Indazole-containing macrocyclic molecules and their use

Abstract

The present invention relates to an indazole-containing macrocyclic compound, a pharmaceutical composition containing the macrocyclic compound, and a method of using the macrocyclic compound for the treatment of diseases such as cancer.

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 350,309, filed Jun. 8, 2022, U.S. Provisional Application No. 63 / 350,310, filed Jun. 8, 2022, and U.S. Provisional Application No. 63 / 503,879, filed May 23, 2023, and incorporates by reference the entire disclosures of all of these.

[0002] Technical Field The present invention relates to indazole-containing macrocyclic compounds, pharmaceutical compositions containing the macrocyclic compounds, and methods of using the macrocyclic compounds for the treatment of diseases such as cancer.

Background Art

[0003] Background Protein kinases are tightly regulated signaling proteins that coordinate the activation of signaling cascades through phosphorylation of 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 diseases, neurodegenerative diseases, immune diseases, infectious diseases, inflammatory diseases and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36:462-469). The molecular basis leading to various diseases includes 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). Due to the important role of kinases in cancer and other diseases, they have become attractive targets for drug discovery. Sixty-two small molecule kinase inhibitors have been approved, 55 of which are for cancer target therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2021 Update. Pharmacol Res 2021, 165:105463). Kinase inhibitors have achieved dramatic success in cancer target therapies, but the emergence of treatment resistance remains a challenge for small molecule kinase inhibitors.Acquired secondary mutations within the kinase domain during treatment often result in 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). Resistance can also arise from a subpopulation of tolerant / dormant surviving cells that survive in the presence of treatment. Various processes contribute to the emergence of tolerant dormant surviving cells, including the release of negative feedback loops, transcription rewiring mediated by chromatin remodeling, and pathway rebounds via autocrine / paracrine signaling between tumor cells and within the tumor microenvironment (Swayden M, et al Tolerant / Persister Cancer Cells and the Path to Resistance to Targeted Therapy. Cells 2020, 9, 2601). Therefore, there is a need for the invention of kinase inhibitors that target not only the most frequent resistance mutations to overcome kinase oncogenic drivers but also tolerant dormant surviving cancer cells that overcome resistance to achieve better 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 the short in-frame deletion (del19) in exon 19 of the EGFR gene and the 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).

[0005] 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 treatments in this setting. However, over time, most patients acquire resistance to gefitinib or erlotinib, and 50% to 70% of tumors acquire the EGFR T790M gatekeeper mutation (Sequist LV, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3:75ra26). 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? Dru).

[0006] Afatinib and dacomitinib are more potent EGFR inhibitors with longer progression-free survival (PFS) compared to gefitinib and erlotinib, which are approved as first-line treatments for patients with progressive EGFR mutation-positive (Del19 or L858R) NSCLC. However, the EGFR T790M mutation is acquired over time with afatinib treatment (Tanaka K, et al. Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Onco-target 2017; 8:68123-30). The EGFR T790M mutation confers resistance to dacomitinib in in vitro studies (Kobayashi Y, et al. EGFR T790M and C797S mutations as mechanisms of acquired resistance to dacomitinib. J Thorac Oncol 2018; 13: 727-31). The third-generation EGFR inhibitor osimertinib is an irreversible inhibitor that targets both EGFR activating mutations (Del19 and L858R) and the T790M resistance mutation, with selectivity over wild-type EGFR (Finlay MR, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014; 57:8249-67).Osimertinib was approved for patients with metastatic EGFR T790M-mutant positive NSCLC after failure of first-choice EGFR inhibitors, and then was approved in the first-choice setting for patients with EGFR-mutant positive NSCLC after the Phase III FLAURA trial, a direct-comparison trial comparing it with erlotinib or gefitinib (Soria JC, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378:113-25). The mutation C797S at the EGFR co-crystallization residue with 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] Therefore, there is a need to develop a new generation of reversible EGFR inhibitors that are potent against oncogenic driver EGFR mutations such as L858R, Del19, δ746-750, δ746-750 / T790M, δ746-750 / C979S, L858R / T790M, Del19 / T790M, L858R / C979S, Del19 / C979S, L858R / T790M / C979S and δ746-750 / T790M / C979S, as well as other emerging and established resistance mutations, while maintaining good selectivity over wild-type EGFR.

[0008] The integration of proviruses into the Moloney murine leukemia virus (PIM) kinase phosphorylates a broad range of substrates that control several hallmarks of cancer, including tumor metabolism, survival, metastasis, immune evasion, and inflammation (Toth RK, Warfel NA. Targeting PIM Kinases to Overcome Therapeutic Resistance in Cancer. Mol Cancer Ther. 2021, 20(1):3-10). PIM kinases interact with a number of major oncogenic players, including p53 stabilization, synergy with c-Myc, and prominent parallel signaling with PI3K / Akt. Aberrant PIM kinase activity has an important role in resistance mechanisms to chemotherapy, radiotherapy, anti-angiogenic therapy, and targeted therapy, providing a rationale for co-targeting treatment strategies for more durable patient responses (Malone T, et al Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer. Pharmacol Ther 2020 Mar;207).

[0009] Anaplastic lymphoma kinase (ALK) is a member of the insulin-like tyrosine kinase receptor family that is involved in the carcinogenesis of several tumor types. Approximately 5% of patients with non-small cell lung cancer (NSCLC) have rearrangements in the anaplastic lymphoma kinase (ALK) gene (Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007, 448, 561-566). ALK inhibitors have been approved by the FDA as standard treatment in first- and second-line treatment of ALK-rearranged NSCLC patients. However, because a complete response to ALK inhibitors is rare, almost all patients with ALK-rearranged NSCLC will inevitably acquire resistance to ALK inhibitors and tumor recurrence will occur. The drug resistance mechanisms include ALK-independent and ALK-dependent processes. ALK-independent resistance mechanisms include activation of bypass pathways such as EGFR, c-MET, KRAS, and AXL or transformation to small cell lung cancer (Gainor, J. F. et al. Molecular mechanisms of resistance to first- and second generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 2016, 6, 1118-1133). Five ALK inhibitors have been approved, but the clinical ability to overcome ALK-independent resistance mechanisms is limited. Therefore, for better efficacy and longer response duration, there is a need to develop next-generation multi-target ALK inhibitors with the ability to target not only primary ALK fusions and ALK secondary resistance mutations but also mechanisms associated with tolerant quiescent surviving cancer cells.

[0010] The integration of proviruses into the murine leukemia virus (PIM) kinase phosphorylates a wide range of substrates that control some of the hallmarks of cancer, including tumor metabolism, survival, metastasis, immune evasion, and inflammation (Toth RK, Warfel NA. Targeting PIM Kinases to Overcome Therapeutic Resistance in Cancer. Mol Cancer Ther. 2021, 20(1):3-10). PIM kinases interact with a number of major oncogenic players, including p53 stabilization, synergism with c-Myc, and prominent parallel signaling with PI3K / Akt. Aberrant PIM kinase activity plays an important role in resistance mechanisms to chemotherapy, radiotherapy, anti-angiogenic therapy, and targeted therapy, providing a rationale for co-targeting treatment strategies for more durable patient responses (Malone T, et al Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer. Pharmacol Ther 2020 Mar;207).

[0011] Cdc-like kinases (CLKs) are evolutionarily conserved dual-specificity kinases that can phosphorylate serine, threonine, and tyrosine residues. CLKs catalyze the phosphorylation of SR proteins, serine- and arginine-rich splicing factors 1-12 (SRSF1-12), which control the spliceosome molecular machinery (Martin Moyano P, et al Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential. Int J Mol Sci 2020, 21(20):7549). Dysregulation of alternative splicing is a characteristic of cancer. Frequent mutations in SF3B1 or SRSF2 have been reported in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, and acute myeloid leukemia (AML) (Papaemmanuil et al, Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016, 374:2209 - 2221). Furthermore, mutations in splicing-related genes have also been found in various solid cancers, including lung cancer, breast cancer, and pancreatic cancer (Dvinge H, et al RNA splicing factors as oncoproteins and tumour suppressors. Nat Rev Cancer 2016, 16: 413 - 430). Regulation of mRNA precursor splicing through inhibition of CLK kinases is an attractive anti-neoplastic strategy, particularly for cancers that exhibit abnormal mRNA precursor splicing.

Summary of the Invention

Problems to be Solved by the Invention

[0012] Therefore, there is a need to develop a new generation of multi-target EGFR inhibitors and multi-target ALK inhibitors that are potent against oncogenic driver EGFR mutations, ALK fusions and point mutations, other emerging and established EGFR and ALK resistance mutations, and emerging resistance targets for tolerant / persistent cancer cells, such as PIM kinases and CLK kinases.

Means for Solving the Problem

[0013] Summary In one aspect, the present invention provides a compound of formula I

Chem.

[0014] (wherein R 1 , R 2 , R 3 , R 4 , A, B, L, m, n, p and q are as described elsewhere in this specification.) or a pharmaceutically acceptable salt thereof. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p does not contain an -O-CR 6 R 7 -fragment that is covalently bonded directly to ring A.

[0015] In certain embodiments, the present invention provides a compound of formula II

Chem.

