Macrocyclic molecules and their use

Abstract

The present invention relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds in the treatment of diseases such as cancer.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 050,559, filed Jul. 10, 2020; U.S. Provisional Application No. 63 / 143,569, filed Jan. 29, 2021; and U.S. Provisional Application No. 63 / 217,950, filed Jul. 2, 2021, and the entire disclosures of all of these applications are hereby incorporated by reference herein.

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

Background Art

[0003] Background Protein kinases are tightly regulated signaling proteins that integrate 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 bases leading to various diseases include gain-of-function and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res. 2018, 78:15-29). The important role of kinases in cancer and other diseases has made them attractive targets for drug discovery, and 52 small molecule kinase inhibitors have been approved, 46 of which are approvals for cancer target therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2020 Update. Pharmacol Res 2020, 152:104609). Kinase inhibitors have achieved dramatic success in cancer target therapies, but the acquisition 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 but also overcome the most frequent resistance mutations for good efficacy and long-term disease management.

[0004] Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide (World Health Organisation. Cancer Fact Sheet 2017). Activating EGFR mutations have been reported in approximately 10% - 15% of adenocarcinoma cases in white 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 seen in NSCLC tumors are a short in-frame deletion (del19) in exon 19 of the EGFR gene and a single missense mutation in exon 21, L858R (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 progressive EGFR mutation-positive (Del19 or L858R) NSCLC and are used as first-line standard therapy in this setting. However, the majority of patients acquire resistance to gefitinib or erlotinib, with 50% - 70% of tumors having the EGFR T790M gatekeeper mutation, over the course of treatment (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 HER2 and ERB4 of the ERB family (Li D, et al. BIBW2992, an irreversible EGFR / HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702-11; Ou SH, Soo RA. Dacomitinib in lung cancer: a "lost generation" EGFR tyrosine-kinase inhibitor from a bygone era? Drug Des Devel Ther 2015; 9:5641-53). Afatinib and dacomitinib are more potent EGFR inhibitors approved as first-line treatment for advanced EGFR mutation-positive (Del19 or L858R) NSCLC compared with gefitinib and erlotinib, with longer progression-free survival (PFS), but the EGFR T790M is acquired with treatment with afatinib (Tanaka K, et al. Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Onco-target 2017; 8:68123-30). The EGFR T790M contributes to resistance to dacomitinib in in vitro tests (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 targeting both EGFR activating mutations (Del19 and L858R) and the T790M resistant double mutation, and has 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 inhibitors, and was subsequently approved in the first-line setting for patients with EGFR mutation-positive NSCLC by a trial directly comparing it 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 mutation C797S at the EGFR covalent binding residue with the irreversible EGFR inhibitor osimertinib has been detected in osimertinib-resistant patients (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 during transfection (RET) gene occur in diverse 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 multi-kinase inhibitors lenvatinib, sorafenib, and cabozantinib have been approved for specific thyroid cancers. In recent years, 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 RET mutations after treatment with multi-kinase inhibitors or selective RET inhibitors in RET-mutated patients or cell lines have been reported, including gatekeeper mutations V804M and V804L, hinge mutations Y806N and Y806C, solvent-front mutations G810A, G810C, G810S, G810V, and G810R, and other RET kinase domain mutations such as V738A and S904F (Subbiah V, et al. Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations. Ann Oncol. 2020 Nov 5:S0923-7534(20)43127-8). With continuous treatment with multiple RET inhibitors, acquired compound mutations, such as RET M918T / V804M, M918T / V804M / G810C, V804M / G810C, or other combinations, may render current multi-kinase and selective RET inhibitors refractory in the clinic. Therefore, there is a need to develop a new generation of RET inhibitors that can target both primary and secondary RET mutations in RET-mutated patients who have or have not been treated with approved RET inhibitors.

[0008] Chronic myeloid leukemia (CML) is characterized by the Philadelphia (Ph) chromosome, which results from the t(9;22)(q34;q11) balanced reciprocal translocation that gives rise to the production of the chimeric BCR-ABL1 oncoprotein (Salesse S, Verfaillie CM. BCR / ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Oncogene. 2002, 21(56):8547-59). Imatinib, a selective BCR-ABL1 kinase inhibitor, was the first tyrosine kinase inhibitor to revolutionize the treatment and outcome 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 that confer various levels of resistance have been found in CML patients (Apperley J: Part I: Mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007, 8:1018-1029). 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 moderate resistance to nilotinib, and E255V, F317L, Q252H confer moderate resistance to dasatinib, but T315I is resistant to nilotinib, dasatinib, and bosutinib (O’Hare T, et al. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood, 2007, 110, 2242-2249). The third-generation BCR-ABL1 inhibitor ponatinib is effective against T315I; however, it is not effective against T315L and T315M.Diverse complex mutations after continuous treatment with multiple BCR-ABL1 inhibitors are emerging as a new barrier to currently approved BCR-ABL1 inhibitors (Zabriskie MS, et al. Extreme mutational selectivity of axitinib limits its potential use as a targeted therapeutic for BCR-ABL1-positive leukemia. Leukemia 2016, 30(6):1418-21). Furthermore, none of the currently available BCR-ABL1 inhibitors are absolutely safe, and the widespread prescription of second- or third-generation BCR-ABL1 inhibitors is limited by toxicity. Therefore, there is a need to develop a new generation of BCR-ABL1 inhibitors that can target both the BCR-ABL1 fusion protein and acquired mutations and have a favorable safety profile.

[0009] FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is normally expressed in hematopoietic stem or progenitor cells and has an important role in the early stages of development of both the myeloid and lymphoid cell lineages. FLT3 mutations are seen in approximately 30% of newly diagnosed AML cases and occur as intragenic tandem duplications (ITDs) (approximately 25%) or point mutations (7-10%) in the tyrosine kinase domain (TKD) (Daver N, et al. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 2019, 33(2):299-312). Both FLT3-ITD and FLT3-TKD mutations constitutively activate FLT3 kinase activity, leading to AML proliferation and survival. The multi-kinase inhibitor midostaurin has been approved for frontline 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 monotherapy for patients with relapsed or refractory FLT3-mutated AML. Results with FLT3 inhibitor-based treatment are encouraging, but many patients still do not respond to FLT3 inhibitor therapy or relapse thereafter. One mechanism of resistance is the acquisition of secondary mutations in the FLT3 kinase domain, including mutations in the activation 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 a new generation of FLT3 inhibitors that can target both primary and secondary RET mutations in FLT3-mutated cancer patients, with or without treatment with approved FLT3 inhibitors.

[0010] Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract and account for 18% of all human sarcomas (Corless CL, et al Gastrointestinal stromal tumours: 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 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 disease, except those with the PDGFRA D842V mutation. Most patients who initially derive clinical benefit from imatinib ultimately progress after 20-24 months of treatment (Blanke, C. D. et al. Long-term results from a randomized phase II trial of standard - versus higher-dose imatinib mesylate for patients with unresectable or メタstatic gastrointestinal stromal tumors expressing KIT. J. Clin. Oncol. 2008, 26, 620-625).KIT activated by carcinogenesis continues to be an important driver of GIST growth and survival after imatinib failure in up to 90% of patients due to reactivation of KIT signaling by tumor subclones with heterogeneous secondary KIT mutations (Serrano C, et al. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. British Journal of Cancer, 2019, 120: 612-620). Sunitinib and regorafenib show inhibitory activity only against specific secondary mutations and have limited efficacy as second- and third-line treatments, respectively. Therefore, there is a need to develop a new generation of KIT and / or PDGFRA inhibitors that can target both primary and all regions of secondary mutations in GIST patients who have or have not been treated with approved KIT and / or PDGFR inhibitors. Summary of the Invention Problems to be Solved by the Invention

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

[0012] Summary of the Invention In one aspect, the present invention relates to formula I [Chemical formula]

[0013] 〔In the formula,

[0014] A is a 5- to 10-membered heteroarylene or C6-C 10 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 does not contain an -O-O-, -O-S- or -O-N(R 5 )- bond;

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

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

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

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

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

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

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

[0023] Z is a 3- to 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 each hydrogen atom in 3- to 7-membered heterocycloalkylene, C3-C6 cycloalkylene, C6-C 10 arylene and 5- to 10-membered heteroarylene is independently optionally 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)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f, -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN or substituted with -NO2;

[0024] Z 1 is -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 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 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)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -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)2NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -PR a R b 、 -P(O)R a R b 、 -P(O)2R a R b 、 -P(O)NR a R b 、 -P(O)2NR a R b 、 -P(O)OR a 、 -P(O)2OR a 、 -CN or -NO2, where each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NRe R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 is substituted with -CN or -NO2;

[0026] R 2 、 R 5 、 R 11 or R 14 each of which is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl is independently optionally 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)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e’ 、 is 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, 3-7 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)2NR c R d , -NR c R d , -NR c C(O)R d , -N(C(O)R c )(C(O)R d , -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c 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 which, together with one or more carbons to which they are attached, form a C₃ - C₆ cycloalkyl or 4 - 6 - membered heterocycloalkyl, where each hydrogen atom in C₁ - C₆ alkyl, C₂ - C₆ alkenyl, C₂ - C₆ alkynyl, C₃ - C₆ cycloalkyl, 3 - 7 - membered heterocycloalkyl, C₆ - C 10 aryl, 5 - 10 - membered heteroaryl or 4 - 6 - membered heterocycloalkyl may independently be optionally deuterium, halogen, C₁ - C₆ alkyl, C₁ - C₆ haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)₂R e 、 -OS(O)NR e R f 、 -OS(O)₂NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)₂R e 、 -S(O)NR e R f 、 -S(O)₂NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR eC(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2 substituted;

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

[0029] R 7 and each of R 8 is independently a bond to Z, H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 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)2NR a R b 、 -OS(O)NR a R b 、 -OS(O)2NR a R b 、 -NR a R b 、 -NR a C(O)R b 、 -NR a C(O)OR b 、 -NR a C(O)NR a R b 、 -NR a S(O)R b 、 -NR a S(O)2R b 、 -NR a S(O)NR a R b 、 -NR a S(O)2NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -PR a R b 、 -P(O)R a R b 、 -P(O)2R a R b 、 -P(O)NR a R b 、 -P(O)2NR a R b 、 -P(O)OR a 、 -P(O)2OR a 、 -CN or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl is independently optionally 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)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2 substituted; provided that one of R 7 or R 8 is a bond to Z;

[0030] R 9 and R 10Each of them is 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- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a , -NR b C(O)R a , -NR b C(O)OR a , -NR a C(O)NR b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)2NR a R b, -P(O)OR a , -P(O)2OR a , -CN or -NO2; or R 8 and R 9 or R 9 and R 10 and R are combined with the carbon atom to which they are attached to form C4-C6 cycloalkyl, 4-7 membered heterocycloalkyl or C6-C 10 aryl, where each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-7 membered heterocycloalkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NRe 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 、 is substituted with -CN or -NO₂;

[0031] Each R a 、 R b 、 R c 、 R d 、 R e and R f is independently selected from the group consisting of H, deuterium, C₁-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;

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

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

[0034] In certain embodiments, the present invention provides a compound of formula II

Chemical formula

[0035] 〔Wherein, R 1 、 R 2 、 A, L, X, X 1 、 X2 、 X 3 、 X 4 、 Y, Y 1 、 Y 2 、 Z, m and n are as defined herein. ]] provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

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

[0037] [wherein, R 1 、 A, L, X, X 1 、 X 2 、 X 3 、 X 4 、 Y, Y 2 、 Z, Z 1 、 m and n are as defined herein. ]] provides a compound of formula (III) or a pharmaceutically acceptable salt thereof.

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

[0039] [wherein, R 1 、 R 2 、 A, L, X, X 1 、 X 2 、 X 3 、 X 4 、 Y, Y 1 、 Y 2 、 Z, m and n are as defined herein. ]] provides a compound of formula (IV) or a pharmaceutically acceptable salt thereof.

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

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

[0042] In certain embodiments, the present invention is directed to a compound of formula VI [Chemical formula]

[0043] [wherein, R 1 , R 2 , A, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 1 , Y 2 , Z, m and n are as defined herein.] provides a compound of or a pharmaceutically acceptable salt thereof.

[0044] In certain embodiments, the present invention is directed to a compound of formula VII [Chemical formula] [wherein, R 1 , R 2 , A, B, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 1 , Y 2 , Z, m and n are as defined herein.] provides a compound of or a pharmaceutically acceptable salt thereof.

[0045] In certain embodiments, the present invention is directed to a compound of formula VIII [Chemical formula]

[0046] 〔Wherein, R 1 , R 2 , A, B, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 1 , Y 2 , Z, m and n are as defined herein.〕 There is provided a compound of or a pharmaceutically acceptable salt thereof.

[0047] In certain embodiments of each of the above embodiments, ring B(Z) is

Chemical formula

Chemical formula

[0048] In certain embodiments herein, C(R 9 ) is H. In certain embodiments herein, C(R 9 ) is not -Cl. In certain embodiments, C(R 10 ) is H. In certain embodiments herein, C(R 10 ) is not -Cl.

[0049] In certain embodiments herein, the compound is one in which ring B(Z) is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0050] In certain embodiments of the above aspects, the compounds of formulas (I) to (VIII) are compounds selected from those described or exemplified in the following detailed description.

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

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

[0053] In a further aspect, the present invention relates to a method of treating a disease such as cancer, the method comprising administering to a subject in need of such treatment an effective amount of at least one compound of formula (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 a compound and salt for the treatment of such a disease.

[0055] In a further aspect, the present invention relates to a method of inhibiting a tyrosine kinase such as EGFR, the method comprising contacting a cell comprising one or more kinases with an effective amount of at least one compound of formula (I)-(VIII) or a pharmaceutically acceptable salt thereof and / or 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 present invention. The compounds of the present invention can be described as embodiments in any of the following numbered paragraphs. It is understood that any of the embodiments described herein can be used in combination with any of the other embodiments described herein, provided that the embodiments are not mutually inconsistent.

[0057] 1. Formula I [Wherein,

[0058] [In the formula,

[0059] A is a 5- to 10-membered heteroarylene or C6-C 10 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 does not contain an -O-O-, -O-S- or -O-N(R 5 )(R

[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 a 3- to 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 each hydrogen atom in 3- to 7-membered heterocycloalkylene, C3-C6 cycloalkylene, C6-C 10 arylene and 5- to 10-membered heteroarylene is independently optionally 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)2NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O)2R f 、-NR e S(O)NR e R f 、-NR e S(O)2NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O)2R 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 is -NR 2 C(Y 1 )-, -C(Y 1 )NR 2 -, -O-, -N(R 2 )-, -S-, -S(O)- or -S(O)2-, and

[0070] each R 1 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 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)2NR a R b 、 -OS(O)NR a R b 、 -OS(O)2NR a R b 、 -NR a R b 、 -NR a C(O)R b 、 -NR a C(O)OR b 、 -NR a C(O)NR a R b 、 -NR a S(O)R b 、 -NRa S(O)2R b 、 -NR a S(O)NR a R b 、 -NR a S(O)2NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -PR a R b 、 -P(O)R a R b 、 -P(O)2R a R b 、 -P(O)NR a R b 、 -P(O)2NR a R b 、 -P(O)OR a 、 -P(O)2OR a 、 -CN or -NO2, where each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)ORf 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2 substituted;

[0071] R 2 、 R 5 、 R 11 or R 14 each of which is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, where each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e, -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e’ , and is substituted with -CN or -NO2;

[0072] Each R 3 , R 4 , R 12 and R 13is 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- to 10-membered heteroaryl, -OR c 、-OC(O)R c 、-OC(O)NR c R d 、-OC(=N)NR c R d 、-OS(O)R c 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d 、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=N)NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=N)NR c R d 、-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 of which two are combined with one or more carbons to which they are attached to form C₃ - C₆ cycloalkyl or 4 - 6 membered heterocycloalkyl, where each hydrogen atom in C₁ - C₆ alkyl, C₂ - C₆ alkenyl, C₂ - C₆ alkynyl, C₃ - C₆ cycloalkyl, 3 - 7 membered heterocycloalkyl, C₆ - C 10 aryl, 5 - 10 membered heteroaryl or 4 - 6 membered heterocycloalkyl is independently optionally deuterium, halogen, C₁ - C₆ alkyl, C₁ - C₆ haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)₂R e 、 -OS(O)NR e R f 、 -OS(O)₂NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)₂R e 、 -S(O)NR e R f 、 -S(O)₂NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR eS(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 is 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 each of R 8 is independently 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- to 10-membered heteroaryl, -OR a 、 -OC(O)R a 、 -OC(O)NR a R b 、 -OS(O)R a 、 -OS(O)2R a 、 -SR a 、 -S(O)R a 、 -S(O)2R a 、 -S(O)NR a R b 、 -S(O)2NR a Rb 、 -OS(O)NR a R b 、 -OS(O)2NR a R b 、 -NR a R b 、 -NR a C(O)R b 、 -NR a C(O)OR b 、 -NR a C(O)NR a R b 、 -NR a S(O)R b 、 -NR a S(O)2R b 、 -NR a S(O)NR a R b 、 -NR a S(O)2NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -PR a R b 、 -P(O)R a R b 、 -P(O)2R a R b 、 -P(O)NR a R b 、 -P(O)2NR a R b 、 -P(O)OR a 、 -P(O)2OR a 、 -CN or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl is independently optionally 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)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2 substituted; provided that one of R 7 or R 8 is a bond to Z;

[0075] R 9 and R 10Each of them is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 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)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)2NR a R b, -P(O)OR a , -P(O)2OR a , -CN or -NO2; or R 8 and R 9 or R 9 and R 10 and R are combined with the carbon atom to which they are attached to form C4-C6 cycloalkyl, 4-7 membered heterocycloalkyl or C6-C 10 aryl, where each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-7 membered heterocycloalkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NRe 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 、 is substituted with -CN or -NO2;

[0076] Each R a 、 R b 、 R c 、 R d 、 R e and R f is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl, C1-C6 alkyl-C6-C 10 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. ]] A compound of or a pharmaceutically acceptable salt thereof.

