate (17.1 g, 83 mmol, 59% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ = 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)

[0830] 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) with stirring at −70° C. for 5 min. Anhydrous DMF (35.72 g, 488 mmol, 10.0 eq) was added to the mixture with stirring at −70° C. for an additional 1 h. After completion, the mixture was quenched with saturated NH4Cl (300 mL) and extracted with EtOAc (300 mL). The organic layer was washed with brine (80 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified on a 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 a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ = 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)

[0831] Step 3. To a solution of ethyl 5-formyl-1-(methoxymethyl)pyrazole-4-carboxylate (90 mg, 0.424 mmol, 1.0 eq) in EtOH (22 mL), 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) were added. The mixture was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product 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+1) +

[0832] Step 4. To a mixture of 159a (100 mg, 0.208 μmol, 1.0 eq) in MeOH (8.0 mL) and HO (8.0 mL) was added LiOH·HO (105 mg, 2.51 mmol, 12.0 eq). The mixture was stirred at 20 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure, redissolved in water (20.0 mL), adjusted to pH = 6-7 with aqueous HCl (1 M), and then lyophilized. The residue was redissolved in DCM / MeOH (10:1), filtered, and concentrated under reduced pressure to give 159B (120 mg, 0.186 mmol, 89.2% yield) as a red solid. LCMS: m / z 451.2 (M+1) +

[0833] 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 × 30 mL). The organic layer was concentrated under reduced pressure and purified on a silica gel column (DCM:MeOH = 100:4) to give 159c (30.0 mg, 55.4 μmol, 25.0% yield) as a red solid. LCMS: m / z 433.2 (M+1) +

[0834] 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. After completion, the mixture was concentrated under reduced pressure, the pH was adjusted to neutral with saturated NaHCO3, and then lyophilized. The residue was purified on a silica gel column (DCM:MeOH = 100:5) to give 159 (2.05 mg, 5.27 μmol, 11.4% yield) as a yellow solid. 1H 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) +

[0835] Preparation of [16a(17)Z]-19-chloro-2,5,8-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione (164) [ka]

[0836] 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 HCl / 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-deboc HCl salt, which was used directly in the next step. LCMS: m / z 298.0 (M+1) +

[0837] Step 2. To a solution of 2-formyl-5-methyl-1H-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 μL, 3 eq), and DMAP (146 mg, 1.20 mmol, 1 eq). The mixture was stirred at 25° C. for 0.5 h. Then, 6-chloro-5-[2-[methyl-[2-(methylamino)ethyl]amino]ethoxy]indolin-2-one (M-10-deboc HCl 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, 0% to 100% DCM in MeOH) to afford 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, LCMS: m / z 415.1 (M+1) +

[0838] Preparation of [16a(17)Z]-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-19-carbonitrile (168) [ka]

[0839] Step 1. To a solution of dimethyl propanedioate (4.11 g, 31.0 mmol, 3.57 mL, 1.2 eq) in DMF (80 mL), K2CO3 (4.28 g, 31.0 mmol, 1.2 eq) was added portionwise at 0 °C and stirred for 1.0 h. Subsequently, 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. After completion, the mixture was poured into cold water (150 mL) and extracted with EtOAc (250 mL). The organic layer was washed with brine (150 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified on a 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).

[0840] 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), NaH (1.09 g, 27.4 mmol, 60% purity, 2 eq) was added, and the mixture was stirred at 0 °C, followed by the addition of dimethyl 2-(4-cyano-5-fluoro-2-nitrophenyl)propanedioate (3.65 g, 12.3 mmol, 0.9 eq). The mixture was stirred at 20 °C for 30 min and heated at 80 °C for 2 h. The reaction mixture was quenched with HO (80 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous NaSO, filtered, and evaporated. The residue was purified by column chromatography (SiO, 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 a brown oil. LCMS: 518.1 (M+Na). +