[0016] (wherein R 1 , R 2 , R 3 , R 4 , A, B, L, Y, m, n, p and q are as described elsewhere in this specification.) or a pharmaceutically acceptable salt thereof. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p does not contain an -O-CR 6 R 7 -fragment that is covalently bonded directly to ring A.

[0017] In one embodiment, the present invention provides a compound of formula III [Chemical Formula]

[0018] (wherein R 1 , R 2 , R 3 , R 4 , A, B, L, Z, Z 1 , X 1 , X 2 , X 3 , m, n, p and q are as described herein.) or a pharmaceutically acceptable salt thereof. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p does not contain an -O-CR 6 R 7 - fragment that is covalently bonded directly to ring A.

[0019] In one embodiment, the present invention provides a compound of formula IV [Chemical Formula]

[0020] (wherein R 1 , R 2 , R 3 , R 4 , A, B, L, Z, Z 1 , X 1 , X 2 , X 3 , m, n, p and q are as described herein.) or a pharmaceutically acceptable salt thereof. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p does not contain an -O-CR 6 R 7 - fragment that is covalently bonded directly to ring A.

[0021] In a further aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) - (XII) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable additives.

[0022] In a further aspect, the present invention relates to a compound of formula (I) - (XII) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0023] 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 thereof an effective amount of at least one compound of formula (I) - (XII) or a pharmaceutically acceptable salt thereof.

[0024] In a further aspect, the present invention relates to the use of a compound of formula (I) - (XII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease such as cancer and the use of such a compound and salt for treating such a disease.

[0025] In a further aspect, the present invention relates to a method of inhibiting EGFR, PIM kinase and / or CLK kinase comprising a certain mutation described herein, the method comprising contacting a cell comprising one or more of an abnormal EGFR, PMI kinase and / or CLK kinase comprising a certain mutation described herein with an effective amount of at least one compound of formula (I) - (XII) 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.

[0026] Further embodiments, features and advantages of the present invention will become apparent through the following detailed description and the practice of the present invention. The compounds of the present invention may be described as embodiments of any of the following numbered paragraphs. It is understood that any of the embodiments described herein can be used in combination with any other embodiment described herein, provided that the embodiments do not conflict with each other.

[0027] 1. Formula I

Chem.

[0028] 〔wherein,

[0029] ring A is a 5- to 10-membered heteroarylene or C6-C 10 arylene;

[0030] ring B is a 5-membered heteroarylene;

[0031] each L is independently -O-, -S-, -S(O)-, -S(O)2-, -N(R 5 )C(O)-, -C(O)N(R 5 )-, -N(R 5 )-, -N(R 5 )S(O)-, -S(O)N(R 5 )-, -N(R 5 )S(O)2-, -S(O)2N(R 5 )- or -C(R 6 )(R 7 )-, provided that (L) p does not contain an O-O, S-O or N-N bond;

[0032] each R 1 , R 2 and R 3 is, when present, 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 Rb 、 -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 、 -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 may independently be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, R c 、 -OR c 、 -OC(O)R c 、 -OC(O)NR c R d 、 -OC(=N)NRc R d ,-OS(O)R c ,-OS(O)2R c ,-OS(O)NR c R d ,-OS(O)2NR c R d ,-SR c ,-S(O)R c ,-S(O)2R c ,-S(O)NR c R d ,-S(O)2NR c R d ,-NR c R d ,-NR c C(O)R d ,-N(C(O)R c )(C(O)R d ),-NR c C(O)OR d ,-NR c C(O)NR c R d ,-NR c C(=N)NR c R d ,-NR c S(O)R d ,-NR c S(O)2R d ,-NR c S(O)NR c R d ,-NR c S(O)2NR c R d ,-C(O)R c ,-C(O)OR c ,-C(O)NR c R d ,-C(=N)NR c R d ,-PR c R d ,-P(O)R c R d ,-P(O)2R c R d ,-P(O)NR c R d ,-P(O)2NR c R d ,-P(O)OR c ,-P(O)2ORc is substituted with -CN or -NO2;

[0033] or two Rs 1 two Rs 2 or two Rs 3 together with the atoms to which they are attached may optionally combine to form C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl formed when two of R 1 R 2 and R 3 combine together is independently optionally -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 、 is substituted with -CN or -NO₂;

[0034] R 4 is H, deuterium, -C(O)R c 、 -C(O)OR c 、 -C(O)NR c R d 、 -P(O)₂R c R d 、 -P(O)₂NR c R d 、 -P(O)₂OR c or -S(O)₂OR c ;

[0035] Each R 5 is, when present, independently H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, -C(O)R a 、 3- to 7-membered heterocycloalkyl, C₆-C 10 aryl or 5- to 10-membered heteroaryl, where 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 -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 cR d 、 -OS(O)2NR c R d 、 -SR c 、 -S(O)R c 、 -S(O)2R c 、 -S(O)NR c R d 、 -S(O)2NR c R d 、 -NR c R d 、 -NR c C(O)R d 、 -N(C(O)R c )(C(O)R d 、 -NR c C(O)OR d 、 -NR c C(O)NR c R d 、 -NR c C(=N)NR c R d 、 -NR c S(O)R d 、 -NR c S(O)2R d 、 -NR c S(O)NR c R d 、 -NR c S(O)2NR c R d 、 -C(O)R c 、 -C(O)OR c 、 -C(O)NR c R d 、 -C(=N)NR c R d 、 -PR c R d 、 -P(O)R c R d 、 -P(O)2R c R d 、 -P(O)NR c R d 、 -P(O)2NR c R d 、 -P(O)OR c 、 -P(O)2OR c 、 is substituted with -CN or -NO2;

[0036] Each R 6and R 7 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 aR b 、 -P(O)OR a 、 -P(O)2OR a 、 -CN or -NO2, where each hydrogen atom of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl and 5-10 membered heteroaryl may independently be 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;

[0037] or R 5 、 R 6 and R 7 Two of them, together with one or more atoms to which they are attached, optionally combine to form C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl, where R 5 、 R 6 and R 7 Each hydrogen atom in the C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl formed when two of them combine together is independently optionally -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;

[0038] 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 alkylene-C6-C 10 aryl, 5-10 membered heteroaryl and C1-C6 alkylene-5-10 membered heteroaryl or R a and R b or R c and R d or R e and R f forms, together with the atoms to which they are attached, a 3-7 membered heterocycloalkyl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl, C1-C6 alkylene-C6-C 10Each hydrogen atom in aryl, 5- to 10-membered heteroaryl or C1-C6 alkylene-5- to 10-membered heteroaryl is independently, if desired, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2,-P(O)(C2-C6 alkylene), -P(O)2(H or C1-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6 alkyl), -CN or -NO2 substituted;

[0039] m is 0, 1, 2, 3 or 4;

[0040] n is 0, 1, 2 or 3;

[0041] p is 4, 5, 6, 7, 8 or 9; and

[0042] q is 0, 1 or 2. ]]

[0043] a compound of or a pharmaceutically acceptable salt thereof;

[0044] provided that the compound is not of the formula

Chemical formula

[0045] a compound of or a pharmaceutically acceptable salt thereof.

[0046] 2. Formula I

Chemical formula

[0047] 〔Wherein,

[0048] ring A is a 5- to 10-membered heteroarylene or C6-C 10 arylene;

[0049] ring B is a 5-membered heteroarylene;

[0050] Each L is independently -O-, -S-, -S(O)-, -S(O)2-, -N(R 5 )C(O)-, -C(O)N(R 5 )-, -N(R 5 )-, -N(R 5 )S(O)-, -S(O)N(R 5 )-, -N(R 5 )S(O)2-, -S(O)2N(R 5 )- or -C(R 6 )(R 7 )-, provided that (L) p does not contain an O - O, S - O or N - N bond;

[0051] Each R 1 , R 2 and R 3 is, when present, 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 , -NR a S(O)NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)2NR a R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O)2R c , -OS(O)NR c R d , -OS(O)2NR c R d , -SR c , -S(O)R c , -S(O)2R c , -S(O)NR c R d , -S(O)NR c R d , -NR c R d , -NR c C(O)Rd 、 -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 or -NO2 substituted;

[0052] R 4 is H, deuterium, -C(O)R c 、 -C(O)OR c 、 -C(O)NR c R d 、 -P(O)2R c R d 、 -P(O)2NR c R d 、 -P(O)2OR c or -S(O)2OR c ;

[0053] Each R 5 when present, independently represent H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O)2R c , -OS(O)NR c R d , -OS(O)2NR c R d , -SR c , -S(O)R c , -S(O)2R c , -S(O)NR c R d , -S(O)NR c R d , -NR c R d , -NR c C(O)R d , -N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR cS(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 or -NO2 substituted;

[0054] Each R 6 and R 7 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 aC(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 of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl and 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 Rf , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0055] or R 5 , R 6 and R 7 two of which, together with one or more atoms to which they are attached, optionally together form a C3-C6 cycloalkyl, a 3- to 7-membered heterocycloalkyl, wherein R 5 , R 6 and R 7 When two of these are taken together to form a C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl, each hydrogen atom may independently be optionally replaced by -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2Re 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e 、 -NR C(O)R f 、 -NR e 、 -NR C(O)OR f 、 -NR e 、 -NR C(O)NR e R f 、 -NR e 、 -NR S(O)R f 、 -NR e 、 -NR S(O)2R f 、 -NR e 、 -NR S(O)NR e R f 、 -NR e 、 -NR 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;

[0056] each R a 、 R b 、 R c 、 R d 、 R e and R fis independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, and C1-C6 alkylene-5- to 10-membered heteroaryl, or R a and R b or R c and R d or R e and R f and R 10 aryl, C1-C6 alkylene-C6-C 10Each hydrogen atom in aryl, 5- to 10-membered heteroaryl or C1-C6 alkylene-5- to 10-membered heteroaryl is independently, if desired, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2,-P(O)(C2-C6 alkylene), -P(O)2(H or C1-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6 alkyl), -CN or -NO2;

[0057] m is 0, 1, 2, 3 or 4;

[0058] n is 0, 1, 2 or 3;

[0059] p is 4, 5, 6, 7, 8 or 9; and

[0060] q is 0, 1 or 2. ]]

[0061] a compound of or a pharmaceutically acceptable salt thereof;

[0062] provided that the compound is not a compound of the formula

Chemical formula

[0063] or a pharmaceutically acceptable salt thereof.