[0079] 2. A compound of claim 1 having the formula IV

Chemical formula

[0080] or a pharmaceutically acceptable salt thereof.

[0081] 3. A compound of formula VI [Chemical formula]

[0082] The compound of claim 1 or a pharmaceutically acceptable salt thereof, having

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

[0084] 5. The compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein A is pyrrolylene.

[0085] 6. A is [Chemical formula] wherein R 1a is C1-C6 alkyl, -C(O)R a , -C(O)OR a , -C(O)NR a R b or -P(O)2OR, and each hydrogen atom in C1-C6 alkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e Rf 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 A compound of any of the preceding terms or a pharmaceutically acceptable salt thereof, substituted with -CN or -NO2.

[0086] 7. Where A is

Chemical formula

[0087] 8. Each R 1 is -CN or C1-C6 alkyl, where each hydrogen atom in C1-C6 alkyl is independently optionally 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)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 A compound of any of the preceding items or a pharmaceutically acceptable salt thereof, substituted with -CN or -NO2.

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

[0089] 10. R 1a is methyl, a compound of any of the preceding items or a pharmaceutically acceptable salt thereof.

[0090] 11. R 2 is H or C1-C6 alkyl, where each hydrogen atom in C1-C6 alkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)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’ 、 A compound of any of the preceding items or a pharmaceutically acceptable salt thereof, which is substituted with -CN or -NO₂.

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

[0092] 13. Z is a 5- or 6-membered heteroarylene, wherein each hydrogen atom in the 5- or 6-membered heteroarylene is independently optionally deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)₂R e 、 -OS(O)NR e R f 、 -OS(O)₂NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)₂R e 、 -S(O)NR e R f 、 -S(O)₂NR e R f 、 -NR e R f 、 -NR e f 、 -NR e 、 -NR f 、 -NR e 、 -NR e 、 -NR f R e 、 -NR eS(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 A compound of any of the preceding terms or a pharmaceutically acceptable salt thereof, substituted with -CN or -NO2.

[0093] 14. Z is pyrazolylene, oxazolylene, thiazolylene, pyridinylene, pyrimidinylene or pyridin - 2 - onylene, where each hydrogen atom in pyrazolylene, oxazolylene, thiazolylene, pyridinylene, pyrimidinylene and pyridin - 2 - onylene is independently optionally deuterium, halogen, C1 - C6 alkyl, C1 - C6 haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e 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)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , a compound of any of the preceding items or a pharmaceutically acceptable salt thereof, substituted with -CN or -NO2.

[0094] 15. Z is

Chem.

Chem.

Chem.

[0095] 16. Z is C6-C 10 an arylene, where each hydrogen atom in the C6-C 10 arylene is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e Rf 、 -P(O)OR e 、 -P(O)₂OR e 、 A compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt thereof, which is substituted with -CN or -NO₂.

[0096] 17. Z is phenylene, wherein each hydrogen atom in the phenylene is independently optionally deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)₂R e 、 -OS(O)NR e R f 、 -OS(O)₂NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)₂R e 、 -S(O)NR e R f 、 -S(O)₂NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)₂R f 、 -NR e S(O)NR e R f 、 -NR e S(O)₂NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f, -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , a compound of any one of items 1 to 12 or 16 substituted with -CN or -NO2 or a pharmaceutically acceptable salt thereof.

[0097] 18. Z is

Chemical formula

[0098] 19. Z is 3- to 7-membered heterocycloalkylene, where each hydrogen atom in the 3- to 7-membered heterocycloalkylene is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NRe S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 A compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt thereof, substituted with -CN or -NO2.

[0099] 20. Z is pyrrolidinylene or azetidinylene, wherein each hydrogen atom in pyrrolidinylene and azetidinylene is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -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)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 A compound according to any one of items 1 to 12 or 19, or a pharmaceutically acceptable salt thereof, which is substituted with -CN or -NO2.

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

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

[0102] 23. R 12 and R 13 are H, deuterium, fluoro, chloro, bromo, -OR eis independently selected from the group consisting of C1-C6 alkyl; or R 12 and R 13 together with the carbon to which they are attached form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2Re R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 a compound of any of the preceding items substituted with -CN or -NO2.

[0103] 24. A compound of any of the preceding items where R 12 is H and R 13 is methyl.

[0104] 25. A compound of any of the preceding items where R 12 is methyl and R 13 is H.

[0105] 26. A compound of any of the preceding items where R 12 and R 13 are H.

[0106] 27. A compound of any of the preceding items where R 12 is methyl and R 13 is -OH.

[0107] 28. A compound of any of the preceding items where R 12 is -OH and R 13 is methyl.

[0108] 29. A compound of any of items 1 - 12 or 21 where Z is -O- or a pharmaceutically acceptable salt thereof.

[0109] 30. A compound of any of items 1 - 12 or 21 where Z is -N(R 14 )- or a pharmaceutically acceptable salt thereof.

[0110] 31. A compound of any of the preceding items or a pharmaceutically acceptable salt thereof where R 14 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 R is H, methyl or cyclopropyl.

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

[0113] 34. A compound according to any of clauses 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. A compound according to any of the preceding clauses or a pharmaceutically acceptable salt thereof, wherein each L is independently selected from the group consisting of -C(O)-, -O-, -CH2-, -C(H)(CH3)-, -C(H)(OH)-, -C(H)(C(O)OR c )-, -C(H)(C(O)NR c R d )-, -NH- and -NCH3-.

[0120] 41. A compound according to any of the preceding clauses or a pharmaceutically acceptable salt thereof, wherein X is C(R 6 ).

[0121] 42. R 6The compound of any of the preceding items or a pharmaceutically acceptable salt thereof, wherein [the relevant condition] is H.

[0122] 43. The compound of any of the preceding items or a pharmaceutically acceptable salt thereof, wherein Y is O.

[0123] 44. Y 1 The compound of any of the preceding items or a pharmaceutically acceptable salt thereof, wherein Y is O.

[0124] 45. Y 2 The compound of any of the preceding items or a pharmaceutically acceptable salt thereof, wherein Y is -N(R 11 )-.

[0125] 46. X 1 The compound of any of the preceding items or a pharmaceutically acceptable salt thereof, wherein when X is present and X 3 is N.

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

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

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

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

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

[0131] 52. X 4A compound according to any one of items 1 to 45 or a pharmaceutically acceptable salt thereof, wherein [is N].

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

[0133] 54. When C(R 7 ) is present, it is independently H, deuterium, fluoro, chloro, -CN or methyl, a compound according to any of the preceding items or a pharmaceutically acceptable salt thereof.

[0134] 55. When C(R 8 ) is present, it is independently H, deuterium, fluoro, chloro, -CN or methyl, a compound according to any of the preceding items or a pharmaceutically acceptable salt thereof.

[0135] 56. When C(R 9 ) is present, it is independently H, deuterium, fluoro, chloro, -CN or methyl, a compound according to any of the preceding items or a pharmaceutically acceptable salt thereof.

[0136] 57. When C(R 10 ) is present, it is H, a compound according to any of the preceding items or a pharmaceutically acceptable salt thereof.

[0137] 58. -(L) n- is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -C(O)NH-(CH2)2O(CH2)2-, -C(O)N(CH3)-(CH2)2O(CH2)2-, -NHC(O)CH2O(CH2)2-, -N(CH3)-C(O)CH2O(CH2)2-, -CH2O(CH2)2-, -(CH2)2O(CH2)2-, -(CH2)2S(CH2)2-, -O(CH2)2S(CH2)2-, -(CH2)2SO2(CH2)2-, -O(CH2)2SO2(CH2)2-, -(CH2)2SO(CH2)2-, -O(CH2)2SO(CH2)2-, -(CH2)2O(C(H)(C(O)N(H)(azetidin-3-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(CH3))-CH2-, -(CH2)2O(C(H)(C(O)N(CH3)2)-CH2-, -(CH2)2O(C(H)(C(O)N(H)(piperidin-4-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(pyrrolidin-3-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(4-methylpiperazin-1-yl))-CH2-, -(CH2)2O(C(H)(C(O)OCH3)-CH2-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)3-, -CH2CH(CH3)-O(CH2)2-, -CH(CH3)-CH2O(CH2)2-, -O(CH2)2-, -O-(CH2)3-, -OCH2O(CH2)2-, -O-CH2CH(OH)CH2-, -O-(CH2)2O(CH2)2-, -O-CH2CH(CH3)-O(CH2)2-, -O-CH(CH3)-CH2O(CH2)2-, -O-(CH2)2NH-(CH2)2-, -O-CH2CH(CH3)-NH-(CH2)2-, -O-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -O-(CH2)2N(CH3)-(CH2)2-, -O-CH2CH(CH3)-N(CH3)-(CH2)2-, -O-CH(CH3)-CH2N(CH3)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -CH2N(CH2CH3)-(CH2)2--CH2N(CH(CH3))-(CH2)2-, -(CH2)2N(CH3)-(CH2)2-, -CH2CH(CH3)-N(CH3)-(CH2)2- or -O-CH(CH3)-CH2N(CH3)-(CH2)2-, a compound of any of the preceding items or a pharmaceutically acceptable salt thereof.

[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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-3,8(2H,5H)-dione;

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

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

[0143] [3a(4)Z]-9,10,11,12-Tetrahydro-14H-17,1-(azenomethano)pyrazolo[4,3-n]dipyrrolo[3,2-g:3’,4’-j][1,5]oxazacyclopentadecin-3,8(2H,5H)-dione;

[0144] [3a(4)Z]-9,10,11,12-Tetrahydro-14H-1,17-(azenomethano)pyrazolo[4,3-n]dipyrrolo[3,2-g:3’,4’-j][1,5]oxazacyclopentadecin-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]oxazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxatriazacyclohexadecine-4,19(5H,18H)-dione;

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

[0163] [19a(20)Z]-2-Methyl-6,7,9,10-tetrahydro-1H-15,17-(azomethylylidene)pyrazolo[1,5-d]dipyrrolo[3,4-h:2’,3’-k][1,4,7,14]oxatriazacyclohexadecine-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]oxadiazacyclohexadecine-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]oxadiazacyclohexadecine-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]oxadiazacyclohexadecine-4,19(5H,18H)-dione;

[0167] [19a(20)Z]-2,5-Dimethyl-6,7,9,10-tetrahydro-1H-15,17-(azanonemethano)pyrazolo[1,5-d]dipyrrolo[3,4-h:2’,3’-k][1,4,7,14]oxatriazacyclohexadecine-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]triazacyclohexadecine-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]triazacyclohexadecine-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]oxadiazacyclopentadecine-3,8(5H,9H)-dione;

[0171] [3a(4)Z]-6-Methyl-10,11,13,14-tetrahydro-2H-17,1-(azanonemethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]oxazacyclopentadecine-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]oxazacyclopentadecine-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]oxazacyclopentadecin-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]oxazacyclopentadecin-3,8(5H,9H)-dione;

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

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

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

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

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

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

[0213] [3a(4)Z]-9,12,14-Trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-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]triazacyclopentadecin-3,8(2H,5H)-dione.

[0216] 60. A compound of item 1 or a pharmaceutically acceptable salt thereof, 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]benzoxadiazacyclotetradecin-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]benzoxazacyclotetradecin-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]benzoxadiazacyclotetradecin-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]benzoxadiazacyclotetradecin-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]benzoxazadiazacyclotetradecin-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]benzoxazadiazacyclotetradecin-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 claim 1 or a pharmaceutically acceptable salt thereof, 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]oxazadiazacyclotetradecin-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]oxazadiazacyclotetradecin-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]oxazadiazacyclotetradecin-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-(azenomethano)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 according to item 1 or a pharmaceutically acceptable salt thereof, 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-(azenomethano)tripyrrolo[1,2-a:3’,2’-i:3’’,4’’-l][1,4,7]triazacyclopentadecine-3,8(5H,9H)-dione;

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

[0232] [16a(17)Z]-2,11-Dimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenomethano)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-(azenomethano)dipyrrolo[3,2-f:3’,4’-i][1,4,13]oxadiazacyclopentadecine-4,16(5H,15H)-dione;

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

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

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

[0237] [16a(17)Z]-2,5,11-Trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenomethano)dipyrrolo[3,2-i:3’,4’-l][1,4,7]triazacyclopentadecine-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]tetraazacyclopentadecine-4,16(5H,15H)-dione;

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

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

[0242] [10R,16a(17)Z]-2,5,10-Trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azenomethano)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-(azenomethano)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-(azenomethano)dipyrrolo[3,2-f:3’,4’-i][1,4,13]oxadiazacyclopentadecin-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]oxatriazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxadiazacyclopentadecine-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]dioxadiazacyclopentadecine-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]oxatriazacyclopentadecine-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]oxatriazacyclopentadecine-4,16(1H,15H)-dione;

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

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

[0253] [9S,16a(17)Z]-2,5,9-Trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azanonemethano)dipyrrolo[3,4-d:2’,3’-g][1,13,3,10]dioxadiazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]oxazazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]oxathiazacyclohexadecine-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]oxathiazacyclohexadecine-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]dioxazacyclohexadecine-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]dioxazacyclohexadecine-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]dioxazacyclohexadecine-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]dioxazacyclohexadecine-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]oxadiazacyclohexadecine-4,10,17(5H,9H,16H)-trione;

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

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

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

[0276] [17a(18)Z]-2,11-dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azenomethano)dipyrrolo[3,2-f:3’,4’-i][1,4,14]oxadiazacyclohexadecine-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]oxadiazacycloheptadecine-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]oxadiazacycloheptadecine-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]oxadiazacycloheptadecine-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]oxadiazacycloheptadecine-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]oxadiazacycloheptadecine-4,12,18(5H,13H,17H)-trione;

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

[0284] [13S,18a(19)Z]-2,13-Dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(azomethano)dipyrrolo[3,2-f:3’,4’-i][1,4,15]oxadiazacycloheptadecine-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]oxadiazacycloheptadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecin-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]dioxazacyclopentadecin-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-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]dioxazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-4,11,11,16(5H,10H,15H)-tetrone.

[0314] 63. A pharmaceutical composition comprising at least one compound of 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 of treating a disease such as cancer, comprising administering to a subject in need of such treatment an effective amount of any of the compounds of claims 1 - 62 or a pharmaceutically acceptable salt thereof.

[0316] 65. Any of the compounds of claims 1 - 62 or a pharmaceutically acceptable salt thereof for use in a method of treating cancer in a subject.

[0317] 66. Any of the compounds of claims 1 - 62 or a pharmaceutically acceptable salt thereof for treating cancer in a subject.

[0318] 67. Use of any of the compounds of claims 1 - 62 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject.

Mode for Carrying Out the Invention

[0319] Detailed Description Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described, as it can naturally vary. Also, since the scope of the present invention is limited only by the appended claims, it should be understood that the terms described herein are used only for the purpose of explaining specific embodiments and are not intended to limit it.

[0320] The descriptions of publications, including patents, cited herein are incorporated herein by reference for the sake of brevity. 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. All patents, applications, published applications, and other publications mentioned herein are incorporated herein by reference in their entirety. If the definitions defined in this section conflict with or are inconsistent with the definitions shown in the patents, applications, or other publications incorporated herein by reference, the definitions in this section shall prevail over the definitions incorporated by reference.

[0321] As used herein and in the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Further, the claims may be drafted to exclude any optional element. That is, this description is intended to serve as a basis for the use of exclusive terms such as “solely,” “only,” etc. or the use of “negative” limitations in connection with the recitation of claim elements.

[0322] As used herein, the terms “comprise,” “comprising,” and “including” are used in their open, non-limiting sense.

[0323] To provide a more concise description, the quantitative terms shown herein are not qualified by the term “about.” Whether or not the term “about” is explicitly used, all numbers recited herein are meant to refer to actual measured values, and also approximations of such values reasonably inferred based on common general knowledge in the art, including equivalents and approximations due to experimental and / or measurement conditions for such a value. When a yield is recited as a percentage, such yield refers to the mass of the substance shown relative to the maximum amount of that substance that should be obtained under specific stoichiometric conditions. Concentrations shown as percentages refer to mass ratios unless otherwise indicated.