[0841] 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 for 2 hours at 20° C. The reaction mixture was concentrated under reduced pressure to give compound 168-4 (80 mg, 0.184 mmol, 60.8% yield) as a brown oil. 1 H NMR (400 MHz, CDCl3) δ = 8.67 - 8.40 (m, 1H), 8.32 (s, 0.5H), 8.01 (s,0.5H), 7.19 (s, 1H), 5.48 (s, 1H), 4.72 (s, 4H), 4.39 (s, 1H), 3.93 - 3.77 (m, 3H), 3.77 - 3.74 (m, 3H), 3.29 - 3.17 (m, 1H), 3.00 - 2.86 (m, 3H), 2.75 (s, 2H). LCMS: 396.1 (M+H) +

[0842] Step 4. A mixture of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (85.2 mg, 0.556 mmol, 1 eq), DIEA (287 mg, 2.23 mmol, 4 eq), T3P (265 mg, 0.835 mmol, 1.5 eq) and 168-4 (220 mg, 0.556 mmol, 1 eq) in DMF (2 mL) was stirred at 20 °C for 2 h, quenched with HO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (10 mL × 3), dried over anhydrous NaSO, filtered and evaporated. The residue was purified by preparative TLC (SiO, 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) +

[0843] 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.

[0844] 1 H 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, LCMS: m / z 393.2 (M+1) +

[0845] Preparation of [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione (172) [ka]

[0846] Step 1. To a solution of dimethyl propanedioate (4.11 g, 31.0 mmol, 1.2 eq) in THF (80 mL), NaH (1.24 g, 31.09 mmol, 60% purity, 1.2 eq) was added portionwise at 0 °C. The mixture was stirred for 1.0 h, followed by the addition of 2,4-dichloro-5-nitro-pyridine (5.0 g, 25.9 mmol, 1.0 eq) portionwise. 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, and concentrated under reduced pressure. The residue was purified on a silica gel column (PE:EA = 100:0 to 100:30) to give 172-2 (3.6 g, 11.2 mmol, 43.3% yield) as a yellow oil. 1 H NMR (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) +

[0847] 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 NaCO (2 M, 3.12 mL, 3.0 eq) in dioxane (8.0 mL) was added Pd(dppf)Cl (152 mg, 0.207 mmol, 0.1 eq). The mixture was stirred at 90 °C under nitrogen atmosphere for 2 h. After completion, the mixture was concentrated under reduced pressure and purified on a 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). +

[0848] Step 3. ...