[0064] 3. (L) p which is -NR directly covalently bonded to ring A 5 a compound of item 1 or 2 or a pharmaceutically acceptable salt thereof that does not contain C(O)-.

[0065] 4. A compound of any of the preceding items or a pharmaceutically acceptable salt thereof, wherein ring A is C6-C 10 arylene and m is 0, 1 or 2.

[0066] 5. A compound of any of the preceding items or a pharmaceutically acceptable salt thereof, wherein ring A is phenylene and m is 0, 1 or 2.

[0067] 6. A compound according to any of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein ring A is phenylene and m is 0 or 1.

[0068] 7. A compound according to any of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein ring A is phenylene, m is 1, and R 1 is methyl, ethyl, F, Cl, Br, -CN,

Chemical formula

Chemical formula

[0069] 8. A compound according to any of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein ring A is

Chemical formula

[0070] represents a covalent bond point.

Chemical formula

[0071] 9. A compound according to any of paragraphs 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 10-membered heteroarylene and m is 0, 1, 2 or 3.

[0072] 10. A compound according to any of paragraphs 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 10-membered heteroarylene and m is 0, 1 or 2.

[0073] 11. Formula II

Chemical formula

[0074] [wherein, Y is a single or double bond, -O-, -S-, =C(H)-, =C(R 1 )-, -N(H)-, -N(R 1 )- or =N-, and ring A is a 5- to 10-membered heteroarylene.] A compound according to any one of items 1 to 4 or 10 having the same, or a pharmaceutically acceptable salt thereof.

[0075] 12. Formula III

Chemical formula

[0076] [wherein, Z is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0077] 13. Formula IV [Chemical formula]

[0078] [wherein

[0079] X 1 , X 2 and X 3 are each independently -O-, -S-, =C(H)-, =C(R 1 ), -, -N(H)-, -N(R 1 ), - or =N-, provided that X 1 , X 2 and X 3 at least one of is not =C(H)- or =C(R 1 );

[0080] Z is [Chemical formula] where * is the covalent bond point to (L) p , provided that * is not an N-O or N-N bond, and ** is the covalent bond point to Z 1 ; [Chemical formula] represents the covalent bond point to ring A, [Chemical formula] where one bond is a single bond and one bond is a double bond **and [Chemistry] represents the condition between the bonding points; Z 1 is [Chemistry] where *** is the covalent bonding point to "=", and **** is the covalent bonding point to Z, [Chemistry] represents the covalent bonding point to ring A, [Chemistry] where one bond is a single bond and one bond is a double bond ****and [Chemistry] represents the condition between the bonding points, provided that neither Z nor Z 1 is a nitrogen atom; and

[0081] ring A is a 5- to 10-membered heteroarylene. ] A compound according to any one of items 1 to 4 or 10 to 12 having

[0082] 14. Ring A is [Chemistry] a 5- to 10-membered heteroarylene selected from the group consisting of

[0083] where each [Chemistry] represents a covalent bonding point, a compound according to any of the preceding items or a pharmaceutically acceptable salt thereof.

[0084] 15. Ring A is [Chem.] a 5- to 10-membered heteroarylene selected from the group consisting of

[0085] where each [Chem.] represents a covalent bond point, a compound of any of the preceding items or a pharmaceutically acceptable salt thereof.

[0086] 16. Ring A is [Chem.] [Chem.] [Chem.] [Chem.] a 5- to 10-membered heteroarylene selected from the group consisting of

[0087] where each [Chem.] represents a covalent bond point, a compound of any of the preceding items or a pharmaceutically acceptable salt thereof.

[0088] 17. Ring B is [Chem.] a 5-membered heteroarylene selected from the group consisting of

[0089] where each [Chem.] represents a covalent bond point, a compound of any of the preceding items or a pharmaceutically acceptable salt thereof.

[0090] 18. Ring B is

Chem.

[0091] wherein each

Chem.

[0092] 19. Ring B is

Chem.

[0093] wherein each

Chem.

[0094] 20. A compound of any of the preceding items or a pharmaceutically acceptable salt thereof, wherein q is 0, 1 or 2.

[0095] 21. A compound of any of the preceding items or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.

[0096] 22. A compound of any of the preceding items or a pharmaceutically acceptable salt thereof, wherein R 3 is F.

[0097] 23. A compound of any of the preceding items or a pharmaceutically acceptable salt thereof, wherein R 4 is H or methyl.

[0098] 24. Each L is independently -C(R 6 )(R 7)-, -C(O)-, -O- or -N(R 5 )- provided that (L) p does not contain an -O-O- or -O-N(R 5 )- bond, and the point of covalent attachment of (L) p to ring A of the previous compounds or a pharmaceutically acceptable salt thereof does not form an -N-N- or -O-N- bond.

[0099] 25. -(L) p - is -CR 6 R 7 -O(CR 6 R 7 )2O-, -CR 6 R 7 -O(CR 6 R 7 )3O-, -(CR 6 R 7 )C(O)N(R 5 )-(CR 6 R 7 )2-, -(CR 6 R 7 )N(R 5 )C(O)-(CR 6 R 7 )2-, -O(CR 6 R 7 )2N(R 5 )C(O)-(CR 6 R 7 )O-, -N(R 5 )-C(O)(CR 6 R 7 )2O(CR 6 R 7 )2-, -CR 6 R 7 O(CR 6 R 7 )2O-(CR 6 R 7 )2, -O(CR 6 R 7 )2O(CR 6 R 7 )2O-, -CR 6 R 7 O-CR 6 R 7 -C(O)N(R 5 )-(CR 6 R7 ) 2-, -(CR 6 R 7 ) 3O(CR 6 R 7 ) 2-, -(CR 6 R 7 ) 2O(CR 6 R 7 ) 3-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 ) 4O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 ) 3O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 ) 2O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 ) 2-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 ) 3O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 ) 3-, -O(CR 6 R 7 ) 2O-CR 6 R 7 -, -O(CR 6 R 7 ) 2O(CR 6 R 7 ) 2-, -O(CR 6 R 7 ) 2O(CR 6 R 7 ) 3-, -(CR 6 R 7 ) 2-N(R 5 )-(CR 6 R 7 ) 3-, -O(CR 6 R 7 ) 2-N(R 5 )-CR6 R 7 -, -(CR 6 R 7 )2-N(R 5 )-(CR 6 R 7 )2-, -O-(CR 6 R 7 )2-, -O-(CR 6 R 7 )3-, -O-(CR 6 R 7 )4-, -O-(CR 6 R 7 )5-, -O-(CR 6 R 7 )2O-, -O-(CR 6 R 7 )3O-, -O-(CR 6 R 7 )4O- or -O-(CR 6 R 7 )5O- or a compound of any of the preceding items or a pharmaceutically acceptable salt thereof.

[0100] 26. Each R 5 is independently H, methyl, ethyl, -C(O)CH3 or -C(O)CH2CH3; or when R 5 is present, and when R 6 or R 7 is present, together with one or more atoms to which they are attached, they form a 3- to 7-membered heterocycloalkyl together; wherein each hydrogen atom in the 3- to 7-membered heterocycloalkyl formed by R 5 and R 6 or R 7 when combined is independently optionally -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 C(O)R e , -NR f C(O)OR e , -NR e C(O)NR f R e , -NR f S(O)R e , -NR f S(O)2R e , -NR e S(O)NR f R e , -NR e S(O)2NR f R e , -C(O)R e , -C(O)OR e , -C(O)NR f R e , -PR f R e , -P(O)R f R e , -P(O)2R f R e , -P(O)NR f R e , -P(O)2NR f R e , -P(O)OR e , -P(O)2OR

[0101] 27. R 6 and R 7 , when present, together with one or more atoms to which they are attached, form a 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in the 3- to 7-membered heterocycloalkyl formed when R 6 and R 7 are joined together is independently optionally -OR e , -OC(O)R e , -OC(O)NR eR f 、 -OS(O)R e 、 -OS(O)₂R e 、 -OS(O)NR e R f 、 -OS(O)₂NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)₂R e 、 -S(O)NR e R f 、 -S(O)₂NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)₂R f 、 -NR e S(O)NR e R f 、 -NR e S(O)₂NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)₂R e R f 、 -P(O)NR e R f 、 -P(O)₂NR e R f 、 -P(O)OR e 、 -P(O)₂OR e 、 A compound of any of the preceding terms or a pharmaceutically acceptable salt thereof, substituted with -CN or -NO₂.