[0324] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can 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 herein by reference for the purpose of disclosing and describing the methods and / or materials related to the publications' citation.

[0325] Unless otherwise indicated, the methods and techniques of this embodiment generally follow the common usage well-known in the art and are carried out as described in various general and more specific cited references cited and described herein. For example, see 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] The chemical names of the 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 that are described in separate embodiments for clarity may be provided in combination in a single embodiment. Conversely, for the sake of brevity, it is also recognized that the various features of the invention that are described in the context of a single embodiment may be provided separately or in any suitable subcombination. All combinations of embodiments in which chemical groups are represented by variable groups are specifically encompassed by this disclosure, provided that such combinations provide compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), and are specifically disclosed by this disclosure as if each and every combination were individually and explicitly disclosed herein. Further, all subcombinations of such chemical groups listed in the embodiments that describe variable groups are also specifically encompassed by this disclosure and are disclosed as if each and every such subcombination of chemical groups were individually and explicitly disclosed herein.

[0328] Chemical Definitions 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 certain embodiments, C1-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 "alkyl" or "alkylene", such as alkylene or C1-C6 alkyl or C1-C6 alkylene, to a specific 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 are considered equivalent to any of the foregoing examples based on 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), iso-propylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), and the like. It is recognized that an alkyl or alkylene group may or may not be substituted, as described herein. An alkyl or alkylene group may contain one or more of any of the substituents described in the various embodiments and may be substituted.

[0329] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group having one or more double bonds. The term "alkenylene" refers to a straight-chain or branched-chain divalent hydrocarbon group 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 "alkenyl" or "alkenylene", such as alkenylene or C2-C6 alkenyl or C2-C6 alkenylene, to a specific 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 alkenyl or alkenylene groups may or may not be substituted, as described herein. An alkenyl or alkenylene group may contain one or more of any of the substituents described in the various embodiments described and may be substituted.

[0330] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group having one or more triple bonds. The term "alkynylene" refers to a straight-chain or branched-chain divalent hydrocarbon group 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 "alkynyl" or "alkynylene", such as alkynylene or C2-C6 alkynyl or C2-C6 alkynylene, to a specific range of atoms. Examples of alkynyl groups include ethynyl (-C≡CH), propargyl (-CH2C≡CH), but-3-yne-1,4-diyl (-C≡C-CH2CH2-), and the like. It is recognized that alkynyl or alkynylene groups may or may not be substituted, as described herein. An alkynyl or alkynylene group may contain one or more of any of the substituents described in the various embodiments described and may be substituted.

[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 "cycloalkyl" or "cycloalkylene", such as from 3 to 12 ring atoms. Polycyclic carbocyclic rings include fused, bridged and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include the monovalent radicals of the following, while cycloalkylene groups include the divalent radicals of the following in the form of appropriately bonded moieties: [Chemical Formula] In particular, the cyclopropyl moiety may be represented by the structural formula [Chemical Formula] In particular, the cyclopropylene moiety may be represented by the structural formula [Chemical Formula] It is recognized that cycloalkyl or cycloalkylene groups may or may not be substituted as described herein. A cycloalkyl or cycloalkylene group may contain one or more of any of the substituents described in the various embodiments and may be substituted.

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

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

[0335] The term "heterocycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic ring structure having one or more non-carbon ring atoms. The term "heterocycloalkylene" refers to a saturated or partially saturated monocyclic or polycyclic ring structure having one or more non-carbon ring atoms. In certain embodiments, it may be advantageous to limit the number of atoms in "heterocycloalkyl" or "heterocycloalkylene" to a specific range of ring atoms, such as 3 to 12 ring atoms (3- to 12-membered), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6-membered), or 4 to 6 ring atoms (4- to 6-membered), or 5 to 7 ring atoms (5- to 7-membered). In certain embodiments, it may be advantageous to limit the number and type of ring heteroatoms in "heterocycloalkyl" or "heterocycloalkylene" to a specific 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 include an oxo group on a carbon ring member or up to 2 oxo groups on a sulfur ring member. Illustrative examples of heterocycloalkyl groups include the monovalent radicals of the following, while heterocycloalkylene groups include the divalent radicals of the following in the form of appropriately connected moieties:

Chemical formula

[0336] The 3-membered heterocycle may contain at least 1 heteroatom ring atom that is sulfur, oxygen, or nitrogen. Non-limiting examples of 3-membered heterocyclic groups include the monovalent and divalent radicals of oxirane, azetidine, and thiirane. The 4-membered heterocycle may contain at least 1 heteroatom ring atom that is sulfur, oxygen, or nitrogen. Non-limiting examples of 4-membered heterocyclic groups include the monovalent and divalent radicals of azetidine, oxetane, and thietane. The 5-membered heterocycle may contain up to 4 heteroatom ring atoms, where (a) at least 1 ring atom is oxygen and sulfur, and 0, 1, 2, or 3 ring atoms are nitrogen or (b) 0 ring atoms are oxygen or sulfur, and up to 4 ring atoms are nitrogen. Non-limiting examples of 5-membered heterocyclic groups include the 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. The 6-membered heterocycle may contain up to 4 heteroatom ring atoms, where (a) at least 1 ring atom is oxygen and sulfur, and 0, 1, 2, or 3 ring atoms are nitrogen or (b) 0 ring atoms are oxygen or sulfur, and up to 4 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-oxazinane-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. "Heterobicyclic" is a fused bicyclic system that includes a heterocycle fused to a cycloalkyl or another heterocycle.

[0337] It is recognized that a heterocycloalkyl or heterocycloalkylene group may or may not be substituted as described herein. A heterocycloalkyl or heterocycloalkylene group may contain one or more of any of the substituents in the various embodiments described and may be substituted.

[0338] The term "heteroaryl" refers to a monovalent monocyclic, fused bicyclic or fused polycyclic aromatic heterocyclic ring (a ring structure having ring atoms or members selected from carbon atoms and up to 4 heteroatoms selected from nitrogen, oxygen and sulfur) that is completely unsaturated and has 3 to 12 ring atoms per heterocycle. The term "heteroarylene" refers to a divalent monocyclic, fused bicyclic or fused polycyclic aromatic heterocyclic ring (a ring structure having ring atoms or members selected from carbon atoms and up to 4 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 "heteroaryl" or "heteroarylene", such as 5- to 10-membered heteroaryl or 5- to 10-membered heteroarylene, to a particular range of atomic members. In some cases, a 5- to 10-membered heteroaryl 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. In some 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 the monovalent radicals of the following, while examples of 5- to 10-membered heteroarylene groups include the divalent radicals of the following, in the form of appropriately linked moieties:

Chemical formula

[0339] In certain embodiments, a “monocyclic” heteroaryl can be an aromatic 5- or 6-membered heterocycle. A 5-membered heteroaryl or heteroarylene may contain up to 4 heteroatom ring atoms, where (a) at least 1 ring atom is oxygen and sulfur and 0, 1, 2, or 3 ring atoms are nitrogen or (b) 0 ring atoms are oxygen or sulfur and up to 4 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 6-membered heteroaryl or heteroarylene may contain up to 4 heteroatom ring atoms, where (a) at least 1 ring atom is oxygen and sulfur and 0, 1, 2, or 3 ring atoms are nitrogen or (b) 0 ring atoms are oxygen or sulfur and up to 4 ring atoms are nitrogen. Non-limiting examples of 6-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of 6-membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. “Bicyclic heteroaryl” or “bicyclic heteroarylene” is a fused bicyclic system that includes a heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, 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 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

Chem.

Chem.

[0340] It is recognized that a heteroaryl or heteroarylene group may or may not be substituted as described herein. A heteroaryl or heteroarylene group may contain one or more of the substituents described in the various embodiments described and may be substituted.

[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 at any location permitted by valence in the system. In one embodiment, "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] All formulas described herein are intended to represent compounds of the structural formulas and certain variants or forms thereof. For example, the formulas shown herein are intended to include racemates or one or more enantiomers, diastereomers or geometric isomers or mixtures thereof. Further, all formulas shown herein are intended to refer to hydrates, solvates or polymorphs of such compounds or mixtures thereof.

[0344] All formulas shown herein are also intended to represent unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures represented by the formulas shown herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl and 125 I. Such isotopically labeled compounds are useful in metabolic studies (preferably 14 C), 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. Further, deuterium (i.e., 2Substitution with heavy isotopes such as (H) etc. can provide certain therapeutic advantages resulting from greater metabolic stability, such as an extended in vivo half-life or a reduced required dose. The isotopically labeled compounds and prodrugs of the present invention can generally be prepared by changing the unlabeled reactants to readily available isotopically labeled reactants and implementing the methods disclosed in the following schemes or examples and production.

[0345] The nomenclature “(atom) i-j ”, where j > i, when applied to a group of substituents, means an embodiment of the present invention in which each of the atomic numbers from i to j including i and j is independently realized. As an example, the term C 1-3 refers independently to embodiments having one carbon member (C1), embodiments having two carbon members (C2), and embodiments having three carbon members (C3).

[0346] Any disubstituent described herein is intended to include various bondable positions if possible at more than one position. For example, the disubstituent -A-B- (where A ≠ B) here refers to a disubstituent having A bonded to the first substituent member and B bonded to the second substituent member, and also refers to a disubstituent having A bonded to the second substituent member and B bonded to the first substituent member. For example, in certain embodiments, if applicable, the compound moiety -(L)- having the formula -CH(CH3)-CH2NH-(CH2)2- connecting the two groups A and B n - is understood to include both A-CH(CH3)-CH2NH-(CH2)2-B and B-CH(CH3)-CH2NH-(CH2)2-A in the embodiment. More specifically in this example, the compound moiety -(L)- of the formula -CH(CH3)-CH2NH-(CH2)2- connecting the group -Z- and -NR 2 - in compounds of formulas (I) to (VIII) having n - is -Z-CH(CH3)-CH2NH-(CH2)2-NR 2 - and -NR 2It is understood to include both embodiments of -CH(CH3)-CH2NH-(CH2)2-A.

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

[0348] "Pharmaceutically acceptable salts" are intended to mean salts of the free acids or bases of the compounds shown herein that are non-toxic, biologically tolerable or otherwise biologically suitable for administration to a subject. See generally, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a subject 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, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0350] For the compounds of formulas (I)-(VIII) containing a basic nitrogen, pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid or organic acids 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 acids such as 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 suitable mixtures of the acids exemplified herein and any other acids and mixtures thereof regarded as equivalent or acceptable alternatives in light of the ordinary skill in this art by treatment of the free base with such acids.

[0351] The present invention also relates to pharmaceutically acceptable prodrugs of the compounds of formulas (I)-(VIII) and methods of treatment using such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a designated compound that, upon 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., a prodrug at physiological pH is converted to a compound of formulas (I)-(VIII)). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerated and otherwise biologically suitable for administration to a subject. Exemplary 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 the compounds of formulas (I)-(VIII) and to the use of such metabolites in the methods of the present invention. "Pharmaceutically active metabolite" means a pharmacologically active metabolite in vivo of a compound of formulas (I)-(VIII) or a salt thereof. The prodrugs and active metabolites of the compounds can be determined using routine techniques known or available in the art. See, 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; 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 generally 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 subsequent chemical reactions. It is recognized that such protecting groups are subsequently removed from the functional group at a later point in the synthesis, providing the opportunity to react with such functional groups further or, in the case of the final product, to unmask such functional groups. Protecting groups are described, for example, in Wuts, P. G. M., Greene, T. W., Greene, T. W., & John Wiley & Sons. (2006). Greene's protective groups in organic synthesis. Hoboken, N.J: Wiley-Interscience. Those skilled in the art readily recognize the chemical process conditions under which such protecting groups can be introduced onto functional groups. 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

Chemical formula

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

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

[0357] [wherein, R 1 , R 2 , A, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 1 , Y 2 , Z, m and n are as defined herein.] or a pharmaceutically acceptable salt thereof.

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

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

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

[0361] [wherein, R 1 , R 2 , A, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 1 , Y 2 , Z, m and n are as defined herein.] To provide a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0362] In certain embodiments, the invention provides a compound of formula V

Chemical formula

[0363] 〔Wherein, R 1 , A, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 1 , Z, Z 1 , m and n are as defined herein.〕 To provide a compound of formula (V) or a pharmaceutically acceptable salt thereof.

[0364] In certain embodiments, the invention provides a compound of formula VI

Chemical formula

[0365] 〔Wherein, R 1 , R 2 , A, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 1 , Y 2 , Z, m and n are as defined herein.〕 To provide a compound of formula (VI) or a pharmaceutically acceptable salt thereof.

[0366] In certain embodiments, the invention provides a compound of formula VII

Chemical formula

[0367] In certain embodiments, the present invention provides a compound of formula VIII

Chemical formula

[0368] [wherein, R 1 , R 2 , A, B, L, X, X 1 , X 2 , X 3 , X 4 , Y, Y 1 , Y 2 , Z, m and n are as defined herein. ]] provides a compound of formula or a pharmaceutically acceptable salt thereof.

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

[0370] In certain embodiments, ring A is a C6-C 10 arylene, and Z is a 3- to 7-membered heterocycloalkylene, C3-C6 cycloalkylene, C6-C 10 arylene or a 5- to 10-membered heteroarylene (also known as ring B). In certain embodiments, ring A is a C6-C 10is an arylene, and ring B is a 5- to 10-membered heteroarylene. In certain embodiments, ring A is C6-C 10 is an arylene, and ring B is a 3- to 7-membered heterocycloalkylene. In certain embodiments, ring A is C6-C 10 is an arylene, and ring B is a C3-C6 cycloalkylene. In certain embodiments, ring A is C6-C 10 is an arylene, and ring B is C6-C 10 is an arylene.

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

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

Chemical formula

[0374] is C1-C6 alkyl, -C(O)R 1a is -C(O)R a is -C(O)OR a is -C(O)NR a R b or -P(O)2OR, and each hydrogen atom in C1-C6 alkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e is -OC(O)R e is -OC(O)NR e R f is -OS(O)R e is -OS(O)2R e is -OS(O)NR e R f is -OS(O)2NR e R f is -SR e is -S(O)R e, -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e , -NR f , -NR e , -NR f , -NR e , -NR e R f , -NR e , -NR f , -NR e , -NR f , -NR e , -NR e R f , -NR e , -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 substituted.

[0375] In one embodiment, ring A has the formula

Chemical formula

[0376] In one embodiment, ring B(Z) has the formula

Chemical formula

[0377] In one embodiment, ring B(Z) has the formula [Chemical formula] as follows.

[0378] In one embodiment, ring B(Z) has the formula [Chemical formula] as follows.

[0379] In one embodiment, ring B(Z) is [Chemical formula] not. In one embodiment, ring B(Z) is [Chemical formula] not.

[0380] In one embodiment, ring B(Z) is a C6-C 10 arylene, where each hydrogen atom in the C6-C 10 aryl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)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)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 is substituted with -CN or -NO2.

[0381] In one embodiment, ring B is phenylene, where each hydrogen atom in the phenylene is independently optionally 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)2NRe R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 is substituted with -CN or -NO2.

[0382] In one embodiment, ring B has the formula

Chemical formula

[0383] In one embodiment, ring B(Z) is a 3- to 7-membered heterocycloalkylene, where each hydrogen atom in the 3- to 7-membered heterocycloalkylene is independently optionally 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)₂NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)₂R f 、 -NR e S(O)NR e R f 、 -NR e S(O)₂NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)₂R e R f 、 -P(O)NR e R f 、 -P(O)₂NR e R f 、 -P(O)OR e 、 -P(O)₂OR e 、 is substituted with -CN or -NO₂.

[0384] In certain embodiments, ring B is pyrrolidinylene or azetidinylene, where each hydrogen atom in pyrrolidinylene and azetidinylene is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR e R f 、-OS(O)2NR e R f 、-SR e 、-S(O)R e 、-S(O)2R e 、-S(O)NR e R f 、-S(O)2NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O)2R f 、-NR e S(O)NR e R f 、-NR e S(O)2NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O)2R e R f 、-P(O)NR e R f 、-P(O)2NR e R f、 -P(O)OR e 、 -P(O)₂OR e 、 substituted with -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, is 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- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)₂R a , -SR a , -S(O)R a , -S(O)₂R a , -S(O)NR a R b , -S(O)₂NR a R b , -OS(O)NR a R b , -OS(O)₂NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)₂R b , -NR a S(O)NR a R b , -NRa S(O)2NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -PR a R b 、 -P(O)R a R b 、 -P(O)2R a R b 、 -P(O)NR a R b 、 -P(O)2NR a R b 、 -P(O)OR a 、 -P(O)2OR a 、 -CN or -NO2, where each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)Rf 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2 substituted.

[0387] In certain embodiments, R 1 is, when present, -CN or C1-C6 alkyl, where each hydrogen atom in C1-C6 alkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -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)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2 substituted. In certain embodiments, R 1 is, when present, R 1 is -CN or methyl.

[0388] In certain embodiments, R 1a is, 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 C1-C6 alkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NRe R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2 substituted. In certain embodiments, R 1a is methyl when present.