Claims

1. Formula I 【Chemical 1】 [During the ceremony, A is 5- to 10-membered heteroarylene or C ６ -C １０ is arylene; Each L is independently -C(R ３ )(R ４ )-, -C(O)-, -O-, -N(R ５ )-, -S-, -S(O)- or -S(O) ２ -, where (L) ｎ is -O-O-, -O-S- or -O-N(R ５ )-does not contain bonds; X is N or C(R ６ ) and X １ is N or C(R ７ ) and X ２ is N or C(R ８ ) and X ３ is N or C(R ９ ) and X ４ is N or C(R １０ ) and Y and Y １ are each independently O or S; Y ２ is -O-, -N(R １１ )- or -S-; Z is a 3- to 7-membered heterocycloalkylene; C ３ -C ６ Cycloalkylene, C ６ -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 -, where 3 to 7 membered heterocycloalkylene, C ３ -C ６ Cycloalkylene, C ６ -C １０ Each hydrogen atom in the arylene and 5- to 10-membered heteroarylene is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, —OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ is substituted with; Z １ Ha-NR ２ C(Y １ )-, -C(Y １ )NR ２ -, -O-, -N(R ２ )-, -S-, -S(O)- or -S(O) ２ - and Each R １ are independently deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -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) ２ R ａ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ａ R ｂ , -S(O) ２ NR ａ R ｂ , -OS(O)NR ａ R ｂ , -OS(O) ２ NR 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) ２ R ｂ , -NR ａ S(O)NR ａ R ｂ , -NR ａ S(O) ２ NR 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) ２ R ａ R ｂ , -P(O)NR ａ R ｂ , -P(O) ２ NR ａ R ｂ , -P(O)OR ａ , -P(O) ２ OR ａ , —CN or —NO ２ , where C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ is substituted with; R ２ , R ５ , R １１ or R １４ each independently represents H, deuterium, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -C １０ aryl or 5-10 membered heteroaryl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ’ , —CN or —NO ２ is substituted with; Each R ３ , R ４ , R １２ and R １３ are independently H, deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -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) ２ R ｃ , -OS(O)NR ｃ R ｄ , -OS(O) ２ NR ｃ R ｄ , -SR ｃ , -S(O)R ｃ , -S(O) ２ R ｃ , -S(O)NR ｃ R ｄ , -S(O) ２ NR 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) ２ R ｄ , -NR ｃ S(O)NR ｃ R ｄ , -NR ｃ S(O) ２ NR 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) ２ R ｃ R ｄ , -P(O)NR ｃ R ｄ , -P(O) ２ NR ｃ R ｄ , -P(O)OR ｃ , -P(O) ２ OR ｃ , -CN, -NO ２ or R ３ , R ４ , R １２ and R １３ The two of them, together with one or more carbons to which they are attached, form C ３ -C ６ cycloalkyl or 4-6 membered heterocycloalkyl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocycloalkyl is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ 、-OC(O)R ｅ 、-OC(O)NR ｅ R ｆ 、-OS(O)R ｅ 、-OS(O) ２ R ｅ 、-OS(O)NR ｅ R ｆ 、-OS(O) ２ NR ｅ R ｆ 、-SR ｅ 、-S(O)R ｅ 、-S(O) ２ R ｅ 、-S(O)NR ｅ R ｆ 、-S(O) ２ NR 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) ２ R ｆ 、-NR ｅ S(O)NR ｅ R ｆ 、-NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ 、-P(O)NR ｅ R ｆ 、-P(O) ２ NR ｅ R ｆ 、-P(O)OR ｅ 、-P(O) ２ OR ｅ , —CN or —NO ２ is substituted with; R ６ H, deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl or —CN; R ７ and R ８ each independently represents a bond to Z, H, deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -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) ２ R ａ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ａ R ｂ , -S(O) ２ NR ａ R ｂ , -OS(O)NR ａ R ｂ , -OS(O) ２ NR 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) ２ R ｂ , -NR ａ S(O)NR ａ R ｂ , -NR ａ S(O) ２ NR 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) ２ R ａ R ｂ , -P(O)NR ａ R ｂ , -P(O) ２ NR ａ R ｂ , -P(O)OR ａ , -P(O) ２ OR ａ , —CN or —NO ２ where C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ substituted with; ７ or R ８ is a bond to Z; R ９ and R １０ each independently represents H, deuterium, a halogen, or C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -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) ２ R ａ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ａ R ｂ , -S(O) ２ NR ａ R ｂ , -OS(O)NR ａ R ｂ , -OS(O) ２ NR 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) ２ R ｂ , -NR ａ S(O)NR ａ R ｂ , -NR ａ S(O) ２ NR 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) ２ R ａ R ｂ , -P(O)NR ａ R ｂ , -P(O) ２ NR ａ R ｂ , -P(O)OR ａ , -P(O) ２ OR ａ , —CN or —NO ２ or R ８ and R ９ or R ９ and R １０ together with the carbon atoms to which they are attached, ４ -C ６ cycloalkyl, 4- to 7-membered heterocycloalkyl or C ６ -C １０ aryl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ４ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ is substituted with; Each R ａ , R ｂ , R ｃ , R ｄ , R ｅ and R ｆ are independently H, deuterium, and C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -C １０ Aryl, C １ -C ６ Alkyl-C ６ -C １０ selected from the group consisting of aryl and 5-10 membered heteroaryl; m is 0, 1, 2, 3, or 4; and n is 2, 3, 4, 5, 6, 7, or 8. or a pharmaceutically acceptable salt thereof.

2. Formula IV 【Chemistry 2】 2. The compound of claim 1, wherein:

3. Equation VI 【Chemistry 3】 2. The compound of claim 1, wherein:

4. 4. The compound of claim 1, wherein A is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, or a pharmaceutically acceptable salt thereof.

5. 4. The compound of claim 1, wherein A is pyrrolylene, or a pharmaceutically acceptable salt thereof.

6. A is 【Chemistry 4】 where R １ａ is C １ -C ６ Alkyl, —C(O)R ａ , -C(O)OR ａ , —C(O)NR ａ R ｂ or -P(O) ２ OR and C １ -C ６ Each hydrogen atom in the alkyl is independently optionally deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ 4. The compound of claim 1, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof;

7. A is 【Chemistry 5】 4. The compound of claim 1, wherein:

8. Each R １ -CN or C １ -C ６ alkyl, where C １ -C ６ Each hydrogen atom in the alkyl is independently optionally deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ 8. The compound of claim 1, wherein R is substituted with R, or a pharmaceutically acceptable salt thereof.