[0102] 28. R 5 or R 7Each R that is not incorporated 6 is independently H or C1-C6 alkyl, a compound according to any of the preceding paragraphs or a pharmaceutically acceptable salt thereof.

[0103] 29. R 5 or R 7 One R that is not incorporated 6 is methyl and the remaining R 6 and R 7 are H, a compound according to any of the preceding paragraphs or a pharmaceutically acceptable salt thereof.

[0104] 30. -(L) p- is -O-(CH2)2O-CH2-, -OC(H)(CH3)-CH2-O-CH2-, -CH2O-(CH2)2O-, -C(H)(CH3)-O-(CH2)2O-, -CH2N(H)-(CH2)2O-, -CH2N(CH3)-(CH2)2O-, -CH2N(CH2CH3)-(CH2)2O-, -O(CH2)2N(H)CH2-, -O(CH2)2N(CH3)CH2-, -OCH2-C(H)(CH3)-N(CH(CH3)2)CH2-, -OCH2-C(H)(CH2F)-N(CH3)CH2-, -OCH2-C(H)(CH2CH3)-N(CH3)CH2-, -O(CH2)2N(C(O)CH3)CH2-, -OC(H)(CH3)CH2N(H)CH2-, -OC(H)(CH3)CH2N(CH3)CH2-, -OC(H)(CH2CN)CH2N(CH3)CH2-, -OC(H)(CH2CH3)CH2N(CH3)CH2-, -OC(H)(CH2F)CH2N(CH3)CH2-, -OC(H)(CHF2)CH2N(CH3)CH2-, -OC(H)(CH2OH)CH2N(CH3)CH2-, -OC(H)(CH3)C(O)N(CH3)CH2-, -OC(H)(cyclobutyl)CH2N(CH3)CH2-, -OC(H)(CH3)CH2N(CH2CH3)CH2-, -OC(H)(CH3)CH2N(CH(CH3)2)-CH2-, -OC(H)(CH3)CH2N(CH3)-C(H)(CH3)-, -OC(H)(CH3)CH2N(CH(oxetan-3-yl)-CH2-, -OC(H)(CH3)CH2N(cyclopropyl)-CH2-, -OCH2C(H)(CH3)N(cyclopropyl)-CH2-, -OC(H)(CH3)CH2N(C(O)CH3)CH2-, -O(C(H)(CH3))CH2N(C(O)CH2CH3)CH2-, -CH2N(H)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-C(H)(CH3)-CH2O-, -CH2N(CH3)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-(CH2)-(C(H)CH3)O-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, -O(CH2)3O-, -O(CH2)4O-, -O(CH2)5O-, -O-(C(H)(CH3)-(CH2)2O-, -O(CH2)2-C(H)(CH3)-O-,-O(CH2)2C(H)(CH3)CH2O-, -O(CH2)3C(H)(CH3)CH2O-, -O(CH2)2N(H)C(O)-(CH2)O-, -O(CH2)2N(CH3)C(O)-(CH2)O-, -O(CH2)2O(CH2)2O-, -OC(H)(CH3)CH2OCH2-, -O(CH2)2OCH2C(H)(CH3)O-, -O(CH2)2OC(H)(CH3)-CH2O-

Chem.

[0105] 31. (11E)-1-Methyl-1,18,19,21-tetrahydro-8H-10,7,4-(ethane[1]yl[1,2]diylidene)pyrazolo[3,4-f][1,4,12,13]benzodioxadiazacyclooctadecine;

[0106] (11E)-1-[(Methanesulfonyl)methyl]-19,20-dihydro-1H,8H,18H-10,7,4-(ethane[1]yl[1,2]diylidene)pyrazolo[3,4-f][1,5,12,13]benzodioxadiazacyclooctadecine;

[0107] (11E)-1-Methyl-18,19,20,21-tetrahydro-1H,8H-10,7,4-(ethane[1]yl[1,2]diylidene)pyrazolo[3,4-g][1,6,13,14]benzodioxadiazacyclononadecine;

[0108] (10R,16E)-3-Methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoazacyclooctadecine-25-one;

[0109] (10R,16E)-3-Methyl-13-[(4-methylpiperazin-1-yl)methyl]-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoazacyclooctadecin-25-one;

[0110] (10R,16E)-13-[(Dimethylamino)methyl]-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoazacyclooctadecin-25-one;

[0111] (10R,16E)-3-Methyl-13-(1-methylpiperidin-4-yl)-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoazacyclooctadecin-25-one;

[0112] (10R,16E)-13-(2-Methoxypropan-2-yl)-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoazacyclooctadecin-25-one;

[0113] (10R,16E)-3-Methyl-13-(4-methylpiperazin-1-yl)-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoazacyclooctadecin-25-one;

[0114] (10R,16E)-14-Fluoro-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoazacyclooctadecin-25-one;

[0115] (10R,16E)-14-(2-Hydroxypropan-2-yl)-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoaazacyclooctadecin-25-one;

[0116] (10R,16E)-14-{(2S)-2-[(Methanesulfonyl)methyl]azetidin-1-yl}-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoaazacyclooctadecin-25-one;

[0117] (10R,16E)-3-Methyl-25-oxo-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoaazacyclooctadecin-14-carbonitrile; and

[0118] (10R,16E)-3-Methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoaazacyclooctadecine;

[0119] A compound according to item 1 or 2 or a pharmaceutically acceptable salt thereof, selected from the group consisting of

[0120] 32. (18E)-8-Methyl-N-(propan-2-yl)-8,9,11,12-tetrahydro-2H-3,5-ethenodipyrazolo[3’,4’:9,10;4’’,3’’:13,14][1,4]dioxacyclopentadecinol[5,6-b]pyridine-16-carboxamide;

[0121] (18E)-N,8-Dimethyl-8,9,11,12-tetrahydro-2H-3,5-ethenodipyrazolo[3’,4’:9,10;4’’,3’’:13,14][1,4]dioxacyclopentadecano[5,6-b]pyridine-16-carboxamide;

[0122] (18E)-N,N,8-Trimethyl-8,9,11,12-tetrahydro-2H-3,5-ethenodipyrazolo[3’,4’:9,10;4’’,3’’:13,14][1,4]dioxacyclopentadecano[5,6-b]pyridine-16-carboxamide;

[0123] (18E)-N-Ethyl-8-methyl-8,9,11,12-tetrahydro-2H-3,5-ethenodipyrazolo[3’,4’:9,10;4’’,3’’:13,14][1,4]dioxacyclopentadecano[5,6-b]pyridine-16-carboxamide;

[0124] (10S,18E)-8,10,16-Trimethyl-2,8,11,12-tetrahydro-10H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,5]dioxacyclopentadecano[7,6-b]pyridine;

[0125] (10S,18E)-17-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-3,5-ethenodipyrazolo[3,4-j:4’,3’-n]pyrido[4,3-f][1,4]oxazacyclopentadecine; and

[0126] (10S,18E)-16-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-3,5-ethenodipyrazolo[3,4-j:4’,3’-n]pyrido[3,2-f][1,4]oxazacyclopentadecine;

[0127] A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

[0128] 33. (17E)-8,14,16-Trimethyl-2,8,9,11,12,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[11,10-c:15,14-c’:6,7-c’’]tripyrazole;

[0129] 2-[(17E)-8,9,16-Trimethyl-8,9,11,12-tetrahydro-3,5-etheno[1,4]dioxacyclopentadecano[11,10-c:15,14-c’:6,7-c’’]tripyrazol-14(2H)-yl]ethan-1-ol;

[0130] (17E)-8,14,16-Trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0131] (17E)-19-Fluoro-8,14,16-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0132] (17E)-16-Ethyl-8,14-dimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0133] 1-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-2-methylpropan-2-ol;

[0134] 1-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]propan-2-one;

[0135] 2-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]ethan-1-ol;

[0136] (17E)-8,16-dimethyl-14-[2-(pyrrolidin-1-yl)ethyl]-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0137] (3S)-1-{2-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]ethyl}pyrrolidin-3-ol;

[0138] (17E)-16-ethyl-8,12,14-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0139] (10S,17E)-8,10,14,16-tetramethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0140] (10R,17E)-8,10,14,16-Tetramethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0141] (12S,17E)-16-Ethyl-8,12,14-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0142] (12R,17E)-16-Ethyl-8,12,14-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0143] (10S,17E)-16-Ethyl-8,10,14-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0144] (10S,17E)-16-Cyclopropyl-8,10,14-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0145] (17E)-16-(Methoxymethyl)-8,14-dimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0146] (17E)-8,14,16-Trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0147] 1-[(17E)-8,14,16-Trimethyl-2,8,10,11,13,14-hexahydro-12H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-12-yl]ethan-1-one;