[0389] In certain embodiments, R 2is 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- to 10-membered heteroaryl, wherein each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR e R f 、-OS(O)2NR e R f 、-SR e 、-S(O)R e 、-S(O)2R e 、-S(O)NR e R f 、-S(O)2NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O)2R f 、-NR e S(O)NR e R f 、-NR e S(O)2NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e 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’ 、 is substituted with -CN or -NO₂.

[0390] In certain embodiments, R 2 is H or C₁-C₆ alkyl, where each hydrogen atom in the C₁-C₆ alkyl is independently optionally deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)₂R e 、 -OS(O)NR e R f 、 -OS(O)₂NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)₂R e 、 -S(O)NR e R f 、 -S(O)₂NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)₂R f 、 -NR e S(O)NR e R f 、 -NR e S(O)₂NR e R f, -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e’ , -CN or -NO2 substituted. In certain 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 does not contain an -O-O-, -O-S- or -O-N(R 5 )- bond.

[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, 3-7 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)₂NR c R d 、 -NR c R d 、 -NR c C(O)R d 、 -N(C(O)R c )(C(O)R d )、 -NR c C(O)OR d 、 -NR c C(O)NR c R d 、 -NR c C(=N)NR c R d 、 -NR c S(O)R d 、 -NR c S(O)₂R d 、 -NR c S(O)NR c R d 、 -NR c S(O)₂NR c R d 、 -C(O)R c 、 -C(O)OR c 、 -C(O)NR c R d 、 -C(=N)NR c R d 、 -PR c R d 、 -P(O)R c R d 、 -P(O)₂R c R d 、 -P(O)NR c R d 、 -P(O)₂NR c R d 、 -P(O)OR c 、 -P(O)₂OR c 、 -CN, -NO₂ or R 3 、 R 4 、 R 12 and R 13Two of them, together with one or more carbons to which they are attached, form a C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl, 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 aryl, 5- to 10-membered heteroaryl or 4- to 6-membered heterocycloalkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR e R f 、-OS(O)2NR e R f 、-SR e 、-S(O)R e 、-S(O)2R e 、-S(O)NR e R f 、-S(O)2NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O)2R f 、-NR e S(O)NR e R f 、-NR e S(O)2NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e Rf 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 is substituted with -CN or -NO2.

[0393] In certain embodiments, R 12 and R 13 , when present, are independently selected from the group consisting of H, deuterium, fluoro, chloro, bromo, -OR e and C1-C6 alkyl; or R 12 and R 13 are joined together with the carbon to which they are attached to form C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)Rf 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2 substituted.

[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 certain embodiments, when present, R 12 and R 13 are H. In certain embodiments, when present, R 12 is methyl, and R 13 is -OH. In certain 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-. In certain embodiments, -(L) n- is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -C(O)NH-(CH2)2O(CH2)2-, -C(O)N(CH3)-(CH2)2O(CH2)2-, -NHC(O)CH2O(CH2)2-, -N(CH3)-C(O)CH2O(CH2)2-, -CH2O(CH2)2-, -(CH2)2O(CH2)2-, -(CH2)2S(CH2)2-, -O(CH2)2S(CH2)2-, -(CH2)2SO2(CH2)2-, -O(CH2)2SO2(CH2)2-, -(CH2)2SO(CH2)2-, -O(CH2)2SO(CH2)2-, -(CH2)2O(C(H)(C(O)N(H)(azetidin-3-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(CH3))-CH2-, -(CH2)2O(C(H)(C(O)N(CH3)2)-CH2-, -(CH2)2O(C(H)(C(O)N(H)(piperidin-4-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(pyrrolidin-3-yl))-CH2-, -(CH2)2O(C(H)(C(O)N(H)(4-methylpiperazin-1-yl))-CH2-, -(CH2)2O(C(H)(C(O)OCH3)-CH2-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)3-, -CH2CH(CH3)-O(CH2)2-, -CH(CH3)-CH2O(CH2)2-, -O(CH2)2-, -O-(CH2)3-, -OCH2O(CH2)2-, -O-CH2CH(OH)CH2-, -O-(CH2)2O(CH2)2-, -O-CH2CH(CH3)-O(CH2)2-, -O-CH(CH3)-CH2O(CH2)2-, -O-(CH2)2NH-(CH2)2-, -O-CH2CH(CH3)-NH-(CH2)2-, -O-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -O-(CH2)2N(CH3)-(CH2)2-, -O-CH2CH(CH3)-N(CH3)-(CH2)2-, -O-CH(CH3)-CH2N(CH3)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -CH2N(CH2CH3)-(CH2)2--CH2N(CH(CH3))-(CH2)2-, -(CH2)2N(CH3)-(CH2)2-, -CH2CH(CH3)-N(CH3)-(CH2)2- or -O-CH(CH3)-CH2N(CH3)-(CH2)2-. In certain embodiments, -Z-(L), n -Z 1 - does not contain an -O-O-, -O-S- or -O-N(R x )- bond.

[0396] In certain embodiments, R 5 is H or C1-C6 alkyl, where each hydrogen atom in the C1-C6 alkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)Re , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e’ , -CN or substituted with -NO2. In certain embodiments, R 5 is H or methyl.

[0397] In certain embodiments, X is -N-. In certain embodiments, X is C(R 6 ). In certain embodiments, R 6 , when present, is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or -CN. In certain embodiments, R 6 , when present, is H.

[0398] In certain embodiments, X 1 is N or C(R 7 ); and X 2 is N or C(R 8 ); provided that one of R 7 or R 8 is a bond to Z. In certain embodiments, X 1 is N or C(R 7 ). In certain embodiments, X 1 is N. In certain embodiments, X 1 is C(R 7 ). In certain embodiments, X 2 is N- or C(R 8 ). In certain embodiments, X 2 is N. In certain embodiments, X 2 is C(R 8) is. In certain embodiments, X 3 is N or C(R 9 ). In certain embodiments, X 3 is N. In certain embodiments, X 3 is C(R 9 ). In certain embodiments, X 4 is N or C(R 10 ). In certain embodiments, X 4 is N. In certain embodiments, X 4 is C(R 10 ). In certain embodiments, X 1 and X 3 are N. In certain embodiments, X 1 and X 4 are N. In certain embodiments, X 3 and X 4 are N. In certain embodiments, X 1 is C(R 7 ), X 3 is C(R 9 ), and X 4 is C(R 10 ). In certain embodiments, the compound is such that X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), and R 10 is not H. In certain embodiments, the compound is such that X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), and R 9 is not H. In certain embodiments, the compound is such that X 1 is C(R 7 ), X 3 is C(R 9 ), X 4 is C(R 10 ), and R 9 and R 10 are not H.

[0399] In one embodiment, R 7 and R 8 each independently is 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- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a , -NR b , -NR a , -NR b , -NR a , -NR a R b , -NR a , -NR b , -NR a , -NR b , -NR a , -NR a R b , -NR a , -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, each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e Rf ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f ,-P(O)2NR e R f ,-P(O)OR e ,-P(O)2OR e ,-substituted with -CN or -NO2; provided that one of R 7 or R 8 is a bond to Z;

[0400] In certain embodiments, each of R 9 and R 10 is 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- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a , -NR b , -NR a , -NR b , -NR a , -NR a R b , -NR a , -NR b 、-NRa S(O)2R b 、 -NR a S(O)NR a R b 、 -NR a S(O)2NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -PR a R b 、 -P(O)R a R b 、 -P(O)2R a R b 、 -P(O)NR a R b 、 -P(O)2NR a R b 、 -P(O)OR a 、 -P(O)2OR a 、 -CN or -NO2; or R 8 and R 9 or R 9 and R 10 are, together with the carbon atom to which they are attached, C4 - C6 cycloalkyl, 4 - 7 membered heterocycloalkyl or C6 - C 10 aryl, where each hydrogen atom in C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, C4 - C6 cycloalkyl, 3 - 7 membered heterocycloalkyl, C6 - C 10 aryl, 5 - 10 membered heteroaryl or 4 - 7 membered heterocycloalkyl is independently optionally deuterium, halogen, C1 - C6 alkyl, C1 - C6 haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2Re 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 is substituted with -CN or -NO2.

[0401] In one embodiment, R 9 and R 10 each 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- to 10-membered heteroaryl, -OR a 、 -OC(O)R a 、 -OC(O)NR a R b 、 -OS(O)R a, -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a , -NR b , -NR a , -NR b , -NR a , -NR a R b , -NR a , -NR b , -NR a , -NR b , -NR a , -NR a R b , -NR a , -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 , not -CN or -NO2; or R 8 and R 9 or R 9 and R 10 and they combine with the carbon atom to which they are attached to form C4 - C6 cycloalkyl, 4 - 7 membered heterocycloalkyl or C6 - C 10Form an aryl, where each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl or 4- to 7-membered heterocycloalkyl may independently be in some cases deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e Rf 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 is substituted with -CN or -NO2.

[0402] In certain embodiments, C(R 7 ) is H, deuterium, fluoro, chloro, -CN or methyl. In certain embodiments, C(R 8 ) is H, deuterium, fluoro, chloro, -CN or methyl. In certain embodiments, each C(R 9 ) is H, deuterium, fluoro, chloro, -CN or methyl. In certain embodiments, C(R 10 ) is H, deuterium, fluoro, chloro, -CN or methyl. In certain embodiments, C(R 9 ) is H. In certain embodiments, C(R 9 ) is not -Cl. In certain embodiments, C(R 10 ) is H. In certain embodiments, C(R 10 ) is not -Cl.

[0403] In certain embodiments, the compound, wherein ring B(Z) is

Chemical Structure

Chemical Structure

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical Structure

Chemical Structure

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

[0405] In certain embodiments, n is 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8.

[0406] In certain embodiments, the present invention [3a(4)Z]-10,11-dihydro-2H,13H-16,1-(azenomethano)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-(azenomethano)pyrazolo[3,4-b]dipyrrolo[3,4-f:2’,3’-i][1,5,12]oxadiazacyclopentadecine-3,8(2H,5H)-dione;

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

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

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

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

[0412] [3a(4)Z]-9,10,11,12-Tetrahydro-14H-1,17-(azenomethano)pyrazolo[4,3-n]dipyrrolo[3,2-g:3’,4’-j][1,5]oxazacyclopentadecin-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]oxazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxatriazacyclohexadecine-4,19(5H,18H)-dione;

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

[0431] [19a(20)Z]-2-Methyl-6,7,9,10-tetrahydro-1H-15,17-(azenomethano)pyrazolo[1,5-d]dipyrrolo[3,4-h:2’,3’-k][1,4,7,14]oxatriazacyclohexadecine-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]oxadiazacyclohexadecine-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]oxadiazacyclohexadecine-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]oxadiazacyclohexadecine-4,19(5H,18H)-dione;

[0435] [19a(20)Z]-2,5-Dimethyl-6,7,9,10-tetrahydro-1H-15,17-(azenomethano)pyrazolo[1,5-d]dipyrrolo[3,4-h:2’,3’-k][1,4,7,14]oxatriazacyclohexadecine-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]triazacyclohexadecine-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]triazacyclohexadecine-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]oxadiazacyclopentadecine-3,8(5H,9H)-dione;

[0439] [3a(4)Z]-6-Methyl-10,11,13,14-tetrahydro-2H-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]oxazacyclopentadecine-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]oxazacyclopentadecine-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]oxazacyclopentadecine-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]oxazacyclopentadecine-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]triazacyclopentadecine-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]triazacyclopentadecine-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]diazacyclopentadecine-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]triazacyclopentadecine-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]triazacyclopentadecine-3,8(2H,5H)-dione;

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

[0452] [3a(4)Z]-6,9,20-Trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azomethino)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-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-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-3,8(2H,5H)-dione;

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

[0456] [3a(4)Z]-16-Cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-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]triazacyclopentadecin-3,8(2H,5H)-dione;

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

[0459] [3a(4)Z]-6,9,16-Trimethyl-10,11,12,13-tetrahydro-2H-17,1-(azenomethano)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-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]diazacyclopentadecin-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]diazacyclopentadecin-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]diazacyclopentadecin-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]oxazacyclopentadecin-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]diazacyclopentadecin-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]diazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-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]diazacyclopentadecin-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]diazacyclopentadecin-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]oxazacyclopentadecin-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]diazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-3,8(2H,5H)-dione;

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

[0481] [3a(4)Z]-9,12,14-Trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-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] Provided is a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0485] In another embodiment, the present invention [3a(4)Z]-6-methyl-9,10,11,12-tetrahydro-1,18-(ethanediylidene)dipyrrolo[3,2-g:3’,4’-j][1,5,12]benzoxadiazacyclopentadecine-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-(azenomethano)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]benzodiazacyclopentadecine-3,8(5H,9H)-dione A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof is provided.

[0493] In another embodiment, the present invention [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-(azomethino)pyrido[1,2-e]dipyrrolo[3,4-i:2’,3’-l][1,5]diazacyclotetradecine-3,8,14(2H,5H)-trione;

[0498] A compound selected from the group consisting of ,

[0498] , or a pharmaceutically acceptable salt thereof is provided.

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

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

[0501] [16a(17)Z]-2,11-dimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azomethino)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-(azomethino)dipyrrolo[3,2-f:3’,4’-i][1,4,13]oxadiazacyclopentadecine-4,16(5H,15H)-dione;

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

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

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

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

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

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

[0511] [10R,16a(17)Z]-2,5,10-Trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azomethano)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-(azomethano)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-(azomethano)dipyrrolo[3,2-f:3’,4’-i][1,4,13]oxadiazacyclopentadecin-4,16(5H,15H)-dione;

[0514] [10S,16a(17)Z]-2,5,10-Trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azomethano)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-(azonomethano)dipyrrolo[3,2-i:3’,4’-l][1,4,7]dioxazacyclopentadecin-4,16(5H,15H)-dione;

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

[0518] [10S,16a(17)Z]-2,5,10-Trimethyl-5,6,7,8,9,10-hexahydro-12,14-(azonomethano)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-(azonomethano)dipyrrolo[3,2-i:3’,4’-l][1,4,7]oxadiazacyclopentadecin-4,16(1H,15H)-dione;

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

[0522] [9S,16a(17)Z]-2,5,9-Trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azenomethano)dipyrrolo[3,4-d:2’,3’-g][1,13,3,10]dioxadiazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]oxadiazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]oxathiazacyclohexadecine-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]oxathiazacyclohexadecine-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]dioxazacyclohexadecine-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]oxadiazacyclohexadecin-4,10,17(5H,9H,16H)-trione;

[0537] [17a(18)Z]-2,5-Dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azometheno)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-(azometheno)dipyrrolo[3,2-f:3’,4’-i][1,4,14]oxadiazacyclohexadecin-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]oxatriazacyclohexadecine-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]oxatriazacyclohexadecine-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]oxatriazacyclohexadecine-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]oxatriazacyclohexadecine-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]oxadiazacyclohexadecine-4,10,17(5H,9H,16H)-trione;

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

[0545] [17a(18)Z]-2,11-Dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azanonemethano)dipyrrolo[3,2-f:3’,4’-i][1,4,14]oxadiazacyclohexadecin-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]oxadiazacycloheptadecin-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]oxadiazacycloheptadecin-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]oxadiazacycloheptadecin-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]oxadiazacycloheptadecin-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]oxadiazacycloheptadecin-4,12,18(5H,13H,17H)-trione;

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

[0553] [13S,18a(19)Z]-2,13-Dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(azenomethano)dipyrrolo[3,2-f:3’,4’-i][1,4,15]oxadiazacycloheptadecine-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]oxadiazacycloheptadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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-methylpiperazin-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecin-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]oxathiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxathiazacyclopentadecin-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]oxathiazacyclopentadecin-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]oxathiazacyclopentadecin-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]oxathiazacyclopentadecin-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]oxathiazacyclopentadecin-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]oxathiazacyclopentadecin-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]dioxazacyclopentadecin-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]oxazazacyclopentadecin-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]oxazazacyclopentadecin-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-4,11,11,16(5H,10H,15H)-tetrone

[0583] To provide a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0584] The following are representative examples of embodiments of the compound 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 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

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

[0586] Pharmaceutical composition For treatment purposes, a pharmaceutical composition containing the compounds described herein may further contain one or more pharmaceutically acceptable additives. Pharmaceutically acceptable additives are substances that are non-toxic and otherwise biologically suitable for administration to a subject. Such additives facilitate the 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. The pharmaceutical composition can be manufactured using mixing techniques known or available to those skilled in the art.

[0587] Sterile compositions are also contemplated by the present invention and include compositions that comply with the regulations of the countries and regions that regulate such compositions.

[0588] The pharmaceutical compositions and compounds described herein can be formulated as solutions, emulsions, suspensions or dispersions in a suitable pharmaceutical solvent or carrier or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, reconstitutable powders or capsules together with a solid carrier by conventional methods known in the field of the manufacture of various dosage forms. The pharmaceutical compositions of the present invention can be administered by a suitable delivery route such as oral, parenteral, rectal, nasal, topical or ophthalmic route or by inhalation. Preferably, the composition is formulated for intravenous or oral administration.