9. Each R １ The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is -CN or methyl.

10. R １ａ 10. The compound of claim 1, wherein R is methyl, or a pharmaceutically acceptable salt thereof.

11. R ２ is H or C １ -C ６ alkyl, where C １ -C ６ Each hydrogen atom in the alkyl is independently optionally deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ’ , —CN or —NO ２ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, substituted with:

12. R ２ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein is H or methyl.

13. Z is a 5- or 6-membered heteroarylene, wherein each hydrogen atom in the 5- or 6-membered heteroarylene is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, substituted with:

14. Z is pyrazolylene, oxazolylene, thiazolylene, pyridinylene, pyrimidinylene, or pyridine-2-onylene, wherein each hydrogen atom in the pyrazolylene, oxazolylene, thiazolylene, pyridinylene, pyrimidinylene, and pyridine-2-onylene is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, substituted with:

15. Z is 【Chemistry 6】 15. The compound of any one of claims 1 to 14, wherein:

16. Z is C ６ -C １０ arylene, wherein C ６ -C １０ Each hydrogen atom in the arylene is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, substituted with:

17. Z is phenylene, wherein each hydrogen atom in the phenylene is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ 17. The compound of any one of claims 1 to 12 or 16, or a pharmaceutically acceptable salt thereof, substituted with:

18. Z is 【Chemistry 7】 18. The compound of any one of claims 1 to 12, 16 or 17, or a pharmaceutically acceptable salt thereof.

19. Z is a 3- to 7-membered heterocycloalkylene, wherein each hydrogen atom in the 3- to 7-membered heterocycloalkylene is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, substituted with:

20. Z is pyrrolidonylene or azetidinylene, wherein each hydrogen atom in the pyrrolidonylene and azetidinylene is independently optionally selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ 20. The compound of any one of claims 1 to 12 or 19, or a pharmaceutically acceptable salt thereof, substituted with:

21. Z is -C(R １２ )(R １３ )-, -O-, -N(R １４ )-, -S-, -S(O)- or -S(O) ２ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:

22. Z is -C(R １２ )(R １３ 22. The compound of claim 1, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof.

23. R １２ and R １３ is H, deuterium, fluoro, chloro, bromo, -OR ｅ and C １ -C ６ alkyl; or R １２ and R １３ together with the carbon to which they are bonded to form C ３ -C ６ cycloalkyl or 4-6 membered heterocycloalkyl, wherein C ３ -C ６ Each hydrogen atom in the cycloalkyl or 4- to 6-membered heterocycloalkyl is independently optionally deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , —CN or —NO ２ 23. The compound of any one of claims 1 to 22, substituted with:

24. R １２ is H and R １３ The compound of any one of claims 1 to 23, wherein is methyl.

25. R １２ is methyl, and R １３ The compound of any one of claims 1 to 24, wherein is H.

26. R １２ and R １３ The compound of any one of claims 1 to 25, wherein is H.

27. R １２ is methyl, and R １３ The compound of any one of claims 1 to 26, wherein is -OH.

28. R １２ is —OH, and R １３ The compound of any one of claims 1 to 27, wherein is methyl.

29. 22. The compound of any one of claims 1 to 12 or 21, or a pharmaceutically acceptable salt thereof, wherein Z is -O-.

30. Z is -N(R １４ 22. The compound of claim 1, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof.

31. R １４ H, deuterium, C １ -C ６ Alkyl or C ３ -C ６ 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

32. R １４ 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein is H, methyl, or cyclopropyl.

33. 22. The compound of any one of claims 1 to 12 or 21, or a pharmaceutically acceptable salt thereof, wherein Z is -S-.

34. Z is -S(O) ２ 22. The compound of any one of claims 1 to 12 or 21, or a pharmaceutically acceptable salt thereof, wherein:

35. 35. The compound of any one of claims 1 to 34, wherein n is 3, or a pharmaceutically acceptable salt thereof.