[0148] (17E)-8,12,14,16-Tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0149] (17E)-6,8,12,14,16-Pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0150] (17E)-16-Ethyl-8,12,14-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0151] (17E)-7,14,16-Trimethyl-2,10,11,12,13,14-hexahydro-7H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0152] (17E)-7,12,14,16-Tetramethyl-2,10,11,12,13,14-hexahydro-7H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0153] 2-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0154] (17E)-8,14,16-Trimethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0155] (17E)-8,10,14,16-Tetramethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0156] 2-[(17E)-8,16-Dimethyl-2,8,9,10,11,12-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0157] 2-[(17E)-8,10,16-Trimethyl-2,8,9,10,11,12-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0158] 2-[(17E)-10-Ethyl-8,16-dimethyl-2,8,9,10,11,12-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0159] (19E)-8,13,16,18-Tetramethyl-2,11,12,13,14,16-hexahydro-8H,10H-3,5-etheno[1,7]dioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazole;

[0160] 2-[(19E)-8,13,18-Trimethyl-2,8,11,12,13,14-hexahydro-10H,16H-3,5-etheno[1,7]dioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazol-16-yl]ethan-1-ol;

[0161] (19E)-8,16,18-Trimethyl-2,11,12,16-tetrahydro-8H,10H-3,5-ethenotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,7,4]dioxoazacycloheptadecin-13(14H)-one;

[0162] (19E)-8,12,16,18-Tetramethyl-2,11,12,16-tetrahydro-8H,10H-3,5-ethenotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,7,4]dioxoazacycloheptadecin-13(14H)-one;

[0163] (13R,19E)-8,13,16,18-Tetramethyl-2,10,11,13,14,16-hexahydro-8H-3,5-etheno[1,4,7]trioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazole;

[0164] (13S,19E)-8,13,16,18-Tetramethyl-2,10,11,13,14,16-hexahydro-8H-3,5-etheno[1,4,7]trioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazole;

[0165] 2-[(19E)-8,13,18-Trimethyl-2,8,10,11,13,14-hexahydro-16H-3,5-etheno[1,4,7]trioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazol-16-yl]ethan-1-ol;

[0166] (19E)-8,13,18-Trimethyl-16-[2-(pyrrolidin-1-yl)ethyl]-2,10,11,13,14,16-hexahydro-8H-3,5-etheno[1,4,7]trioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazole;

[0167] (3S)-1-{2-[(17E)-16-Ethyl-8-methyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecin[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]ethyl}pyrrolidin-3-ol;

[0168] (19E)-22-Fluoro-8,16,18-trimethyl-2,10,11,13,14,16-hexahydro-8H-3,5-etheno[1,4,7]trioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazole;

[0169] 3-[(17E)-16-Ethyl-8-methyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecin[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-N,N-dimethylpropan-1-amine;

[0170] (rac)-4-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecin[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]pyrrolidin-3-ol;

[0171] (rac)-4-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-1-methylpyrrolidin-3-ol;

[0172] (3R,4S)-4-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]oxolan-3-ol;

[0173] (3S,4R)-4-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]oxolan-3-ol;

[0174] (rac)-2-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]cyclobutan-1-ol;

[0175] (rac)-4-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]piperidin-3-ol;

[0176] (rac)-4-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-1-methylpiperidin-3-ol;

[0177] (rac)-1,5-anhydro-3-O-2,3-dideoxy-3-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-L-threo-pentitol;

[0178] (rac)-1,5-anhydro-2,4-dideoxy-2-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-L-threo-pentitol;

[0179] (12R,17E)-8,10,12,14,16-pentamethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0180] (12S,17E)-8,10,12,14,16-pentamethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0181] (rac)-(3S,4S)-1-methyl-4-[(17E)-8,10,16-trimethyl-2,8,9,10,11,12-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]pyrrolidin-3-ol;

[0182] (11S,17E)-8,11,14,16-Tetramethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0183] (17E)-8,9,16-Trimethyl-14-[2-(pyrrolidin-1-yl)ethyl]-2,8,9,11,12,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecino[11,10-c:15,14-c’:6,7-c’’]tripyrazole;

[0184] [(10S,17E)-8,10,14-Trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c’:6,7-c’’]tripyrazol-16-yl]methanol;

[0185] N 1 -{(1s,3s)-3-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]cyclobutyl}-N 1 ,N2,N2-Trimethylethane-1,2-diamine;

[0186] (11S,17E)-8,10,11,14,16-Pentamethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0187] N2-{(1s,3s)-3-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]cyclobutyl}-N 1 ,N 1-Dimethylethane-1,2-diamine;

[0188] (10R,15E)-3,12,14-Trimethyl-5,6,9,10,12,18-hexahydro-3H,8H-19,21-etheno-7,10-methanotripyrazolo[3,4-i:3’,4’-m:4’’,3’’-q][1,8,4]dioxoazacyclooctadecin-24-one;

[0189] (17E)-16-Ethyl-8,10,14-trimethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0190] (17E)-10-Ethyl-8,14,16-trimethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0191] 2-[(10S,17E)-8,10,16-Trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]ethan-1-ol;

[0192] 2-[(10S,17E)-19-Fluoro-8,10,12,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]ethan-1-ol;

[0193] (17E)-8,10,16-Trimethyl-14-(1-methylpyrrolidin-3-yl)-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0194] 2-[(10S,17E)-16-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]ethan-1-ol;

[0195] (10S,17E)-8,10,12,14,16-Pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0196] (10R,19E)-8,16,18-Trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0197] (2S)-1-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]propan-2-ol;

[0198] 2-[(10S,17E)-19-Chloro-8,10,12,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]ethan-1-ol;

[0199] (2R)-1-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0200] 2-[(10S,17E)-16-Ethyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0201] 2-[(10S,17E)-12-Ethyl-8,10,16-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0202] (10S,17E)-8,10,12,14-Tetramethyl-16-[(piperidin-4-yl)oxy]-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0203] 2-[(10R,19E)-18-Ethoxy-8-methyl-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecin-16(8H)-yl]ethan-1-ol;

[0204] 2-[(10S,17E)-6,8,10,12,16-Pentamethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0205] (10S,17E)-8,10,14,16-Tetramethyl-12-(oxetan-3-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0206] 2-[(10S,17E)-16-Ethoxy-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0207] (10S,17E)-16-{[1-(Methanesulfonyl)piperidin-4-yl]oxy}-8,10,12,14-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0208] (10S,13R,17E)-8,10,12,13,14,16-Hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0209] (10S,13S,17E)-8,10,12,13,14,16-Hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0210] 2-{(10S,17E)-8,10,12-Trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0211] (10S,17E)-8,10,12,14-Tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-ol;

[0212] (10S,17E)-16-[(azetidin-3-yl)oxy]-8,10,12,14-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0213] (10S,17E)-16-{[1-(methanesulfonyl)azetidin-3-yl]oxy}-8,10,12,14-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0214] 2-[(10S,17E)-16-Ethoxy-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0215] 2-[(17E)-10-Cyclobutyl-8,12,16-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0216] (10S,17E)-8,10,12,14-Tetramethyl-16-{[(3S)-pyrrolidin-3-yl]oxy}-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0217] (10S,17E)-16-{[(3S)-1-(Methanesulfonyl)pyrrolidin-3-yl]oxy}-8,10,12,14-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0218] (2S)-2-[(10S,17E)-16-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0219] (10S,17E)-16-Ethoxy-8,10,14-trimethyl-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0220] (10S,17E)-8,10,14-Trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole-16-carbonitrile;

[0221] (10S,17E)-8,10,12,14-Tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-16-carbonitrile;

[0222] (10R,19E)-18-Ethoxy-8,16-dimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0223] (10S,17E)-12-Cyclopropyl-8,10,14,16-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0224] (10S,17E)-8,10,12,14-Tetramethyl-16-(2,2,2-trifluoroethoxy)-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0225] {[(10S,17E)-8,10,12,14-Tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-16-yl]oxy}acetonitrile;

[0226] (10S,17E)-10,14,16-Trimethyl-8-[(methylsulfanyl)methyl]-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0227] (10S,17E)-12-Ethyl-8,10,14,16-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0228] 2-[(10S,17E)-16-Ethoxy-8-ethyl-10,12-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]ethan-1-ol;

[0229] 2-{(10S,17E)-8-Ethyl-10,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl}ethan-1-ol;

[0230] (2R)-2-[(10S,17E)-16-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol;

[0231] 2-[(10S,17E)-16-Ethoxy-19-fluoro-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0232] 2-[(10S,17E)-16-{[1-(Methanesulfonyl)piperidin-4-yl]oxy}-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0233] (10S,19E)-8,16,18-Trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0234] 2-[(10S,17E)-16-Ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0235] 2-[(10S,17E)-16-Ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0236] 2-{(10S,17E)-19-Fluoro-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0237] 2-[(10S,17E)-16-{[(3S)-1-(Methanesulfonyl)pyrrolidin-3-yl]oxy}-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0238] 2-[(10S,17E)-16-Bromo-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0239] 2-{(10S,17E)-16-[(Azetidin-3-yl)oxy]-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0240] (10S,17E)-14-(2-Hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-ol;

[0241] (10S,17E)-16-{[3-(Methanesulfonyl)cyclobutyl]oxy}-8,10,12,14-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0242] (10S,19E)-18-Ethoxy-8,16-dimethyl-2,8,11,12,15,16-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine-13(10H)-one;

[0243] (10R,19E)-18-Ethoxy-8,16-dimethyl-2,8,11,12,15,16-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine-13(10H)-one;