[0589] For oral administration, the compounds of the invention are provided as solids such as tablets or capsules, or as solutions, emulsions or suspensions. To prepare the oral compositions, the compounds of the invention can be formulated in dosages of, for example, about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. Oral tablets can 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 carbonates, sodium and calcium phosphates, 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, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose and alginic acid are examples of disintegrants. Binders can include starch and gelatin. Lubricants, if present, can be magnesium stearate, stearic acid or talc. Optionally, the tablets can be coated with a substance such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract or with an enteric coating.

[0590] Capsules for oral administration 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, an 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] The liquid for oral administration may be in the form of a suspension, solution, emulsion or syrup or may be lyophilized for reconstitution with water or other suitable vehicle before use or presented as a dry product. Such liquid compositions may, if desired, contain a suspending agent (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); a non-aqueous vehicle, e.g., an oil (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; a preservative (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid); a wetting agent such as lecithin; and, if desired, pharmaceutically acceptable additives such as flavoring or coloring agents.

[0592] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal or subcutaneous routes, the agents of the invention are provided in a sterile aqueous solution or suspension buffered and isotonic at an appropriate pH or in a parenterally acceptable oily vehicle. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be provided in unit dosage forms such as ampoules or disposable infusion devices, in multi-dose forms such as vials from which appropriate doses may be withdrawn or as solids or pre-concentrates which may be used in the preparation of injectable formulations. Exemplary infusion doses range from about 1 to 1000 μg / kg / min of a solution agent mixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0593] For nasal, inhalation or oral administration, the pharmaceutical compositions of the invention may be administered, for example, using a spray formulation which similarly contains a suitable carrier. The compositions of the invention may be formulated for rectal administration as suppositories.

[0594] For topical application, the compounds of the invention are preferably formulated as a cream or ointment or a similar vehicle suitable for topical administration. For topical administration, the compounds of the invention are mixed with a pharmaceutical carrier at a drug concentration of about 0.1% to about 10% relative to the vehicle. Other methods of administering the agents of the invention may utilize patch formulations for transdermal delivery.

[0595] As used herein, the term "treating" or "treatment" encompasses both "preventive" and "curative" treatments. "Preventive" treatment means to delay the progression of a disease, disease symptom or medical condition, suppress the occurrence of possible symptoms or reduce the risk of progression or recurrence of a disease or symptom. "Curative" treatment includes reducing the severity of an existing disease, symptom or condition or suppressing its exacerbation. Thus, treatment includes improving existing disease symptoms or preventing their exacerbation, preventing further symptom manifestation, improving or preventing the underlying systemic causes of symptoms, preventing a disorder or disease, e.g., halting the progression of a disorder or disease, reducing a disorder or disease, inducing regression of a disorder or disease, reducing the condition caused by a disease or disorder or stopping 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 +Breast cancer, colorectal adenocarcinoma, glioblastoma, glioblastoma multiforme, undifferentiated thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epitheloid hemangioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid cancer, Spitzoid tumor, sarcoma, astrocytoma, low-grade glioma of the brain, secretory carcinoma of the breast, breast-like carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, cutaneous melanoma, squamous cell carcinoma of the head and neck, pediatric glioma CML, prostate cancer, squamous cell carcinoma of the lung, serous cystadenocarcinoma of the ovary, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin lymphoma and serous and clear cell endometrial cancer, including but not limited to. In certain embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophageal gastric cancer, glioblastoma, head and neck cancer, inflammatory myofibroblastic tumor and anaplastic large cell lymphoma. Pain includes pain of any origin or etiology, including, for example, cancer pain, pain from chemotherapy treatment, neuropathic pain, pain from injury or other sources. 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, allergy and inflammation from infection or trauma.

[0598] In certain embodiments, the compounds and pharmaceutical compositions of the invention specifically target tyrosine receptor kinases, particularly EGFR. Thus, these compounds and pharmaceutical compositions can be used for the prevention, reversal, slowdown or inhibition of the activity of one or more of these kinases. In preferred embodiments, 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 invention, "effective amount" means an amount sufficient to inhibit the target protein. Measurement of such target modification can be carried out by routine analytical methods as described hereinafter. Such modification is useful in a variety of settings including in vitro assays. In such methods, the cells are preferably cancer cells with abnormal signal transduction due to upregulation of EGFR.

[0600] In the treatment method of the present invention, "effective amount" generally means an amount or dosage sufficient to provide the desired therapeutic benefit to a subject in need of such treatment. The effective amount or dosage of the compounds of the present invention can be determined 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 health status, condition and weight of the subject, and the judgment of the treating physician. Examples of dosages are in the range of approximately 0.1 mg to 1 g per day or approximately 1 mg to 50 mg per day or approximately 50 to 250 mg per day or approximately 250 mg to 1 g per day. The total dosage can be given in single or divided dosage units (e.g., BID, TID, QID).

[0601] If the patient's disease improves, the dosage can be adjusted for prophylactic or maintenance treatment. For example, the dosage or dosing frequency or both can be decreased to a level at which the desired therapeutic or prophylactic effect is maintained, in response to the symptoms. Of course, if the symptoms are reduced to an appropriate level, treatment can be stopped. However, the patient may require intermittent treatment on a long-term basis due to any recurrence of the symptoms. The patient may also require chronic treatment on a long-term basis.

[0602] Drug combinations The compounds of the present invention described herein can 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. Further, the additional active ingredient can include other treatments or agents that reduce the adverse effects of the treatment on the intended disease target. Such combinations can serve to increase effectiveness, improve other disease symptoms, reduce one or more side effects or reduce the required dosage of the compounds of the present invention. The additional active ingredient can be administered in a separate pharmaceutical composition from the compound of the present invention or can be included in a single pharmaceutical composition together with the compound of the present invention. The additional active ingredient can be administered simultaneously with, prior to or after the administration of the compound of the present invention.

[0603] The combination agents include additional active ingredients known or discovered to be effective in the treatment of the diseases and disorders described herein, including those that are active against other targets associated with the disease. For example, the compositions, formulations, and methods of treatment of the present invention may further include other drugs or medicaments, such as other active agents useful or symptomatic in the treatment of the target disease or related symptoms or conditions. For cancer indications, additional such agents include 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, hormonal therapy, or corticosteroids, but are not limited thereto. 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 of such active agents, and the methods of treatment may further include administration of an effective amount of one or more of such active agents.

[0604] Chemical synthesis method The following examples are provided by way of illustration and not limitation of the invention. Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified by the selection of appropriate starting materials and reagents to obtain other compounds of formulas (I)-(VIII).

[0605] In certain embodiments, the present invention provides a compound of formula (IX)

Chemical formula

[0606] 〔Wherein, A’ is optionally deuterium, halogen, -OC1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 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)2NR a R b 、 -OS(O)NR a R b 、 -OS(O)2NR a R b 、 -NR a R b 、 -NR a 、 -NR b 、 -NR a C(O)OR b 、 -NR a C(O)NR a R b 、 -NR a S(O)R b 、 -NR a S(O)2R b 、 -NR a S(O)NR a R b 、 -NR a S(O)2NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -C(S)R a 、 -C(S)OR a 、 -C(S)NR a R b 、 -PR a R b 、 -P(O)R a R b 、 -P(O)2R a R b 、 -P(O)NR a R b 、 -P(O)2NR a R b 、 -P(O)OR a 、 -P(O)2OR a 、 -CN or -NO2 substituted by one or more of 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 aryl or 5- to 10-membered heteroaryl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、-OC(O)R e 、-OC(O)NR e R f 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR e R f 、-OS(O)2NR e R f 、-SR e 、-S(O)R e 、-S(O)2R e 、-S(O)NR e R f 、-S(O)2NR e R f 、-NR e R f 、-NR e C(O)R f 、-NR e C(O)OR f 、-NR e C(O)NR e R f 、-NR e S(O)R f 、-NR e S(O)2R f 、-NR e S(O)NR e R f 、-NR e S(O)2NR e R f 、-C(O)R e 、-C(O)OR e 、-C(O)NR e R f 、-PR e R f 、-P(O)R e R f 、-P(O)2R e R f 、-P(O)NRe R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 is substituted with -CN or -NO2;

[0607] Z’ is 3 - 7 membered heterocycloalkyl, C3 - C6 cycloalkyl, C6 - C 10 aryl, 5 - 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 and wherein each hydrogen atom in 3 - 7 membered heterocycloalkyl, C3 - C6 cycloalkyl, C6 - C 10 aryl and 5 - 10 membered heteroaryl is independently optionally deuterium, halogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, 3 - 7 membered heterocycloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR eC(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2 substituted;

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

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

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

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

[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 is 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- to 10-membered heteroaryl, -OC1-C6 alkyl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a Rb 、 -NR a S(O)2NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -PR a R b 、 -P(O)R a R b 、 -P(O)2R a R b 、 -P(O)NR a R b 、 -P(O)2NR a R b 、 -P(O)OR a 、 -P(O)2OR a 、 -CN or -NO2; or R 3 and R 4 or R 4 and R 5 and R are combined with the carbon atom to which they are attached to form C4-C6 cycloalkyl, 4-7 membered heterocycloalkyl or C6-C 10 aryl, where each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-7 membered heterocycloalkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e 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)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 substituted with -CN or -NO2;

[0616] R 11 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e 、 -OC(O)R e, -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e , -NR f , -NR e , -NR f , -NR e , -NR e R f , -NR e , -NR f , -NR e , -NR f , -NR e , -NR e R f , -NR e , -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’ , is substituted with -CN or -NO2;

[0617] each R a , R b , R c , Rd , R e and R f are independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl, C1-C6 alkyl-C6-C 10 aryl and 5-10 membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl, C1-C6 alkyl-C6-C 10Aryl and 5- to 10-membered heteroaryl are each independently optionally substituted with -OH, -OPG, -CN, -OC1-C6 alkyl, -NH2, -NHPG, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)NH2, -NHC(O)NHC1-C6 alkyl, -N(C1-C6 alkyl)C(O)NH2, -N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, -NHC(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -NHS(O)(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), -NHS(O)NH2, -NHS(O)2NH2, -N(C1-C6 alkyl)S(O)NH2, -N(C1-C6 alkyl)S(O)2NH2, -NHS(O)NH(C1-C6 alkyl), -NHS(O)2NH(C1-C6 alkyl), -NHS(O)N(C1-C6 alkyl)2, -NHS(O)2N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), -N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, -CO2H, -COOPG, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHPG, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)NH(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2, -S(O)2N(C1-C6 alkyl)2, -P(C1-C6 alkyl)2, -P(O)(C1-C6 alkyl)2, C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl; and

[0618] PG is a protecting group. To provide a compound of.

[0619] Abbreviations: The examples described herein include, but are not limited to, substances represented by the following abbreviations known to those skilled in the art: [Table 32] [Table 33]

[0620] General method A [Chemical formula]

[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 obtain A-1. If no precipitate was 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 following table: [Table 34] [Table 35] [Table 36] [Table 37] [Table 38]

Table 39

[0623] General method B-I

Chem.

[0624] To the DMF (0.25 M) solutions of Engineering 1. B1-1 (1.0 eq.) and B2-1 (1.5 eq.), Cs2CO3 (2.0 eq.) was added, and the mixture was stirred at 60 - 80 °C under nitrogen until the reaction was completed. Water (5 equivalent volumes of DMF) was added to the cooled DMF solution, and the product was extracted 3 times with ethyl acetate (1 equivalent volume of water). The combined extracts were washed with water, aqueous HCl solution (1 N), and brine, and dried over magnesium sulfate. After filtration and concentration, the crude product was purified by silica gel column to obtain the pure product B3-1.

[0625] Separate process 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 minutes, B2-1 (1.0 eq) was added to the above suspension. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted 3 times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column to obtain B3-1.

[0626] Engineering 2. To a dry acetonitrile (0.25 M) solution of B3-1 (1.0 eq.), N-bromosuccinimide (1.05 eq.) was added, and the solution was stirred at ambient temperature until the reaction was completed. The reaction was quenched with aqueous sodium thiosulfate solution (0.1 N), and then 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 by silica gel column to obtain the pure product B4-1.

[0627] Step 3. A mixture of B4-1 (1.0 eq), bis(pinacolato)diboron (1.2 eq), KOAc (3.0 eq) and the catalyst Pd(dppf)Cl2 / CH2Cl2 (0.05 eq) in anhydrous DMF (0.5 M) was purged with nitrogen gas. It was heated at about 95 °C for about 15 h under nitrogen. 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 obtain the pure product B-I-1.

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

[0629] General method B-II [Chemical formula]

[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 at 60 - 80 °C under nitrogen until the reaction was complete. Water (5 volumes of DMF) was added to the cooled DMF solution and the product was extracted 3 times with ethyl acetate (1 volume of water). The combined extracts were washed with water, aqueous HCl solution (1 N) and brine, and dried over magnesium sulfate. After filtration and concentration, the crude product was purified by a silica gel column to obtain the pure product B6-1.

[0631] Step 2. A mixture of B6-1 (1.0 eq), bis(pinacolato)diboron (1.2 eq), KOAc (3.0 eq) and the catalyst Pd(dppf)Cl2 / CH2Cl2 (0.05 eq) in anhydrous DMF (0.5 M) was purged with nitrogen gas. It was heated at about 95 °C for about 15 hours under nitrogen. 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 obtain the pure product B-II-1.

[0632] The following boronic acid pinacols B-II-1 to B-II-10 were prepared from the corresponding starting materials B5 and B2 shown in the table below according to General Method B-II: [Table 43] [Table 44]

[0633] General Method B-III [Chemical formula]

[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 minutes, B8-1 (1.0 eq) was added to the above suspension. The mixture was stirred at ambient temperature until the reaction was complete, quenched with a saturated aqueous ammonium chloride solution, extracted 3 times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated and purified by a silica gel column to obtain B9-1.

[0635] To a solution of Project 2. B9-1 (1.0 eq.) in anhydrous THF (0.2 M), n-BuLi (2.5 M in hexane, 1.1 eq.) was added at 0 °C. The reaction solution was stirred at ambient temperature for 1 hour and then cooled to -78 °C. To the reaction solution, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.05 eq.) was added. After 15 minutes at -78 °C, the reaction mixture was warmed to 0 °C over 1 hour. The reaction mixture was diluted with saturated NH4Cl solution and extracted with DCM. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column to obtain B-III-1.

[0636] The following boronic acid pinacols B-III-1 to B-III-6 were prepared from the corresponding starting materials B7 and B8 shown in the table below according to General Method B-III:

Table 45

[0637] General Method B-IV

Chemical formula

[0638] Step 1. To a solution of B10-1 (1 eq.) in methanol (0.2 M) and acetic acid (1.5 eq.), B11-1 (1 eq.) and NaCNBH3 (2 eq.) were added at ambient temperature. The mixture was stirred for 1 hour, 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 CH2Cl2 (0.2 M) and the solution was cooled to 0 °C. Di(tert-butyl) dicarbonate (1.2 eq) was added dropwise to the solution. The ice bath was removed and the mixture was stirred at ambient temperature overnight. The reaction solution was diluted with dichloromethane, washed with water, and dried over magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column to obtain 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 boronic acid pinacols B-IV-1 to B-IV-7 were prepared from the general method B-IV using the corresponding starting materials B10 and B11 shown in the following table: [Table 46] [Table 47]

[0641] General method C [Chemical formula]

[0642] To a solution of A-1 (1.0 eq.), B-1 (1.2 eq.) and Cs2CO3 (3 eq.) in DME / H2O (5:1, 0.2 M) under N2, Pd(PPh3)2Cl2 (0.05 eq.) was added. The mixture was stirred at 85 °C overnight, cooled to ambient temperature, and quenched with H2O. The resulting mixture was extracted three times with EtOAc. The combined extracts were washed with brine and dried over anhydrous Na2SO4. After filtration and concentration, the resulting residue was purified by silica gel column chromatography to obtain the desired product C-1.

[0643] The following intermediates C-1 to C-66 were prepared from the general method C using the corresponding two starting materials A and B shown in the following table: [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 Law D

Chem.

[0645] To a solution of A-9 (1.0 eq.) in toluene (0.2 M) under stirring, D1-1 (1.5 eq.), sodium tert-butoxide (3 eq.), BINAP (0.05 eq.) and Pd(OAc)2 (0.05) were added under nitrogen. The mixture was heated at 85 °C for 20 h and cooled to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined extracts were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel column to give D-1.

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

Table 65

Table 66

Table 67

Table 68

[0647] General method E

Chemical formula

[0648] To a solution of A-23 (1.0 eq.) and E1-1 (1.5 equivalents) in DMF (0.25 M), Cs2CO3 (2.0 eq.) was added and the mixture was stirred at 60 - 80 °C under nitrogen until the reaction was complete. Water (5 volumes of DMF) was added to the cooled DMF solution and the product was extracted 3 times with ethyl acetate (1 volume of water). The combined extracts were washed with water, aqueous HCl (1 N), brine and dried over magnesium sulfate. After filtration and concentration, the crude product was purified by silica gel column to give the pure product E-1.