36. 36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein n is 4.

37. 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein n is 5.

38. 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein n is 6.

39. 39. The compound of any one of claims 1 to 38, wherein n is 7, or a pharmaceutically acceptable salt thereof.

40. Each L is independently —C(O)—, —O—, or —CH ２ -, -C(H)(CH ３ )-, -C(H)(OH)-, -C(H)(C(O)OR ｃ )-, -C(H)(C(O)NR ｃ R ｄ )-, -NH- and -NCH ３ 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

41. X is C(R ６ 41. The compound of claim 1, wherein:

42. R ６ 42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein:

43. 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein Y is O.

44. Y １ 44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein:

45. Y ２ -N(R １１ 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein:

46. X １ exists, and X ３ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein:

47. X １ exists, and X ４ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein:

48. X ３ and X ４ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein:

49. X １ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein, when present, is N.

50. X ２ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein, when present, is N.

51. X ３ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein:

52. X ４ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein:

53. X １ is C(R ７ ) and X ３ is C(R ９ ) and X ４ is C(R １０ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein

54. C(R ７ 54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein, when present, is independently H, deuterium, fluoro, chloro, -CN, or methyl.

55. C(R ８ 55. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, wherein: -, ...

56. C(R ９ 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein, when present, is independently H, deuterium, fluoro, chloro, -CN, or methyl.

57. C(R １０ 57. The compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, wherein, when present, is H.

58. -(L) ｎ -が-(CH ２ ) ２ -、-(CH ２ ) ３ -、-(CH ２ ) ４ -、-(CH ２ ) ５ -、-(CH ２ ) ６ -、-C(O)NH-(CH ２ ) ２ O(CH ２ ) ２ -、-C(O)N(CH ３ )-(CH ２ ) ２ O(CH ２ ) ２ -、-NHC(O)CH ２ O(CH ２ ) ２ -、-N(CH ３ )-C(O)CH ２ O(CH ２ ) ２ -、-CH ２ O(CH ２ ) ２ -、-(CH ２ ) ２ O(CH ２ ) ２ -、-(CH ２ ) ２ S(CH ２ ) ２ -、-O(CH ２ ) ２ S(CH ２ ) ２ -、-(CH ２ ) ２ SO ２ (CH ２ ) ２ -、-O(CH ２ ) ２ SO ２ (CH ２ ) ２ -、-(CH ２ ) ２ SO(CH ２ ) ２ -、-O(CH ２ ) ２ SO(CH ２ ) ２ -, -(CH ２ ) ２ O(C(H)(C(O)N(H)(azetidin-3-yl))-CH ２ -, -(CH ２ ) ２ O(C(H)(C(O)N(H)(CH) ３ ))-CH ２ -, -(CH ２ ) ２ O(C(H)(C(O)N(CH) ３ ) ２ )-CH ２ -, -(CH ２ ) ２ O(C(H)(C(O)N(H)(piperidin-4-yl))-CH ２ -, -(CH ２ ) ２ O(C(H)(C(O)N(H)(pyrrolidin-3-yl))-CH ２ -, -(CH ２ ) ２ O(C(H)(C(O)N(H)(4-methylpiperazin-1-yl))-CH ２ -, -(CH ２ ) ２ O(C(H)(C(O)OCH) ３ )-CH ２ -, -(CH ２ ) ３ O(CH ２ ) ２ -, -(CH ２ ) ２ O(CH ２ ) ３ -, -CH ２ CH(CH ３ )-O(CH ２ ) ２ -, -CH(CH ３ )-CH ２ O(CH ２ ) ２ -, -O(CH ２ ) ２ -, -O-(CH ２ ) ３ -, -OCH ２ O(CH ２ ) ２ --, --O-CH ２ CH(OH)CH ２ -, -O-(CH ２ ) ２ O(CH ２ ) ２ -、-O-CH ２ CH(CH ３ )-O(CH ２ ) ２ -、-O-CH(CH ３ )-CH ２ O(CH ２ ) ２ -、-O-(CH ２ ) ２ NH-(CH ２ ) ２ -、-O-CH ２ CH(CH ３ )-NH-(CH ２ ) ２ -、-O-CH(CH ３ )-CH ２ NH-(CH ２ ) ２ -、-CH ２ NH-(CH ２ ) ２ -、-(CH ２ ) ２ NH-(CH ２ ) ２ -、-CH ２ CH(CH ３ )-NH-(CH ２ ) ２ -、-CH(CH ３ )-CH ２ NH-(CH ２ ) ２ -、-O-(CH ２ ) ２ N(CH ３ )-(CH ２ ) ２ -、-O-CH ２ CH(CH ３ )-N(CH ３ )-(CH ２ ) ２ -、-O-CH(CH ３ )-CH ２ N(CH ３ )-(CH ２ ) ２ -、-CH ２ N(CH ３ )-(CH ２ ) ２ -, -CH ２ N(CH ２ CH ３ )-(CH ２ ) ２ -, -CH ２ N(CH(CH ３ ))-(CH ２ ) ２ -, -(CH ２ ) ２ N(CH ３ )-(CH ２ ) ２ -, -CH ２ CH(CH ３ )-N(CH ３ )-(CH ２ ) ２ - or -O-CH(CH ３ )-CH ２ N(CH ３ )-(CH ２ ) ２ 59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, wherein:

59. 10. 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-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione; [3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(azenometheno)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(azenometheno)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(diazandiylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-9,10,11,12-tetrahydro-14H-17,1-(azenometheno)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(azenometheno)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z,11S]-11-hydroxy-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H,12H-15,17-(ethanediylidene)pyrazolo[4,3-p]dipyrrolo[3,2-i:3',4'-l][1,4,7,14]dioxadiazacycloheptadecyne-4,19(5H,18H)-dione; [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-3,8-dioxo-2,3,5,8,9,10,11,12-octahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-6-carbonitrile; [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)imidazo[4,5-i]pyrazolo[3,4-b]pyrrolo[3,4-f][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,15-dimethyl-9,10,11,12-tetrahydro-15H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,16-dimethyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)dipyrrolo[3,4-f:2',3'-i][1,2]thiazolo[3,4-b][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9-dimethyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,16-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,16-trimethyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)[1,2]oxazolo[3,4-b]dipyrrolo[3,4-f:2',3'-i][1,5,12]oxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,17-(ethanediylidene)pyrazolo[5,1-c]dipyrrolo[3,2-j:3',4'-m][1,4,8]triazacyclotetradecine-3,8(2H,5H)-dione; [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-17,1-(azenometheno)pyrazolo[1,5-e]dipyrrolo[3,4-i:2',3'-l][1,5]diazacyclotetradecine-3,8(2H,5H)-dione; [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecine-4,19(5H,18H)-dione; [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(azenometheno)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecine-4,19(5H,18H)-dione; [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(azenometheno)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,19(5H,18H)-dione; [19a(20)Z]-2-methyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecine-4,19(5H,18H)-dione; [10R,19a(20)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecine-4,19(5H,18H)-dione; [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(ethanediylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,14]oxadiazacyclohexadecine-4,19(5H,18H)-dione; [19a(20)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-15,17-(azenometheno)pyrazolo[1,5-d]dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecin-4,19(5H,18H)-dione; [19a(20)Z]-2-methyl-5,6,7,8,9,10-hexahydro-15,17-(ethanediylidene)pyrazolo[1,5-g]dipyrrolo[3,4-k:2',3'-n][1,4,7]triazacyclohexadecine-4,19(1H,18H)-dione; [19a(20)Z]-2,5-dimethyl-5,6,7,8,9,10-hexahydro-15,17-(ethanediylidene)pyrazolo[1,5-g]dipyrrolo[3,4-k:2',3'-n][1,4,7]triazacyclohexadecine-4,19(1H,18H)-dione; [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6-methyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6,9-dimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6,9,16-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6-methyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-20-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-19-fluoro-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,20-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-9,20-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,16-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-17,1-(azenometheno)[1,2]oxazolo[4,5-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-17,1-(azenometheno)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6,14-dimethyl-10,11,13,14-tetrahydro-2H-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6,9,14-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,16-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,16-trimethyl-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6,9,16-trimethyl-10,11,12,13-tetrahydro-2H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6,9,12,14,16-pentamethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,14,16-tetramethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,14,16-tetramethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-9,14,16-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-9,14,16-trimethyl-10,11,13,14-tetrahydro-2H-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-12-ethyl-6,9,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,14-trimethyl-12-(propan-2-yl)-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-16-cyclopropyl-6,9-dimethyl-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-9,14-dimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9-dimethyl-16-(propan-2-yl)-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-9-methyl-16-(propan-2-yl)-10,11-dihydro-2H,13H-1,17-(ethanediylidene)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]oxazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z]-6,9,14-trimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-9,14-dimethyl-9,10,11,12-tetrahydro-14H-1,17-(ethanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3',4'-j][1,5]oxazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenometheno)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecyne-3,8(2H,5H)-dione; and [3a(4)Z]-9,12,14-trimethyl-9,10,11,12,13,14-hexahydro-1,17-(ethanediylidene)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecyne-3,8(2H,5H)-dione.