[0244] 2-[(10R,19E)-18-Ethoxy-22-fluoro-8-methyl-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine-16(8H)-yl]ethan-1-ol;

[0245] 2-{(11S,17E)-8,11-Dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl}ethan-1-ol;

[0246] 2-{(10R,17E)-8,10-Dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0247] 2-{(11S,17E)-19-Fluoro-8,11-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0248] 2-{(10R,17E)-19-Fluoro-8,10-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0249] 2-[(10R,17E)-12-Cyclopropyl-16-ethoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0250] 2-[(10R,17E)-16-Ethoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0251] 2-[(11S,17E)-12-Cyclopropyl-16-ethoxy-8,11-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0252] 2-[(10R,19E)-22-Fluoro-8-methyl-18-[(propan-2-yl)oxy]-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecin-16(8H)-yl]ethan-1-ol;

[0253] (2S)-2-{(10S,17E)-19-Fluoro-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-1-ol;

[0254] 2-{(11S,17E)-6,8,11-Trimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0255] 2-{(10R,17E)-6,8,10-Trimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0256] {(10S,17E)-14-(2-Hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-yl}oxyacetonitrile;

[0257] 2-[(10R,17E)-12-Cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0258] 2-[(11S,17E)-12-Cyclopropyl-16-ethoxy-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0259] (10S,17E)-16-Ethoxy-12-ethyl-19-fluoro-8,10,14-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0260] (2S)-2-{(10R,17E)-8,10-Dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-1-ol;

[0261] (10S,17E)-14-(2-Hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-carbonitrile;

[0262] (10S,17E)-12-Ethyl-8,10,14-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-ol;

[0263] (10S,17E)-19-Fluoro-14-(2-hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-ol;

[0264] 2-[(10S,17E)-19-Fluoro-8,10,12-trimethyl-16-(2,2,2-trifluoroethoxy)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0265] 2-{(10R,17E)-12-Cyclopropyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0266] 2-{(11S,17E)-12-Cyclopropyl-8,11-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0267] (2S)-2-[(10S,17E)-16-Ethoxy-19-fluoro-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0268] (2S)-2-[(10S,17E)-16-Ethoxy-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0269] 2-{(10S,17E)-12-Ethyl-19-fluoro-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0270] 1-[(10R,17E)-16-Ethoxy-14-(2-hydroxyethyl)-8,10-dimethyl-2,8,10,11,13,14-hexahydro-12H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-12-yl]ethan-1-one;

[0271] Ethyl [(10S,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]acetate;

[0272] (2S)-2-{[(10S,17E)-12-ethyl-19-fluoro-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0273] (10S,17E)-14-(2-hydroxyethyl)-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,12,13,14-tetrahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-11(10H)-one;

[0274] 2-[(10S,17E)-16-{[1-(methanesulfonyl)azetidin-3-yl]oxy}-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0275] 1-[(10S,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]-2-methylpropan-2-ol;

[0276] 2-{(10S,13R,17E)-8,10,12,13-Tetramethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0277] 2-{(10S,13S,17E)-8,10,12,13-Tetramethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0278] 2-{(17E)-10-(Fluoromethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0279] 2-{(17E)-11-(Fluoromethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0280] (2S)-1-{(10R,17E)-12-Ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-2-ol;

[0281] (2S)-2-[(11S,17E)-16-Ethoxy-19-fluoro-8,11-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0282] (2S)-2-[(10R,17E)-16-Ethoxy-19-fluoro-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0283] (2S)-2-{(11S,17E)-19-Fluoro-8,11-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-1-ol;

[0284] (2S)-2-{(10R,17E)-19-Fluoro-8,10-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-1-ol;

[0285] 2-{(10S,17E)-12-Ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}acetamide;

[0286] (10S,17E)-19-Fluoro-14-(2-hydroxyethyl)-8,10,12-trimethyl-2-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-ol;

[0287] 2-[(8aR,19E)-1-(cyclopropylmethoxy)-22-fluoro-9,11-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0288] (10R,18E)-17-Ethoxy-8,15-dimethyl-2,8,11,12,14,15-hexahydro-10H-3,5-etheno-10,13-methanotripyrazolo[3,4-g:3’,4’-k:4’’,3’’-o][1,5]oxazacyclohexadecine;

[0289] {(17E)-14-(2-hydroxyethyl)-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,10,11,12,13,14-hexahydro-7H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-7-yl}acetonitrile;

[0290] (17E)-16-Ethoxy-8,14-dimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno-10,12-methanotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin;

[0291] 2-[(10S,17E)-16-Ethoxy-19-fluoro-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0292] 2-[(8aR,9R,19E)-1-Ethoxy-9,11-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0293] 2-[(8aR,9S,19E)-1-Ethoxy-9,11-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0294] 2-[(19E)-18-Ethoxy-8,21-dimethyl-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecin-16(8H)-yl]ethan-1-ol;

[0295] 2-[(8aR,9R,19E)-1-Ethoxy-22-fluoro-9,11-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0296] 2-[(8aR,9S,19E)-1-Ethoxy-22-fluoro-9,11-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0297] 2-[(19E)-18-Ethoxy-22-fluoro-8,21-dimethyl-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecin-16(8H)-yl]ethan-1-ol;

[0298] 2-{(10S,17E)-8-Cyclopropyl-10,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0299] (10S,13S,19E)-18-Ethoxy-8,13,16-trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0300] (10R,13R,19E)-18-Ethoxy-8,13,16-trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0301] (10R,13S,19E)-18-Ethoxy-8,13,16-trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0302] (10S,13R,19E)-18-Ethoxy-8,13,16-trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0303] 2-{ (10R,17E)-19-Fluoro-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl}ethan-1-ol;

[0304] 2-[(8aR,9S,19E)-9,11-Dimethyl-1-[(propan-2-yl)oxy]-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecine-3(4H)-yl]ethan-1-ol;

[0305] 2-[(8aR,9R,19E)-9,11-Dimethyl-1-[(propan-2-yl)oxy]-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecine-3(4H)-yl]ethan-1-ol;

[0306] 2-[(19E)-8,21-Dimethyl-18-[(propan-2-yl)oxy]-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecin-16(8H)-yl]ethan-1-ol;

[0307] 2-[(8aR,9R,19E)-22-Fluoro-9,11-dimethyl-1-[(propan-2-yl)oxy]-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0308] 2-[(8aR,9S,19E)-22-Fluoro-9,11-dimethyl-1-[(propan-2-yl)oxy]-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0309] 2-[(19E)-22-Fluoro-8,21-dimethyl-18-[(propan-2-yl)oxy]-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecin-16(8H)-yl]ethan-1-ol;

[0310] 2-{(10R,17E)-10-(Hydroxymethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0311] 2-[(11S,17E)-16-Ethoxy-11-ethyl-8,12-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0312] 2-[(10S,17E)-16-Ethoxy-10-ethyl-8,12-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0313] 2-[(10S,17E)-16-(Methoxymethyl)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0314] 1-{(10S,17E)-12-Ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}-2-methylpropan-2-ol;

[0315] 1-{(10S,17E)-12-Ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-2-one;

[0316] (10R,17E)-14-(2-Hydroxyethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-10-carbonitrile;

[0317] 2-{(10S,17E)-8,10,12-Trimethyl-16-[(methylamino)methyl]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0318] 2-{(10S,17E)-16-[(dimethylamino)methyl]-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol:

[0319] (2R)-2-{[(10S,17E)-19-Fluoro-14-(2-hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-yl]oxy}propanenitrile;

[0320] (2S)-2-{[(10S,17E)-19-Fluoro-14-(2-hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-yl]oxy}propanenitrile;

[0321] 2-[(4aS,7aS,13E)-12-Ethoxy-3,6,8-trimethyl-4a,5,6,7,7a,8,9,16-octahydro-17,19-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[3,4-b][1,4]oxazacyclopentadecin-10(3H)-yl]ethan-1-ol;

[0322] 2-[(4aR,7aR,13E)-12-Ethoxy-3,6,8-trimethyl-4a,5,6,7,7a,8,9,16-octahydro-17,19-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[3,4-b][1,4]oxazacyclopentadecin-10(3H)-yl]ethan-1-ol;

[0323] {[(8aR,19E)-3-(2-Hydroxyethyl)-9,11-dimethyl-3,4,7,8,8a,9,11,17-octahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-1-yl]oxy}acetonitrile;

[0324] {[(8aR,9R,19E)-3-(2-Hydroxyethyl)-9,11-dimethyl-3,4,7,8,8a,9,11,17-octahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-1-yl]oxy}acetonitrile;

[0325] 2-{(10S,17E)-10-(Difluoromethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0326] 2-{(10R,17E)-10-(difluoromethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0327] 2-{(10S,17E)-8,10-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0328] 2-[(10R,17E)-16-ethoxy-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0329] (4aS,7aS,13E)-12-ethoxy-3,8,10-trimethyl-3,4a,5,6,7,7a,8,9,10,16-decahydro-17,19-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[3,4-b][1,4]oxazacyclopentadecine;

[0330] (4aR,7aR,13E)-12-ethoxy-3,8,10-trimethyl-3,4a,5,6,7,7a,8,9,10,16-decahydro-17,19-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[3,4-b][1,4]oxazacyclopentadecine;

[0331] (2S)-1-{(10S,17E)-12-Ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-2-ol;