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

[0650] General method F [Chemical formula]

[0651] To a solution of E-16 (1.0 eq.) in DCM (0.2 M), m-chloroperbenzoic acid (m-CPBA) (3 eq.) was added at 0 °C. The reaction mixture was warmed to ambient temperature and stirred for 4 hours. The mixture was quenched with an aqueous sodium thiosulfate solution (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 method G [Chemical formula]

[0653] Step 1. To a solution of A1-19 (1.0 eq.) in DCM (0.2 M) and Et3N (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 Na2SO4. 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 solution 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 an aqueous NaOH solution (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 by silica gel column chromatography to obtain G3-1.

[0655] Step 3. G3-1 was reacted with A2-2 according to General Method A to obtain 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 shown in the following table:

Table 73

[0657] General Method H

Chemical formula

[0658] Step 1. To a solution of A1-22 (1.0 eq.) and H1-1 (1.0 eq.) in DMF (0.2 M), DIPEA (3 eq.) and pentafluorophenyl diphenylphosphinate (FDPP) (1.1 eq) were added. 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 solution (1 N), saturated aqueous Na2CO3 solution, and brine, dried over Na2SO4, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain H2-1.

[0659] Step 2. H2-1 was reacted with A2-2 according to General Method A to obtain 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 shown in the table below:

Table 74

Table 75

Table 76

[0661] General Method I

Chemical formula

[0662] Step 1. To a DMF (0.2 M) solution of A1-31 (1.0 eq.) and D1-13 (1.0 eq.), DIPEA (3 eq.) and pentafluorophenyl diphenylphosphinate (FDPP) (1.1 eq) were added. 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 solution (1 N), saturated aqueous Na2CO3 solution, and brine, dried over Na2SO4, and concentrated. The resulting residue was purified by silica gel column to obtain I1-1.

[0663] Step 2. I1-1 was reacted with A2-2 according to General Method A to obtain 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 shown in the table below:

Table 77

Table 78

Table 79

[0665] General method J

Chem.

[0666] Step 1. To a MeOH (0.2 M) solution of C-1 (1.0 eq.), an aqueous solution of LiOH (3 eq) in H2O (1 M) was added. 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 pH about 4 - 5, and then extracted with CH2Cl2. The combined extracts were dried over Na2SO4, concentrated, and dried under reduced pressure. The resulting crude solid was dissolved in CH2Cl2 (0.2 M), and an HCl solution of dioxane (4 eq HCl) was added to the solution. The solution was stirred at 40 °C until de-Boc was complete. The solvent was removed under rotary evaporation, and the residue was dried under reduced pressure to obtain crude J-1, which was used in the next step without further purification.

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

[0668] Compounds 1 - 66 were prepared from the corresponding C-1 - C-66, Compounds 67 - 82 were prepared from D-1 - D-16, Compounds 83 - 98 were prepared from E-1 - E-16, Compound 99 was prepared from F-1, Compounds 100 - 103 were prepared from G-1 - G-4, Compounds 104 - 113 were prepared from H-1 - H-10, and Compounds 114 - 122 were prepared from I-1 - I-9 according to General method J.

[0669] General method K

Chem.

[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 Cs2CO3 (3 eq) in dioxane and H2O, Pd(PPh3)2Cl2 (0.1 eq) was added under nitrogen. The mixture was stirred at 100 °C for 16 h under N2, then cooled and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to obtain tert-butyl N-methyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate (K-1).

[0671] General method L

Chem.

[0672] To a solution of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (1 eq) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (1.5 eq) in dioxane (17 mL) were added Pd(dppf)Cl2 (0.1 eq) and aqueous Na2CO3 solution (2 M, 3.0 eq) under nitrogen. The mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. After completion, the mixture was concentrated under reduced pressure to obtain the title crude compound. The residue was purified by silica gel column to obtain tert-butyl N-methyl-N-[2-[[2-methyl-4-(2-oxoindolin-5-yl)pyrazol-3-yl]methoxy]ethyl]carbamate (L-1).

[0673] General method M

Chem.

[0674] To a 2-MeTHF 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), DIAD (2.2 eq) was added 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 by silica gel column to give tert-butyl N-methyl-N-[2-[2-(2-oxoindolin-5-yloxyethoxy)ethyl]carbamate (M-1).

[0675] General method N [Chemical formula]

[0676] Step 1. To a DCM solution of tert-butyl N-methyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate (1 eq), HCl / dioxane (4 M, 10 eq) was added and the resulting mixture was stirred at 25 °C for 1 h. 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] Engineering 2.5-[2-[2-[2-(methylamino)ethoxy]ethyl]pyrazol-3-yl]indolin-2-one HCl salt (0.34 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (1 eq) in acetonitrile solution, 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 and then filtered to obtain 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 method O

Chemical formula

[0679] Piperidine (2 eq) was added to an EtOH solution of N-1 (1 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 at 25 °C for 10 min to obtain 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) according to General Method A

Chemical formula

[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 A31 were prepared according to a method similar to that of 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 (B-I-2) by General Method B-I

Chem.

[0686] Procedure 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)2O (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 Na2SO4, 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] Procedure 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, PE solution with 0 - 40% EtOAc, eluting at about 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. 11H 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] In 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), (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) were added 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 and concentrated under reduced pressure, and purified by silica gel column (40 g, PE solution of 0 - 100% EA, eluted at about 35%) to obtain tert-butyl 3-[3-(tert-butoxycarbonylamino)propoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (B-I-2, 2.3 g, 2.9 mmol, 67.2% yield) as a white oil. 1 1H 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] Production of tert-Butyl N-[3-[1-Methyl-4-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-Yl)Pyrazol-3-Yl]Oxypropyl]Carbamate (B-I-5) by General Method B-I

Chemical Structure

[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), K2CO3 (14.79 g, 107.03 mmol, 1.5 eq) was added. 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 silica gel chromatography (PE:EA = 30:1~3:1) to obtain 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] 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. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column silica gel chromatography (PE:EA = 25:1~2:1) to give 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] 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 for 16 h under a nitrogen atmosphere. After 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 straw-colored oil. The crude product was purified by silica gel column (20 g, PE solution of 0~100% EtOAc, eluted at about 60% for 15 min) 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 (B-I-5, 2.9 g, 6.08 mmol, 68% yield) as a brown gum. LCMS: m / z 381.9 (M+1) +

[0694] Example 4

[0695] Production 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 [Chemical formula]

[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), tert-Butyl N-(3-bromopropyl)carbamate (11.9 g, 50.0 mmol, 1.1 eq) was added. 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 (SiO2, PE solution of 0 - 100% EtOAc, eluting with 25%) to obtain 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 (400 MHz, 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] Production 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 produced using a method similar to that for B-II-1.

[0700] Example 6

[0701] Production of [2-[2-[2-(tert-Butoxycarbonylamino)ethoxy]ethyl]pyrazol-3-yl]boronic acid (B-III-7) by General Method B-III [Chemical formula]

[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 NaHCO3 (80 mL) and brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain 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) were 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 obtain a crude product. The residue was purified by column chromatography (SiO2, 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, and then a solution of triisopropyl borate (2.21 g, 11.7 mmol, 2.70 mL, 1.5 eq) in 2-MeTHF (150 mL) was added at -70 °C. The mixture was stirred at 25 °C for 1.5 h. After completion, the mixture was quenched with MeOH (50 mL) and concentrated under reduced pressure, and purified by reverse-phase HPLC to give [2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl]pyrazol-3-yl]boronic acid (B-III-7, 500 mg, 18.1% yield) as a white powder. 11H 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] Production of [2-[2-[2-[tert-Butoxycarbonyl(methyl)amino]ethoxy]ethyl]pyrazol-3-yl]boronic acid (B-III-8) by General Method B-III

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

[0708] Production of [2-[2-[Benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino]ethyl]pyrazol-3-yl]boronic acid (B-III-9) [Chemical formula]

[0709] Procedure 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), MsCl (852 mg, 7.44 mmol, 1.2 eq.) was added 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 NaHCO3 (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] Procedure 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] 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 H2O (12 mL) were added NaHCO3 (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, PE solution with 0% - 100% EtOAc) 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 × 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) were added 1H-pyrazole (721 mg, 10.6 mmol, 1 eq.) and Cs2CO3 (6.91 g, 21.2 mmol, 2 eq.). The mixture was stirred at 50 °C for 3 h. 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, PE solution of 0% - 100% EtOAc) to give benzyl N-[2-(tert-butoxycarbonylamino)ethyl]-N-(2-pyrazol-1-ylethyl)carbamate (3.60 g, 7.88 mmol, 74.2% yield) as a pale yellow gum. LCMS: m / z 389.4 (M+1) +

[0714] Procedure 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), LDA (2 M, 6.18 mL, 3 eq.) was added dropwise at -70 °C under N2 atmosphere. The mixture was stirred at -70 °C for 0.5 h, then triisopropyl borate (1.55 g, 8.24 mmol, 2 eq.) was added. The resulting mixture was stirred at -70 °C for 1.5 h under N2 atmosphere. After completion, the mixture was quenched with MeOH (10 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with pure water (70 mL), and the aqueous phase was lyophilized. The residue was purified by reverse-phase preparative HPLC (0.5% FA as additive) to give [2-[2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino]ethyl]pyrazol-3-yl]boronic acid (B-III-9, 500 mg, 0.925 mmol, 22.4% yield) as a white solid. LCMS: m / z 433.4 (M+1) +

[0715] Example 8

[0716] Preparation of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]carbamate (B-V-1) and tert-butyl N-[2-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]methoxy]ethyl]carbamate (B-VI-1)

Chemical Structure

[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 LiAlH4 (1.65 g, 43.4 mmol, 1 eq). The mixture was stirred at 0 °C for 15 minutes, then quenched slowly 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 afford (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 hour. The mixture was quenched slowly 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 = 25:1~3:1) to afford 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] Procedure 3. A solution of 4-bromo-5-(bromomethyl)-1-methyl-pyrazole (1.00 g, 3.94 mmol, 1 eq) in THF (2 mL) was added with tert-butyl N-(2-hydroxyethyl)carbamate (952 mg, 5.91 mmol, 0.915 mL, 1.5 eq), tetrabutylammonium iodide (145 mg, 0.394 mmol, 0.1 eq) and KOH (663 mg, 11.8 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h under N2. 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 Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 3 / 1) to give tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]carbamate (B-V-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] To a solution of 4-tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methoxy]ethyl]carbamate (1.00 g, 2.99 mmol, 1 eq), KOAc (880 mg, 8.98 mmol, 3 eq) and Pin2B2 (11.4 g, 44.9 mmol, 15 eq) in dioxane (10 mL) was added [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (235 mg, 0.299 mmol, 0.1 eq) at 25 °C under nitrogen. The mixture was stirred at 60 °C for 12 h under N2. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column silica gel chromatography (PE:EA = 25:1~3:1) 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 (B-V-2)

Chemical Structure

[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, and then CH3I (407.71 mg, 2.87 mmol, 1.5 eq) was added. The mixture was stirred at ambient temperature for 1.5 h. After completion, the mixture was poured into ice water (40 mL), extracted with EtOAc (80 mL), and washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (PE:EA = 100:0~100:35) 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 (B-V-3)

Chemical Structure

[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 mixture was stirred at 25 °C for 0.5 h, cooled to 0 °C, and treated with NaBH(OAc)3 (7.66 g, 36.1 mmol, 1.5 eq). The mixture was stirred at 25 °C for 13 h, quenched with water (100 mL), and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 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 NaHCO3 (1.99 g, 23.7 mmol, 3 eq) in H2O (20 mL) was added CbzCl (1.75 g, 10.3 mmol, 1.46 mL, 1.3 eq). The mixture was stirred at 20 °C for 16 h, quenched with water (80 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 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 (B-V-3, 2.89 g, 5.83 mmol, 73.9% yield) as a colorless oil. 11H 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] Production of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (B-V-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)

Chemical formula

[0730] To a solution of tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methylamino]ethyl]-N-methyl-carbamate (3.30 g, 9.50 mmol, 1 eq), (CH2O) n (1.70 g, 18.9 mmol, 1.99 eq) and AcOH (2.10 g, 34.9 mmol, 2 mL, 3.68 eq) in MeOH (80 mL) was added NaBH3CN (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 NH4Cl (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 = 1:0~100:40) to give tert-butyl N-[2-[(4-bromo-2-methyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (B-V-4, 3 g, 8.30 mmol, 87% yield) as a colorless gum.1 1H 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]

Chem.

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

Chem.

[0733] B-V-5 was prepared using a method similar to that for B-V-3.1 1H 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] Production of tert-butyl N-[2-[(4-bromo-5-methyl-isoxazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (B-V-6)

Chemical Structure

[0735] B-V-6 was produced starting from (5-methylisoxazol-3-yl)methanol using a method similar to that for B-V-2. 1 1H 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] Production of tert-butyl N-[2-[benzyloxycarbonyl-[(4-bromo-5-methyl-isoxazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate (B-V-7)

Chemical Structure

[0737] Procedure 1. To a solution of (5-methylisoxazol-3-yl)methanol (10.0 g, 88.0 mmol, 1 eq.) in DCM (100 mL) was added MnO2 (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 afford 5-methylisoxazole-3-carbaldehyde (6.50 g, 35.0 mmol, 39.71% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ = 10.12 (s, 1H), 6.40 (s, 1H), 2.53 (s, 3H)

[0738] Procedure 2. To a solution of 5-methylisoxazole-3-carbaldehyde (6.50 g, 58.0 mmol, 1 eq.) and tert-butyl N-(2-aminoethyl)-N-methyl-carbamate (11.2 g, 64.4 mmol, 11.5 mL, 1.1 eq.) in DCE (50 mL) were added AcOH (3.50 g, 58.0 mmol, 1 eq) and NaBH(OAc)3 (24.8 g, 117 mmol, 2 eq). The mixture was stirred at 25 °C for 16 h. After completion, 50 mL of water was added and the reaction mixture was extracted with EtOAc (3 × 50 mL). The combined extracts were concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM / MeOH, 100:0 - 100:10) to afford 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] In a solution of 3. tert-Butyl N-methyl-N-[2-[(5-methylisoxazol-3-yl)methylamino]ethyl]carbamate (1.20 g, 4.50 mmol, 1 eq.), benzyl chloroformate (912 mg, 5.30 mmol, 1.2 eq.) in THF (10 mL) and H2O (10 mL), NaHCO3 (1.10 g, 13.4 mmol, 3 eq.) was added. The mixture was stirred at 25 °C for 16 h. After completion, the reaction was extracted with EtOAc (3 × 10 ml) and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc, 100:1 - 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] 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 and concentrated under reduced pressure, and purified by silica gel column (petroleum ether:EtOAc, 100:0 to 100:30) to give tert-butyl N-[2-[benzyloxycarbonyl-[(4-bromo-5-methyl-isoxazol-3-yl)methyl]amino]ethyl]-N-methyl-carbamate (B-V-7, 320 mg, 630 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 (B-V-8)

Chemical Structure

[0742] Procedure 1. To a mixture of 2,5-dimethylpyrazole-3-carbaldehyde (2.00 g, 16.1 mmol, 1 eq) and tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (4.55 g, 24.2 mmol, 1.5 eq) in DCE (2 mL), AcOH (967 mg, 16.1 mmol, 1 eq) was added. After 0.5 h at 25 °C, NaBH(OAc)3 (10.2 g, 48.3 mmol, 3 eq) was added at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction was quenched by pouring the mixture into water and then extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel (DCM:MeOH = 25:1 to 10:1) to give tert-butyl N-[2-[(2,5-dimethylpyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (1.80 g, 5.82 mmol, 36% yield) as a yellow oil. 1 H NMR (400 MHz, 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] 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), NBS (1.22 g, 6.88 mmol, 1.2 eq) was added at 25 °C. The mixture was stirred at 60 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel (DCM:MeOH = 25:1~10:1) to give tert-butyl N-[2-[(4-bromo-2,5-dimethyl-pyrazol-3-yl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (M-V-8, 1.3 g, 3.38 mmol, 58.9% yield, 97.5% purity) as a yellow oil. 1 H NMR (400 MHz, 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 (B-V-9)

Chemical formula

[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 (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% - 100% MeOH solution in DCM) to give tert-butyl N-[2-[(2-bromophenyl)methyl-methyl-amino]ethyl]-N-methyl-carbamate (M-V-9, 3.50 g, 8.82 mmol, 81.5% yield) as a colorless gum. LC-MS: m / z 357.9 (M+1) +

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

Chemical Structure

[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. To the residue was added 1,4-dioxane (300 mL), 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). 11H 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) was added NaH (1.11 g, 27.8 mmol, 60% purity, 1.5 eq) at 0 °C under N2. The mixture was stirred for 0.5 h, and then MeI (3.95 g, 27.8 mmol, 1.5 eq) was added at 0 °C. The mixture was stirred at 25 °C for 1 h, water was slowly added to quench the reaction, and the mixture was 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 1H 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] To a solution of tert-butyl N-[3-(2,5-dimethylpyrazol-3-yl)oxypropyl]-N-methyl-carbamate (6 g, 21.2 mmol, 1 eq) in ACN (30 mL) was added NBS (3.77 g, 21.2 mmol, 1 eq) at 25 °C, and the mixture was stirred under N2 for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column silica gel chromatography (PE:EA = 25:1 to 2:1) to give tert-butyl N-[3-(4-bromo-2,5-dimethyl-pyrazol-3-yl)oxypropyl]-N-methyl-carbamate (B-V-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 (B-V-11)