60. 10. 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-(ethanediylidene)dipyrrolo[3,2-g:3',4'-j][1,5,12]benzoxadiazacyclopentadecyne-3,8(2H,5H)-dione; [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione; [3a(4)Z]-6-methyl-10,11-dihydro-2H-17,1-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4]benzoxazacyclotetradecine-3,8(5H,9H)-dione; [3a(4)Z]-16-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione; [3a(4)Z]-15-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione; [3a(4)Z]-14-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione; [3a(4)Z]-13-fluoro-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,11]benzoxadiazacyclotetradecine-3,8(5H,9H)-dione; and [3a(4)Z]-6,9,12-trimethyl-10,11,12,13-tetrahydro-2H-1,18-(ethanediylidene)dipyrrolo[3,2-g:3',4'-j][2,5]benzodiazacyclopentadecyne-3,8(5H,9H)-dione.

61. 10. 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-(ethanediylidene)pyrido[3,2-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione; [3a(4)Z]-6-methyl-10,11-dihydro-2H-1,17-(ethanediylidene)pyrimido[5,4-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione; [3a(4)Z]-6,16-dimethyl-10,11-dihydro-2H-1,17-(ethanediylidene)pyrido[3,4-m]dipyrrolo[3,2-f:3',4'-i][1,4,11]oxadiazacyclotetradecine-3,8(5H,9H)-dione; [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-1,18-(ethanediylidene)pyrido[2,1-c]dipyrrolo[3,2-j:3',4'-m][1,4,8]triazacyclotetradecine-3,8,14(2H,5H)-trione; [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-14H-18,1-(azenometheno)pyrido[1,2-e]dipyrrolo[3,4-i:2',3'-l][1,5]diazacyclotetradecine-3,8,14(2H,5H)-trione; or a pharmaceutically acceptable salt thereof.