[0332] 2-{(11R,17E)-19-Fluoro-8,11-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0333] 2-{(10S,17E)-19-Fluoro-8,10-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0334] 2-[(11R,17E)-16-Ethoxy-19-fluoro-8,11-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-!4H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0335] 2-[(10S,17E)-16-Ethoxy-19-fluoro-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0336] {(10S,17E)-19-Fluoro-14-(2-hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-yl}oxyacetonitrile;

[0337] 2-[(10R,17E)-12-Ethyl-19-fluoro-16-methoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0338] (2S)-2-[(10R,17E)-16-Ethoxy-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0339] 2-[(10S,17E)-16-Ethoxy-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0340] (2S)-2-[(10R,17E)-12-Ethyl-19-fluoro-16-methoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0341] (10S,17E)-16-Ethoxy-12-ethyl-14-(2-hydroxyethyl)-8,10-dimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-6-carbonitrile;

[0342] 2-[(10S,17E)-16-Ethynyl-6-ethynyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0343] 2-[(10S,17E)-12-Ethyl-19-fluoro-16-methoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0344] 2-[(10S,17E)-16-(Ethylamino)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0345] (2S)-1-{(10S,17E)-12-Ethyl-19-fluoro-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-2-ol;

[0346] 2-[(10S,17E)-6-amino-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0347] (2S)-2-[(10S,17E)-12-ethyl-19-fluoro-16-methoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0348] 2,2’-[(10S,17E)-10,12-dimethyl-16-[(propan-2-yl)oxy]-10,11,12,13-tetrahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-8,14(2H)-diyl]di(ethan-1-ol);

[0349] (17E)-16-ethyl-8,14-dimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0350] 2-[(17E)-8,16-dimethyl-2,10,11,13-tetrahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14(8H)-yl]-N-ethylacetamide;

[0351] (17E)-8,14-dimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole-16-carbonitrile;

[0352] (17E)-8,14,16-Trimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0353] (10S,17E)-8,10,14-Trimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0354] (10S,17E)-8,10,14-Trimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole-16-carbonitrile;

[0355] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[6,5-d][1,2]oxazole-16-carbonitrile;

[0356] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[6,5-d][1,2]thiazole-16-carbonitrile;

[0357] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[5,6-c][1,2]oxazole-16-carbonitrile;

[0358] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[5,6-c][1,2]thiazole-16-carbonitrile; and

[0359] (10S,17E)-16-Ethyl-8,10,14-trimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0360] A compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

[0361] 34. (17E)-8,15,16-Trimethyl-2,8,9,11,12,15-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[11,10-c:15,14-c’:6,7-c’’]tripyrazole;

[0362] (17E)-8,15,16-Trimethyl-2,11,12,15-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0363] 1-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]propan-2-one;

[0364] 1-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]-2-methylpropan-2-ol;

[0365] 2-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]ethan-1-ol;

[0366] (17E)-8,16-Dimethyl-15-[2-(pyrrolidin-1-yl)ethyl]-2,11,12,15-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0367] (10S,17E)-8,10,15,16-Tetramethyl-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0368] (17E)-8,15,16-Trimethyl-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0369] 1-[(17E)-8,15,16-Trimethyl-2,8,10,11,13,15-hexahydro-12H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-12-yl]ethan-1-one;

[0370] (17E)-8,12,15,16-Tetramethyl-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0371] 1-[(10S,17E)-8,10,15,16-Tetramethyl-2,8,10,11,13,15-hexahydro-12H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-12-yl]ethan-1-one;

[0372] (10S,17E)-8,10,12,15,16-Pentamethyl-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0373] 2-[(10S,17E)-8,10,16-Trimethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]ethan-1-ol;

[0374] 2-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]ethan-1-ol;

[0375] (10S,17E)-12-Ethyl-8,10,15,16-tetramethyl-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0376] 1-[(10S,17E)-8,10,15,16-Tetramethyl-2,8,10,11,13,15-hexahydro-12H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-12-yl]propan-1-one;

[0377] 2-[(19E)-8,13,18-Trimethyl-2,8,11,12,13,14-hexahydro-10H,17H-3,5-etheno[1,7]dioxacycloheptadecano[12,13-c:17,16-c’:8,9-c’’]tripyrazol-17-yl]ethan-1-ol;

[0378] (13E)-3-Methyl-3,5,6,7,8,16-hexahydro-9,12-(azeno)-17,19-ethenodipyrazolo[3,4-l:4’,3’-p][1,6]oxazacycloheptadecine;

[0379] (18E)-8-Methyl-2,8,10,11,12,13-hexahydro-3,5-ethenotripyrazolo[1,5-f:3’,4’-j:4’’,3’’-n][1,6]oxazacyclopentadecine;

[0380] (17E)-15-(2-Methoxyethyl)-8,16-dimethyl-2,11,12,15-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0381] 2-[(17E)-8,9,16-Trimethyl-8,9,11,12-tetrahydro-3,5-etheno[1,4]dioxacyclopentadecano[11,10-c:15,14-c’:6,7-c’’]tripyrazol-15(2H)-yl]ethan-1-ol;

[0382] (rac)-4-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]piperidin-3-ol;

[0383] (rac)-4-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]-1-methylpiperidin-3-ol;

[0384] (17E)-8,9,16-Trimethyl-15-[2-(pyrrolidin-1-yl)ethyl]-2,8,9,11,12,15-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[11,10-c:15,14-c’:6,7-c’’]tripyrazole;

[0385] (rac)-1,5-Anhydro-2,3-dideoxy-3-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]-L-threo-pentitol;

[0386] 1,5-Anhydro-2,4-dideoxy-2-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]-L-threo-pentitol;

[0387] (10S,17E)-8,10,12,16-Tetramethyl-15-[2-(pyrrolidin-1-yl)ethyl]-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0388] (10S,17E)-8,10,12,16-Tetramethyl-15-[2-(4-methylpiperazin-1-yl)ethyl]-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0389] (20E)-8,18-Dimethyl-2,8,11,12-tetrahydro-10H-3,5-ethenodipyrazolo[3’’,4’’:10’,11’;4’’’,3’’’:14’,15’][1,5]dioxacyclopentadecinol[6’,7’:3,4]pyrazolo[1,5-a]pyrazin-19(18H)-one;

[0390] (10S,17E)-8,10,12,16-Tetramethyl-15-[2-(morpholin-4-yl)ethyl]-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0391] 4-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]butan-2-ol;

[0392] N 1 -{(1s,3s)-3-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecinol[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]cyclobutyl}-N 1 ,N2,N2-Trimethylethane-1,2-diamine;

[0393] 2-Methyl-4-[(10S,17E)-8,10,12,16-tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]butan-2-ol;

[0394] 2-Methyl-1-[(10S,17E)-8,10,12,16-tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]propan-2-ol;

[0395] N2-{ (1s,3s)-3-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecin[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]cyclobutyl}-N 1 ,N 1 -dimethyl ethane-1,2-diamine;

[0396] (17E)-8,10,16-Trimethyl-15-(1-methylpyrrolidin-3-yl)-2,9,10,11,12,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0397] (10R,17E)-8,10,12,16-Tetramethyl-15-[2-(pyrrolidin-1-yl)ethyl]-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0398] (2S)-1-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]propan-2-ol;

[0399] (10S,17E)-8,10,12,14,15-Pentamethyl-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[4,3-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0400] (2R)-1-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]propan-2-ol;

[0401] (10S,17E)-8,10,12,14,16-Pentamethyl-2,10,11,12,13,16-hexahydro-8H-3,5-ethenotripyrazolo[4,3-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0402] (10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[3,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0403] (10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0404] (10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-3,5-ethenodipyrazolo[3,4-j:4’,3’-n][1,2]thiazolo[3,4-f][1,4]oxazacyclopentadecine;

[0405] (10S,20E)-18-[2-(Methanesulfonyl)ethyl]-8,10,12-trimethyl-2,8,10,11,12,13,16,17,18,19-decahydro-3,5-ethenopyrazino[1’,2’:1,5]pyrazolo[3,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0406] (10S,17E)-16-Cyclopropyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0407] (10S,17E)-16-Ethyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0408] (10S,17E)-8,10,12-Trimethyl-16-(propan-2-yl)-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0409] (10S,17E)-8,10,12-Trimethyl-16-(propan-2-yl)-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0410] (10S,17E)-16-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0411] (10R,17E)-8,10,14,15-Tetramethyl-12-(propan-2-yl)-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[4,3-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0412] (10S,17E)-8,10,14,15-Tetramethyl-12-(propan-2-yl)-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[4,3-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0413] (10S,17E)-8,10,16-Trimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecino[7,6-d][1,2]oxazole;

[0414] (10S,17E)-8,10-Dimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecino[7,6-d][1,2]oxazole-16-carbonitrile;

[0415] (10S,17E)-8,10,16-Trimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecino[7,6-d][1,2]thiazole;

[0416] (10S,17E)-8,10-Dimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[7,6-d][1,2]thiazole-16-carbonitrile;

[0417] (10S,17E)-8,10,16-Trimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]oxazole;

[0418] (10S,17E)-8,10-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]oxazole-16-carbonitrile;

[0419] (10S,17E)-8,10,16-Trimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]thiazole;

[0420] (10S,17E)-8,10-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]oxazole-16-carbonitrile;

[0421] (10S,17E)-8,10-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]thiazole-16-carbonitrile;

[0422] (17E)-8,16-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]oxazole;

[0423] (17E)-8,16-Dimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[7,6-d][1,2]oxazole; and

[0424] (17E)-8,16-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]thiazole;

[0425] A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, selected from the group consisting of

[0426] 35. A pharmaceutical composition comprising a compound according to any of the preceding claims and, optionally, one or more additives.