Chemical formula

[0751] To a solution of ethyl 2,5-dimethylpyrazole-3-carboxylate (10 g, 59.4 mmol, 1 eq) in DCE (200 mL) was added NBS (12.7 g, 71.3 mmol, 1.2 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column silica gel 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. 11H 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 LiAlH4 (1.60 g, 42.1 mmol, 1.1 eq). The mixture was stirred at 0 °C for 0.5 h and quenched by slowly adding water (0.086 ml), aqueous sodium hydroxide solution (15%, 1.65 mL) and water (4.8 mL). The reaction mixture was filtered and concentrated under reduced pressure to give (4-bromo-2,5-dimethyl-pyrazol-3-yl)methanol (6.5 g, 31.7 mmol, 82.8% yield) as a colorless oil. 1 1H 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 slowly adding 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 silica gel chromatography (PE:EA = 25:1 - 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] Procedure 4. To a solution of 4-bromo-5-(bromomethyl)-1,3-dimethyl-pyrazole (4 g, 14.9 mmol, 1 eq) in THF (80 mL) were added tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (2.88 g, 16.4 mmol, 1.1 eq), TBAI (551.40 mg, 1.49 mmol, 0.1 eq) and KOH (2.51 g, 44.8 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h under N2. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 1 / 1) to give tert-butyl N-[2-[(4-bromo-2,5-dimethyl-pyrazol-3-yl)methoxy]ethyl]-N-methyl-carbamate (B-V-11, 5.5 g, 14.6 mmol, 97.6% yield) as a yellow oil. 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 (B-V-12)

Chemical Structure

[0756] B-V-12 was prepared starting from 5-cyclopropylisoxazole-3-carboxylic acid using a method similar to that for B-V-1. The bromination procedure was analogous to that of B-V-7. 11H 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 (B - V - 13)

Chemical Structure

[0758] B - V - 13 was prepared using a method similar to that of B - V - 1 starting from ethyl 5 - isopropylisoxazole - 3 - carboxylate. The bromination procedure is analogous to that of B - V - 7. 1 1H 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 (B - V - 14)

Chemical Structure

[0760] B - V - 14 was prepared using a method similar to that of B - V - 10 starting from 2 - methylpyrazol - 3 - ol. 11H 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] Production 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

Chemical Structure

[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 H2O (1 mL), Cs2CO3 (1.61 g, 4.94 mmol, 3 eq) and Pd(PPh3)2Cl2 (115 mg, 0.165 mmol, 0.1 eq) were added. The resulting mixture was stirred at 90 °C for 14 h under a N2 atmosphere. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 100:1 to 20:1) to obtain 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 for C-6a.

Table 81

Table 82

[0764] Production 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]oxazacyclopentadecine-3,8(2H,5H)-dione (6) by the general method J

Chemical formula

[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 H2O (0.4 mL) was added LiOH·H2O (206 mg, 4.93 mmol, 15 eq). The resulting mixture was stirred at 50 °C for 15 h. After 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 solution to precipitate the product. The solid was filtered and triturated with MeOH (15 mL) at 25 °C for 5 min to obtain 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 at 25 °C for 2 h. 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) were 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. After completion, the reaction was quenched with H2O (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). 11H NMR (400 MHz, DMSO-d6) δ (ppm) 13.58 (s, 1H), 12.15 (s, 1H), 11.12 (s, 1H), 8.94 (s, 1H), 8.54 - 8.47 (m, 1H), 8.11 (s, 2H), 8.03 (d, J = 1.6 Hz, 1H), 7.35 (t, J = 2.4 Hz, 1H), 6.83 (s, 1H), 4.43 (t, J = 6.4 Hz, 2H), 3.75 (s, 2H), 2.22 (s, 2H); LCMS m / z 377.4 (M+1) +

[0768] Examples 7, 11, 14, 22, 24, 39 and 123 were prepared according to a method similar to 6.

Table 83

Table 84

[0769] Production 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

Chemical formula

[0770] A mixture of [2-[2-[2-[(tert-Butoxycarbonyl)(methyl)amino]ethoxy]ethyl]pyrazol-3-yl]boronic acid (588 mg, 1.88 mmol, 1 eq), 5-bromoindolin-2-one (517 mg, 2.44 mmol, 1.3 eq) and Cs2CO3 (1.84 g, 5.63 mmol, 3 eq) in dioxane (10 mL) and H2O (2 mL) was added with Pd(PPh3)2Cl2 (131 mg, 0.187 mmol, 0.1 eq) under nitrogen. The mixture was stirred at 100 °C for 16 h under N2, then cooled and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM / MeOH = 30 / 1 to 10 / 1) to give tert-butyl N-methyl-N-[2-[2-[5-(2-oxoindolin-5-yl)pyrazol-1-yl]ethoxy]ethyl]carbamate (K-1, 150 mg, 17% yield) as a yellow oil. 1 H NMR (400 MHz, 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 method similar to that of 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 [Chemical formula]

[0773] 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 with Pd(dppf)Cl2 (125 mg, 0.172 mmol, 0.1 eq) and aqueous Na2CO3 solution (2 M, 2.58 mL, 3.0 eq) under nitrogen. The mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. After completion, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column (DCM:MeOH = 100:0~100:5) to obtain 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 prepared 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) [Chemical formula]

[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)2 (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, H2O (5 mL) was added, and the mixture was partitioned. The organic phase was separated, washed with H2O (10 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give ethyl 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]acetate (13.0 g, crude) 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 LiAlH4 (1.31 g, 34.4 mmol, 1.5 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 2 h. After completion, the reaction was quenched with water (1 mL), followed by addition of aqueous NaOH (15%, 3 mL) and H2O (3 mL). Na2SO4 was added to the combined mixture, and the mixture was stirred 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 - 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. 11H 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] Production of tert-butyl N-[2-[(2R)-2-hydroxypropoxy]ethyl]-N-methyl-carbamate (M5)

Chemical Structure

[0779] Step 1. To a mixture of methyl (2R)-2-hydroxypropanoate (20.0 g, 192 mmol, 1 eq.) and benzyl 2,2,2-trichloroethanimidate (51.0 g, 202 mmol, 1.05 eq.) in a solution of 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 by silica gel column (petroleum ether:EtOAc, 100:1 - 100:3) to obtain methyl (2S)-2-benzyloxypropanoate (8.00 g, 37.0 mmol, 19% yield) as a colorless oil. 1 1H 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 = 6.8 Hz, 3H)

[0780] Procedure 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 quenched with water (2.3 mL) slowly at 0 °C, then with 15% aqueous NaOH solution (2.3 mL) and water (7.0 mL). After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column (petroleum ether:EtOAc, 100:0~100:40) to give (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] Procedure 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 by silica gel column (DCM:MeOH, 100:0~100:2) to give 2-[(2R)-2-benzyloxypropoxy]-N-methyl-acetamide (4.50 g, 17.0 mmol, 40.5% yield) as a colorless oil.

[0782] 11H 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] Procedure 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), LAH (959 mg, 25.3 mmol, 1.5 eq.) was slowly added at 0 °C. The mixture was stirred at 60 °C for 2 h. 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] Procedure 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)2O (4.42 g, 20.3 mmol, 1.2 eq.) and TEA (2.56 g, 25.3 mmol, 1.5 eq.) in DCM (50 mL) was stirred at 20 °C for 16 h. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column (petroleum ether:EtOAc, 100:0~100:10) to afford 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] Procedure 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)2 (825 mg, 1.17 mmol, 20% purity, 0.1 eq) under a nitrogen atmosphere. The mixture was stirred at 25 °C under 50 Psi H2 for 16 h. After completion, the mixture was filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column (petroleum ether:EtOAc, 100:0~100:30) 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] Production of Methyl (2R)-3-[tert-butoxycarbonyl(methyl)amino]-2-(2-hydroxyethoxy)propanoate (M6) [Chemical formula]

[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 that the main peak had the desired MS. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (220 g silica gel column, PE solution with 0% - 100% EtOAc) to obtain 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, PE solution of 0% - 100% EtOAc) 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, DCM solution of 0% - 30% MeOH) to give 2-[(1R)-1-[[benzyl(methyl)amino]methyl]-2-methoxy-2-oxo-ethoxy]acetic acid (8.30 g) as a brown oil. 11H 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 Hz, 1H), 3.75 (s, 3H), 3.66 (d, J = 13.2 Hz, 1H), 3.58 (d, J = 13.2 Hz, 1H), 2.90 - 2.88 (m, 2H), 2.30 (s, 3H), 1.49 (s, 9H); LC-MS: m / z 282.4 (M+1) +

[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, PE solution of 0% - 100% EtOAc, EtOAc solution of 0% - 100% MeOH) 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 H2 (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 Et3N (3.08 g, 30.5 mmol, 4.24 mL, 2 eq.) in DCM (30 mL) were added DMAP (186 mg, 1.52 mmol, 0.1 eq.) and Boc2O (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 combi-flash (20 g silica gel column, PE solution of 0% - 100% EtOAc) 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)

Chemical Structure

[0794] 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 phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1~20 / 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 1H 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] Procedure 2. To a mixture of tert-butyl N-[2-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfanyl]ethyl]carbamate (5.5 g, 16.4 mmol, 1 eq) in THF (90 mL) was added NaH (983 mg, 24.6 mmol, 60% purity, 1.5 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min under N2, and then CH3I (3.49 g, 24.6 mmol, 1.5 eq) was added dropwise. The reaction mixture was stirred at 25 °C for 6 h under N2. After completion, the mixture was quenched with water (10 mL), then diluted with H2O (90 mL) and extracted with EtOAc 90 mL (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1~10 / 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] 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 (100 mL) at 0 °C, then diluted with H2O (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 - 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)

Chemical Structure

[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 × 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% - 100% MeOH solution in DCM) 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 H2O (20 mL) were added CbzCl (1.80 g, 10.5 mmol, 1.50 mL, 1.3 eq) and NaHCO3 (2.05 g, 24.3 mmol, 947 μL, 3 eq). The mixture was stirred at 25 °C for 16 h. After completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (40.0 g silica gel column, 0% - 100% EA solution in PE) 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. 11H 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] 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 × 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% - 100% MeOH solution in DCM) to give tert-butyl N-[2-[benzyloxycarbonyl(2-hydroxyethyl)amino]ethyl]-N-methyl-carbamate (M9, 500 mg, 1.21 mmol, 56.2% yield) as a colorless gum. 1 1H 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] Production of tert-butyl N-[2-[2-(6-chloro-2-oxo-indolin-5-yl)oxyethyl-methyl-amino]ethyl]-N-methyl-carbamate (M10) [Chemical formula]

[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 × 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% - 100% MeOH solution in DCM) 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] 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 × 180 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (180 g silica gel column, 0% - 100% MeOH solution in DCM) 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) according to General Method M

Chemical Structure

[0805] 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 with 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 (DCM:MeOH = 100:0~100:3) to obtain 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 of 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)

Chemical formula

[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 H2O (5 mL). The organic phase was separated, washed with H2O (5 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by 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) were added K2CO3 (303 mg, 2.20 mmol, 1.1 eq) and 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]ethyl 4-methylbenzenesulfonate (597 mg, 1.60 mmol, 0.8 eq). The mixture was stirred at 25 °C for 2 h under N2 atmosphere and partitioned with H2O (10 mL) and EtOAc (10 mL). The organic phase was separated, washed with brine (5 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give tert-butyl N-methyl-N-[2-[2-(2-oxoindolin-5-yl)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) [Chemical formula]

[0811] M-2s was prepared using 6-chloro-5-sulfanylindolin-2-one by a method similar to that for M-1s. 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) according to General Method N

Chemical Structure

[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) was added HCl / dioxane (4 M, 0.94 mL, 10 eq), and the resulting mixture was stirred at 25 °C for 1 h. 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] Engineering 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) solution, 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) 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 (DCM:MeOH = 30:1~10:1). The crude product was triturated with MeOH (5 mL) at 25 °C for 10 min and then filtered to obtain 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 1H 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 similar to that of 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] Production 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]oxadiazacyclohexadecine-4,19(5H,18H)-dione (41) by the general method O

Chemical formula

[0817] Piperidine (43.0 mg, 0.50 mmol, 2 eq) was added to a solution of N-1 (110 mg, 0.25 mmol, 1 eq) in EtOH (30 mL). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure. The crude product was triturated with MeOH (5 mL) at 25 °C for 10 minutes to give 41 (42.2 mg, 0.100 mmol, 40% yield) as an orange solid. 11H 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 a method similar to 41. For 42, 125, 127, 139, 145, 160 and 163, the Cbz protecting group was removed after the cyclization step as follows:

Chemical Structure

[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 obtain a solid. The solid was suspended in DCM / MeOH (10:1), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (DCM:MeOH = 1:0 - 100:7) to obtain 125 (3.3 mg, 6.4% yield) as an orange powder.

[0820] For 133 - 138, the ester 132 was hydrolyzed followed by amide coupling with the corresponding amine, and the amide was synthesized after deprotection of the Boc protecting group if necessary as follows:

Chem.

[0821] Step 1. To a solution of 132 (100 mg, 0.217 mmol, 1 eq.) in THF (1 mL), MeOH (1 mL) and H2O (0.5 mL), LiOH·H2O (27.4 mg, 0.652 mmol, 3 eq.) was added. 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), HATU (51.2 mg, 0.135 mmol, 1.2 eq.) was added 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 layers were 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), TFA (1 mL) was added. 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% - 20% MeOH in DCM solution) to give 133 (7.99 mg) as a yellow solid.

[0824] 144 was oxidized to give 148 and 149 as follows, respectively:

Chem.

[0825] 125 was converted to 152 or 156 by a reductive amination reaction using acetaldehyde or acetone as follows for 152:

Chemical formula

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

Chemical formula

[0827] To a mixture of 154 (20 mg, 0.052 mmol, 1 eq) in DCM (3 mL), m-CPBA (22.0 mg, 0.104 mmol, 85% purity, 2 eq) was added at 0 °C. The mixture was stirred at 25 °C for 1 h, saturated NaHCO3 (1 mL) was added to quench the reaction, and then extracted with DCM (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 100 / 0~30 / 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]dioxazacyclopentadecine-4,16(5H,15H)-dione (159) [Chemistry]

[0829] Engineering 1. To a mixture of ethyl 1H-pyrazole-4-carboxylate (20.0 g, 142 mmol, 1.0 eq) and K2CO3 (39.4 g, 285 mmol, 2.0 eq) in MeCN (250 mL) at 0 °C, MOMCl (18.1 g, 225 mmol, 1.5 eq) was added. 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 a crude product, which was purified by silica gel column (PE:EA = 2:1) to give ethyl 1-(methoxymethyl)pyrazole-4-carboxylate (17.1 g, 83 mmol, 59% yield) as 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] Procedure 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 minutes. 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 minutes. Anhydrous DMF (35.72 g, 488 mmol, 10.0 eq) was added to the mixture with further stirring at -70 °C for 1 hour. 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 obtain a crude product. The crude product was purified by silica gel column (PE:EA = 100:15) to give ethyl 5-formyl-1-(methoxymethyl)pyrazole-4-carboxylate (4.0 g, 16.96 mmol, 34.72% yield) as 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] Procedure 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) were added 6-chloro-5-[2-[2-(methylamino)ethoxy]ethoxy]indolin-2-one (M-4-deboc, 120.76 mg, 0.424 mmol, 1.0 eq) and piperidine (144 mg, 1.70 mmol, 4.0 eq). The mixture was stirred at 80 °C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain a 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 H2O (8.0 mL) was added LiOH·H2O (105 mg, 2.51 mmol, 12.0 eq). The mixture was stirred at 20 °C for 16 h. After completion, the mixture was concentrated 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), then 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 by 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, adjusted to neutral pH with saturated NaHCO3, and then lyophilized. The residue was purified by silica gel column (DCM:MeOH = 100:5) to give 159 (2.05 mg, 5.27 μmol, 11.4% yield) as a yellow solid. 11H 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] [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]oxadiazacyclopentadecine-4,16(1H,15H)-dione (164) Preparation

Chemical Structure

[0836] Step 1. HCl / dioxane (4M, 18.8 mL, 20 eq) was added 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). The mixture was stirred at 25 °C for 2 h. After completion, the mixture was concentrated to obtain M-10-deboc HCl salt, which was used directly in the next step. LCMS: m / z 298.0 (M+1) +

[0837] Procedure 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) were 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% - 100% MeOH solution in DCM) to give 164 (10.7 mg, 2.09% yield) as an orange solid. 1 H NMR (400 MHz, DMSO-d6) δ = 11.48 (d, J = 0.8 Hz, 1H), 10.61 (s, 1H), 8.41 (s, 1H), 7.39 (s, 1H), 6.83 (s, 1H), 6.22 (d, J = 1.8 Hz, 1H), 4.75 - 4.62 (m, 1H), 4.40 - 4.28 (m, 2H), 3.31 (s, 3H), 2.82 (s, 4H), 2.67 (s, 1H), 2.39 (s, 3H), 2.21 (s, 3H). LCMS: m / z 415.1 (M+1) +

[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)

Chem.