62. 10. 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-(azenometheno)tripyrrolo[1,2-a:3',2'-i:3'',4''-l][1,4,7]triazacyclopentadecyne-3,8(5H,9H)-dione; [3a(4)Z,13aR]-6-methyl-9,10,11,12,13,13a,14,15-octahydro-17,1-(azenometheno)azeto[1,2-a]dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecyne-3,8(2H,5H)-dione; [16a(17)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenometheno)dipyrrolo[3,4-g:2',3'-j][1,4,6,13]oxatriazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-2,5,11-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclopentadecyne-4,16(5H,15H)-dione; [17a(18)Z]-2,12-dimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclohexadecine-4,17(5H,16H)-dione; [17a(18)Z]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclohexadecine-4,17(5H,16H)-dione; [17a(18)Z]-2,5,12-trimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,11,13]oxatriazacyclohexadecin-4,17(5H,16H)-dione; [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-2,5,11-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-11-cyclopropyl-2,5-dimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-11-cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecyne-4,16(5H,15H)-dione; [10R,16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenometheno)dipyrrolo[3,4-g:2',3'-j][1,4,6,13]oxatriazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,3,10,13]oxatriazacyclopentadecyne-4,16(1H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,4-d:2',3'-g][1,3,10,13]oxatriazacyclopentadecyne-4,16(1H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(azenometheno)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione; [9R,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione; [9S,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenometheno)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [10R,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,10-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione; [9R,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [9S,16a(17)Z]-2,5,9-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-13,15-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,13,4]oxathiazacyclohexadecine-4,17(5H,16H)-dione; [17a(18)Z]-2-methyl-6,7,10,11-tetrahydro-1H-13,15-(ethanediylidene)-12λ ６ -dipyrrolo[3,2-f:3',4'-i][1,13,4]oxathiazacyclohexadecyne-4,12,12,17(5H,9H,16H)-tetrone; [17a(18)Z]-2-methyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecine-4,17(5H,16H)-dione; [12R,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecine-4,17(5H,16H)-dione; [12S,17a(18)Z]-2,12-dimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecine-4,17(5H,16H)-dione; [12S,17a(18)Z]-2,5,12-trimethyl-6,7,9,10-tetrahydro-1H,12H-13,15-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclohexadecine-4,17(5H,16H)-dione; [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecine-4,10,17(5H,9H,16H)-trione; [17a(18)Z]-2,5-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azenometheno)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-(azenometheno)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-(ethanediylidene)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-(ethanediylidene)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-(ethanediylidene)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-(ethanediylidene)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-(ethanediylidene)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-(azenometheno)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-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecyne-4,10,17(5H,9H,16H)-trione; [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione; [18a(19)Z]-2,5-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione; [18a(19)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione; [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione; [13R,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione; [18a(19)Z]-2-methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(azenometheno)dipyrrolo[3,4-i:2',3'-l][1,4,8,15]oxatriazacycloheptadecin-4,12,18(5H,13H,17H)-trione; [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(ethanediylidene)dipyrrolo[3,4-i:2',3'-l][1,4,8,15]oxatriazacycloheptadecin-4,12,18(5H,13H,17H)-trione; [13S,18a(19)Z]-2,13-dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(azenometheno)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-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-(ethanediylidene)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecyne-4,12,18(5H,13H,17H)-trione; [16a(17)Z]-2-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-19-chloro-2-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; Methyl [7R,16a(17)Z]-19-chloro-2,5-dimethyl-4,16-dioxo-4,5,6,7,9,10,15,16-octahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-7-carboxylate; [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-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-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-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-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-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide; [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-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-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-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-7-carboxamide; [7R,16a(17)Z]-19-chloro-2,5-dimethyl-7-(4-methylpiperazine-1-carbonyl)-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [10S,16a(17)Z]-19-chloro-2,5,10-trimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-19-chloro-2,5-dimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione; [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14-(ethanediylidene)-8λ ６ -dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,8,8,16(1H,5H,15H)-tetrone; [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-12,14-(ethanediylidene)-8λ ４ -dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,8,16(1H,5H,15H)-trione; [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxathiazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-2,5-dimethyl-6,7-dihydro-1H,9H-12,14-(ethanediylidene)-11λ ６ -dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,11,11,16(5H,10H,15H)-tetrone; [16a(17)Z]-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)pyrazolo[4,3-i]pyrrolo[3,4-l][1,4,7]dioxazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-19-chloro-5-methyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-4,16(1H,15H)-dione; [16a(17)Z]-19-chloro-2,5,8-trimethyl-5,6,7,8,9,10-hexahydro-12,14-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]oxadiazacyclopentadecyne-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-(ethanediylidene)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecyne-19-carbonitrile; [16a(17)Z]-19-chloro-2,5-dimethyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,16(5H,15H)-dione; [16a(17)Z]-19-chloro-5-methyl-6,7,9,10-tetrahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-g:2′,3′-j][1,4,13]oxathiazacyclopentadecyne-4,16(5H,15H)-dione; and [16a(17)Z]-19-chloro-5-methyl-6,7-dihydro-1H,9H-12,14-(ethanediylidene)-11λ ６ -dipyrrolo[3,4-g:2',3'-j][1,4,13]oxathiazacyclopentadecyne-4,11,11,16(5H,10H,15H)-tetrone.

63. 63. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

64. 62. A method of treating a disease such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any of claims 1-62 or a pharmaceutically acceptable salt thereof.

65. 63. A compound of any of claims 1 to 62, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.

66. 63. A compound of any of claims 1 to 62, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

67. 63. Use of a compound of any of claims 1 to 62, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

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