[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) was added K2CO3 (4.28 g, 31.0 mmol, 1.2 eq) portionwise at 0 °C, and the mixture was 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 obtain a crude product. The crude product was purified by silica gel column chromatography 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) was added NaH (1.09 g, 27.4 mmol, 60% purity, 2 eq), and the mixture was stirred at 0 °C. Subsequently, dimethyl 2-(4-cyano-5-fluoro-2-nitrophenyl)propanedioate (3.65 g, 12.3 mmol, 0.9 eq) was added. The mixture was stirred at 20 °C for 30 min and heated at 80 °C for 2 h. The reaction mixture was quenched by adding H2O (80 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous Na2SO4, filtered, and dried. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 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 at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford 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 by addition of H2O (10 mL), and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and dried. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1) to afford Compound 168-5 (140 mg, 0.251 mmol, 45.1% yield) as a yellow oil. LCMS: m / z 531.1 (M+1) +

[0843] Procedure 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 afford 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, 3H), 3.93 - 3.75 (m, 3H), 3.69 (s, 1H), 3.01 (dd, J = 4.8, 14.4 Hz, 1H), 2.82 (s, 3H), 2.42 (s, 3H); LCMS: m / z 393.2 (M+1) +

[0845] Preparation of [3a(4)Z]-6,9,12,14-tetramethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-3,8(2H,5H)-dione (172)

Chemical Structure

[0846] Step 1. To a solution of dimethyl propanedioate (4.11 g, 31.0 mmol, 1.2 eq) in THF (80 mL) was added NaH (1.24 g, 31.09 mmol, 60% purity, 1.2 eq) portionwise at 0 °C. The mixture was stirred for 1.0 h, and then 2,4-dichloro-5-nitro-pyridine (5.0 g, 25.9 mmol, 1.0 eq) was added portionwise. 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. The residue was purified by silica gel column (PE:EA = 100:0~100:30) 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 Na2CO3 (2 M, 3.12 mL, 3.0 eq) in dioxane (8.0 mL) was added Pd(dppf)Cl2 (152 mg, 0.207 mmol, 0.1 eq). The mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. After completion, the mixture was concentrated under reduced pressure and purified by silica gel column (DCM:MeOH = 100:2) to give 172-3 (800 mg, 1.50 mmol, 71.9% yield) as a red to brown gum. LCMS: m / z 535.4 (M+1) +

[0848] Step 3. To a solution of 3.172-3 (350 mg, 654 μmol, 1.0 eq) in DCM (10 mL) was added HCl / dioxane (4 M, 1.64 mL, 10 eq). The mixture was stirred at 20 °C for 1 h. After completion, the mixture was concentrated under re...

Claims

1. Formula I 【Chemical 1】 〔wherein, A is a 5- to 10-membered heteroarylene or C ６ -C １０ arylene; Each L is independently -C(R ３ )(R ４ )-, -C(O)-, -O-, -N(R ５ )-, -S-, -S(O)- or -S(O) ２ -, provided that (L) ｎ does not contain an -O-O-, -O-S- or -O-N(R ５ )- bond; X is N or C(R ６ ), 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 each independently is 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 each hydrogen atom in the 3- to 7-membered heterocycloalkylene, C ３ -C ６ cycloalkylene, C ６ -C １０ arylene and 5- to 10-membered heteroarylene may independently be optionally 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 and is substituted with; Z １ is -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 is 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 aryl or 5- to 10-membered heteroaryl 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 and is substituted with; R ２ 、R ５ 、R １１ or R １４ each of which is independently 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- to 10-membered heteroaryl, where each hydrogen atom in 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- to 10-membered heteroaryl may independently be 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 and 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 、-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 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 、 -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 is or R ３ 、 R ４ 、 R １２ and R １３ two of which, together with one or more carbons to which they are attached, form C ３ -C ６ cycloalkyl or 4-6 membered heterocycloalkyl, where C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, 3-7 membered heterocycloalkyl, C ６ -C １０ aryl, 5-10 membered heteroaryl or 4-6 membered heterocycloalkyl, each hydrogen atom in which 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 is substituted; R ６ is 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 , -NR ２ S(O) 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)RR ａ R ｂ , -P(O) ２ R ａ R ｂ , -P(O)NRR ａ R ｂ , -P(O) ２ NR ａ R ｂ , -P(O)OR ａ , -P(O) ２ OR ａ , -CN or -NO ２ 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 aryl or 5- to 10-membered heteroaryl, each hydrogen atom 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 is substituted; provided that one of R ７ or R ８ is a bond to Z; R ９ and R １０ each independently is 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 , -NR 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; or R ８ and R ９ or R ９ and R １０ are combined with the carbon atom to which they are attached to form C ４ -C ６ cycloalkyl, 4- to 7-membered heterocycloalkyl or C ６ -C １０ aryl, where each hydrogen atom in 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 aryl, 5- to 10-membered heteroaryl or 4- to 7-membered heterocycloalkyl may independently be 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 is substituted; Each R ａ 、R ｂ 、R ｃ 、R ｄ 、R ｅ and R ｆ are independently selected from the group consisting of 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, C １ -C ６ alkyl-C ６ -C １０ aryl and 5- to 10-membered heteroaryl; m is 0, 1, 2, 3 or 4; and n is 2, 3, 4, 5, 6, 7 or 8.〕 The compound or a pharmaceutically acceptable salt thereof.

2. Formula IV [Chemical 2] The compound according to Claim 1, or a pharmaceutically acceptable salt thereof, having

3. The compound according to any one of Claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene or triazinylene.

4. A is [Chemical Formula 3] and wherein 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 each hydrogen atom in C １ -C ６ 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 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted with

5. R ２ is H or C １ -C ６ alkyl, where each hydrogen atom in the C １ -C ６ 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 , -NR ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ , -NR 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 The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, which is substituted by

6. Z is pyrazolylene, triazolylene, oxazolylene, thiazolylene, pyridinylene, pyrimidinylene or pyridine-2-onylene, where each hydrogen atom in pyrazolylene, triazolylene, oxazolylene, thiazolylene, pyridinylene, pyrimidinylene and pyridine-2-onylene 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 A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which is substituted with

7. The compound according to any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein n is 5.

8. Each L is independently selected from the group consisting of —C(O)—, —O—, —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 —, and is a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. wherein X is C(R ６ ), a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Y is O.

11. Y １ A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein Y is O.

12. Y ２ is -N(R １１ )-, a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

13. X １ is C(R ７ ), X ３ is C(R ９ ), X ４ is C(R １０ ), a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

14. -(L) ｎ - is -(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 -, -NHCOCH ２ O(CH ２ ) ２ -, -N(CH ３ )-COCH 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 - 1. -CH ２ N(CH ２ CH ３ ))-(CH ２ ) ２ - 2. -CH ２ N(CH(CH ３ ))-(CH ２ ) ２ - 3. -(CH ２ ) ２ N(CH ３ )-(CH ２ ) ２ - 4. -CH ２ CH(CH ３ ))-N(CH ３ )-(CH ２ ) ２ - or -O-CH(CH ３ ))-CH ２ N(CH ３ )-(CH ２ ) ２ - is a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. The compound according to Claim 1 or a pharmaceutically acceptable salt thereof, 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]oxadiazacyclopentadecine-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]oxadiazacyclopentadecine-3,8(2H,5H)-dione; [3a(4)Z]-9,10,11,12-tetrahydro-14H-1,17-(diazanediylidene)pyrazolo[4,3-n]dipyrrolo[3,2-g:3’,4’-j][1,5]oxazacyclopentadecine-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]oxadiazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-9,10,11,12-Tetrahydro-14H-17,1-(azenomethano)pyrazolo[4,3-n]dipyrrolo[3,2-g:3’,4’-j][1,5]oxazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-9,10,11,12-Tetrahydro-14H-1,17-(azenomethano)pyrazolo[4,3-n]dipyrrolo[3,2-g:3’,4’-j][1,5]oxazacyclopentadecin-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]oxazacyclopentadecin-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]oxadiazacyclopentadecin-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]dioxadiazacycloheptadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecin-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]oxadiazacyclopentadecine-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]oxatriazacyclohexadecine-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-(azomethano)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-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]oxadiazacyclopentadecine-3,8(5H,9H)-dione; [3a(4)Z]-6-Methyl-10,11,13,14-tetrahydro-2H-17,1-(azomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]oxazacyclopentadecine-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]oxazacyclopentadecine-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]oxazacyclopentadecine-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]oxazacyclopentadecin-3,8(5H,9H)-dione; [3a(4)Z]-6-Methyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-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]triazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-6-Methyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-6,9-Dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[3,4-f]dipyrrolo[3,4-j:2',3'-m][1,4,9]triazacyclopentadecin-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]triazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-6,9-Dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3',4'-i][1,4]diazacyclopentadecin-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]diazacyclopentadecin-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]diazacyclopentadecin-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]diazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-6,9,20-Trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-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]triazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-6,16-Dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-6,9,16-Trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-16-Cyclopropyl-6,9-dimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-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]triazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-6,9,16-Trimethyl-10,11,12,13-tetrahydro-2H-17,1-(azenomethano)[1,2]oxazolo[4,5-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-3,8(5H,9H)-dione; [3a(4)Z]-6,9,16-Trimethyl-10,11,12,13-tetrahydro-2H-17,1-(azenomethano)[1,2]oxazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-3,8(5H,9H)-dione; [3a(4)Z]-6,14-Dimethyl-10,11,13,14-tetrahydro-2H-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]oxazacyclopentadecin-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]oxazacyclopentadecin-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]diazacyclopentadecin-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]diazacyclopentadecin-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]diazacyclopentadecin-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]oxazacyclopentadecin-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]diazacyclopentadecin-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]diazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-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]diazacyclopentadecin-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]diazacyclopentadecin-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]oxazacyclopentadecin-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]diazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-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]oxazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-6,9,12,14-Tetramethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-3,8(2H,5H)-dione; [3a(4)Z]-9,12,14-Trimethyl-9,10,11,12,13,14-hexahydro-17,1-(azenomethano)pyrazolo[4,3-m]dipyrrolo[3,2-f:3’,4’-i][1,4]diazacyclopentadecin-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]triazacyclopentadecin-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]triazacyclopentadecin-3,8(2H,5H)-dione.

16. A compound of claim 1 or a pharmaceutically acceptable salt thereof, 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; [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-(azenomethano)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]benzodiazacyclopentadecine-3,8(5H,9H)-dione.

17. A compound of Claim 1 or a pharmaceutically acceptable salt thereof, 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-(azenomethano)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.

18. A compound according to 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-(azenomethano)tripyrrolo[1,2-a:3',2'-i:3'',4''-l][1,4,7]triazacyclopentadecine-3,8(5H,9H)-dione; [3a(4)Z,13aR]-6-Methyl-9,10,11,12,13,13a,14,15-octahydro-17,1-(azenomethano)azeto[1,2-a]dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecine-3,8(2H,5H)-dione; [16a(17)Z]-2,11-Dimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azenomethano)dipyrrolo[3,4-g:2',3'-j][1,4,6,13]oxatriazacyclopentadecine-4,16(5H,15H)-dione; [16a(17)Z]-2,5,11-Trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azanonamethylene)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclopentadecine-4,16(5H,15H)-dione; [17a(18)Z]-2,12-Dimethyl-6,7,9,10,11,12-hexahydro-1H-13,15-(azanonamethylene)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-(azanonamethylene)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-(azanonamethylene)dipyrrolo[3,2-f:3',4'-i][1,4,11,13]oxatriazacyclohexadecine-4,17(5H,16H)-dione; [16a(17)Z]-2,5,11-Trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azanonamethylene)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecine-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]tetraazacyclopentadecine-4,16(5H,15H)-dione; [16a(17)Z]-2,5,11-Trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azanonamethylene)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecine-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]tetraazacyclopentadecine-4,16(5H,15H)-dione; [16a(17)Z]-11-Cyclopropyl-2-methyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azanonemethano)dipyrrolo[3,2-k:3',4'-n][1,3,6,9]tetraazacyclopentadecine-4,16(5H,15H)-dione; [10R,16a(17)Z]-2,5,10-Trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azanonemethano)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecine-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-Trimethyl-6,7,8,9,10,11-hexahydro-1H-12,14-(azanonemethano)dipyrrolo[3,2-i:3',4'-l][1,4,7]triazacyclopentadecine-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-Trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azanonemethano)dipyrrolo[3,2-f:3',4'-i][1,4,13]oxadiazacyclopentadecine-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-Trimethyl-6,7,10,11-tetrahydro-1H,9H-12,14-(azanonemethano)dipyrrolo[3,4-g:2',3'-j][1,4,6,13]oxatriazacyclopentadecine-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-Trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azanonemethano)dipyrrolo[3,2-i:3',4'-l][1,4,7]dioxazacyclopentadecine-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-Trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azanonemethano)dipyrrolo[3,4-d:2',3'-g][1,13,3,10]dioxadiazacyclopentadecine-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]dioxadiazacyclopentadecine-4,16(5H,15H)-dione; [10S,16a(17)Z]-2,5,10-Trimethyl-5,6,7,8,9,10-hexahydro-12,14-(azanonemethano)dipyrrolo[3,4-d:2’,3’-g][1,3,10,13]oxatriazacyclopentadecine-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]oxatriazacyclopentadecine-4,16(1H,15H)-dione; [10S,16a(17)Z]-2,5,10-Trimethyl-5,6,7,8,9,10-hexahydro-12,14-(azanonemethano)dipyrrolo[3,2-i:3’,4’-l][1,4,7]oxadiazacyclopentadecine-4,16(1H,15H)-dione; [9R,16a(17)Z]-2,5,9-Trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azanonemethano)dipyrrolo[3,4-d:2’,3’-g][1,13,3,10]dioxadiazacyclopentadecine-4,16(5H,15H)-dione; [9S,16a(17)Z]-2,5,9-Trimethyl-6,7,9,10-tetrahydro-1H-12,14-(azanonemethano)dipyrrolo[3,4-d:2’,3’-g][1,13,3,10]dioxadiazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]oxazazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]oxathiazacyclohexadecine-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]oxazazacyclohexadecine-4,10,17(5H,9H,16H)-trione; [17a(18)Z]-2,5-Dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azometheno)dipyrrolo[3,4-h:2’,3’-k][1,4,7,14]oxatriazacyclohexadecine-4,10,17(5H,9H,16H)-trione; [17a(18)Z]-2,5-Dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azometheno)dipyrrolo[3,2-f:3’,4’-i][1,4,14]oxazazacyclohexadecine-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]oxatriazacyclohexadecine-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]oxatriazacyclohexadecine-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]oxatriazacyclohexadecine-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]oxatriazacyclohexadecine-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]oxadiazacyclohexadecine-4,10,17(5H,9H,16H)-trione; [17a(18)Z]-2,11-Dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azomethino)dipyrrolo[3,4-h:2',3'-k][1,4,7,14]oxatriazacyclohexadecine-4,10,17(5H,9H,16H)-trione; [17a(18)Z]-2,11-Dimethyl-6,7,11,12-tetrahydro-1H-13,15-(azomethino)dipyrrolo[3,2-f:3',4'-i][1,4,14]oxadiazacyclohexadecine-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]oxadiazacycloheptadecine-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]oxadiazacycloheptadecine-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]oxadiazacycloheptadecine-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]oxadiazacycloheptadecine-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]oxadiazacycloheptadecine-4,12,18(5H,13H,17H)-trione; [18a(19)Z]-2-Methyl-6,7,10,11-tetrahydro-1H,9H-14,16-(azomethano)dipyrrolo[3,4-i:2',3'-l][1,4,8,15]oxatriazacycloheptadecine-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]oxatriazacycloheptadecine-4,12,18(5H,13H,17H)-trione; [13S,18a(19)Z]-2,13-Dimethyl-6,7,10,11-tetrahydro-1H,9H-14,16-(azomethano)dipyrrolo[3,2-f:3',4'-i][1,4,15]oxadiazacycloheptadecine-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]oxadiazacycloheptadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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-methylpiperazin-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; [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]dioxazacyclopentadecine-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]dioxazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxadiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-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]dioxazacyclopentadecine-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]oxazacyclopentadecine-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]oxazacyclopentadecine-4,16(1H,15H)-dione; [16a(17)Z]-19-Chloro-5,8-dimethyl-5,6,7,8,9,10-hexahydro-1H-12,14-(ethanediylidene)dipyrrolo[3,4-i:3’,4’-l][1,4,7]oxazacyclopentadecine-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]dioxazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-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]oxathiazacyclopentadecine-4,11,11,16(5H,10H,15H)-tetrone.

19. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable additives.

20. A pharmaceutical composition for use in treating an autoimmune disease in a subject, comprising a compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

21. Use of a compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating an autoimmune disease in a subject.

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