[0427] 36. A method of treating a disease in a subject, comprising administering a therapeutically effective amount of a compound according to any of claims 1 to 34 or the pharmaceutical composition of claim 35.

[0428] 37. A compound according to any of claims 1 to 34 for use in a method of treating a disease in a subject.

[0429] 38. Use of a compound according to any of claims 1 to 34 in the manufacture of a medicament for the treatment of a disease in a subject. DETAILED DESCRIPTION

[0430] 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 they may vary. It should also be understood that the terms used herein are for the purpose of only the specific embodiments and are not intended to be limiting, as the scope of the present invention is limited only by the appended claims.

[0431] For brevity, the disclosures of publications cited in this specification, including patents, are incorporated herein by reference. 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. All patents, patent applications, published applications and other publications cited herein are incorporated herein by reference in their entirety. If the definitions set forth in this section are contrary to or otherwise inconsistent with the definitions in the patents, patent applications or other publications incorporated herein by reference, the definitions set forth in this section shall control.

[0432] In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. It should be further noted that the claims may have been drafted to exclude any optional element. That is, this description is intended to serve as a basis for the use of exclusionary terms such as "merely", "only", etc. or the use of "negative" limitations in connection with the recitation of elements in the claims.

[0433] The terms "comprising" and "including" as used herein are used in an open, non-limiting sense.

[0434] For the sake of greater accuracy of description, some of the quantitative expressions shown herein are not modified by the term "about". Whether or not the term "about" is explicitly used, all of the amounts shown herein mean the actually indicated values, and also include equivalents and approximations due to experimental and / or measurement conditions of such indicated values, and it is to be understood that it is also intended to refer to approximations of such indicated values reasonably inferred based on ordinary techniques in the art. When a yield is not shown as a percentage, such a yield refers to the mass of the same substance, which is the yield shown with respect to the maximum amount of the substance that can be obtained under specific stoichiometric conditions. Concentrations shown as percentages refer to mass ratios, unless otherwise indicated.

[0435] 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. Methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, but 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 related methods and / or materials cited in the publications.

[0436] Unless otherwise indicated, the methods and techniques in this embodiment are generally carried out according to the customary usage well known in the art and as described in various general and more specific cited references cited and described throughout this specification. See, for example, Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360 - 361, 1084 - 1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley - Interscience, 2001.

[0437] The naming of the compounds described herein is generally derived using commercially available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0438] With respect to the chemical structures used herein and described in the various embodiments herein, "*", "**", and

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[0439] It is also recognized that, for clarity, certain features of the invention described in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may be provided separately or in any suitable sub-combination. All combinations of embodiments involving chemical groups represented by variable groups are specifically included by this disclosure, and each and every combination is included herein to the same extent as if individually and explicitly disclosed, provided that the combination is a compound that is a stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity). Further, all sub-combinations of such chemical groups listed in the embodiments describing variable groups are also specifically included in the present invention and are disclosed herein to the same extent as each and every such sub-combination of chemical groups is individually and explicitly disclosed herein.

[0440] Chemical Definitions The term "alkyl" refers to a straight or branched chain monovalent hydrocarbon group. The term "alkylene" refers to a straight 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 12It may be advantageous to limit the number of atoms of "alkyl" or "alkylene" to a specific atomic range such as alkylene or C1-C6 alkyl or C1-C6 alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl and groups that may be considered equivalent to any of the foregoing examples in light of 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 the alkyl or alkylene group may be unsubstituted or substituted as described herein. The alkyl or alkylene group may be substituted with any of the substituents described in the various embodiments herein and may contain one or more of such substituents and be substituted.

[0441] 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 of "alkenyl" or "alkenylene" to a specific atomic range such as alkenylene or C2-C6 alkenyl or C2-C6 alkenylene. 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. Cis and trans isomers and mixtures thereof are included within the scope of this term. It is recognized that alkenyl or alkenylene groups can be unsubstituted or substituted as described herein. Alkenyl or alkenylene groups can be substituted with one or more of any of the substituents described in the various embodiments described herein.

[0442] 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 of "alkynyl" or "alkynylene" to a specific atomic range such as alkynylene or C2-C6 alkynyl or C2-C6 alkynylene. 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 can be unsubstituted or substituted as described herein. Alkynyl or alkynylene groups can be substituted with one or more of any of the substituents described in the various embodiments described herein.

[0443] 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 of "cycloalkyl" or "cycloalkylene" to a specific atomic range such as having 3 to 12 ring atoms. Polycyclic carbocyclic rings include fused, bridged and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include the following monovalent radicals, while cycloalkylene groups include the following divalent radicals in the form of appropriately bonded moieties:

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[0444] The term "halogen" or "halo" represents chlorine, fluorine, bromine or iodine.

[0445] 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)-.

[0446] The term "aryl" refers to a monocyclic or fused polycyclic group of all carbon with a fully conjugated pi electron system. The term "arylene" refers to a divalent monocyclic or fused polycyclic group of all carbon with a fully conjugated pi electron system. In certain embodiments, it may be advantageous to limit the number of atoms of "aryl" or "arylene" to specific atomic ranges such as a monocyclic or fused polycyclic group of all carbon with 6 to l4 carbon atoms (C6-C 14 aryl), a monocyclic or fused polycyclic group of all carbon with 6 to 10 carbon atoms (C 6- C 10 aryl), a divalent monocyclic or fused polycyclic group of all carbon with 6 to 14 carbon atoms (C6-C 14 arylene), a divalent monocyclic or fused polycyclic group of all carbon with 6 to 10 carbon atoms (C6C 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 can be unsubstituted or substituted as described herein. An aryl or arylene group can be substituted with one or more of any of the substituents in the various embodiments described herein.

[0447] The term "heterocycloalkyl" refers to a saturated or partially saturated, monovalent monocyclic or polycyclic ring structure having one or more non-carbon ring atoms. The term "heterocycloalkylene" refers to a saturated or partially saturated, divalent 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 ring atoms of "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), 5 to 7 ring atoms (5 to 7-membered), or 4 to 10 ring atoms (4 to 10-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, 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 carbocyclic member or an imino group or up to 2 oxo groups on a sulfur ring member. Illustrative examples of heterocycloalkyl groups include the following monovalent radicals, while heterocycloalkylene groups include the following divalent radicals in the form of appropriately linked moieties:

Chemical formula

[0448] The 3-membered heterocycle may contain at least one heteroatomic ring atom, where the heteroatomic ring atom 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 one heteroatomic ring atom, where the heteroatomic ring atom 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 heteroatomic ring atoms, where (a) at least one 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 heteroatomic ring atoms, where (a) at least one 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 containing one heterocyclic ring fused to a cycloalkyl or other heterocyclic ring.

[0449] It is recognized that a heterocycloalkyl or heterocycloalkylene group may be unsubstituted or substituted as described herein. A heterocycloalkyl or heterocycloalkylene group may be substituted with any of the substituents described herein and may contain one or more of such substituents.

[0450] The term "heteroaryl" refers to a monovalent monocyclic, fused bicyclic or fused polycyclic aromatic heterocycle (a ring structure having ring atoms or members selected from carbon atoms and up to 4 heteroatoms selected from up to 4 nitrogen, oxygen and sulfur atoms), which 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 heterocycle (a ring structure having ring atoms or members selected from carbon atoms and up to 4 heteroatoms selected from up to 4 nitrogen, oxygen and sulfur atoms) having 3 to 12 ring atoms per heterocycle. In certain embodiments, it may be advantageous to limit the number of ring atoms of "heteroaryl" or "heteroarylene" to a particular range of ring atoms, such as 5- to 10-membered heteroaryl or 5- to 10-membered heteroarylene. In certain cases, a 5- to 10-membered heteroaryl may be a monocyclic ring or a fused bicyclic ring having 5 to 10 ring atoms, where at least one ring atom is a heteroatom such as N, O or S. In certain cases, a 5- to 10-membered heteroarylene may be a monocyclic ring or a fused bicyclic ring having 5 to 10 ring atoms, where at least one ring atom is a heteroatom such as N, O or S. The ring structure may optionally contain an oxo group on a carbocyclic member or an imino group or up to 2 oxo groups on a sulfur ring member. Illustrative examples of 5- to 10-membered heteroaryl groups include the following monovalent radicals, while examples of 5- to 10-membered heteroarylene groups include the following divalent radicals in the form of appropriately linked moieties:

Chemical formula

[0451] In certain embodiments, a “monocyclic” heteroaryl can be an aromatic 5- or 6-membered heterocycle. A 5-membered heteroaryl or heteroarylene can 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 can 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 one heteroaryl ring fused to a phenyl or other heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.Non-limiting examples of bicyclic heteroarylene groups include 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.

[0452] In particular, the pyrazolyl moiety has the structural formula

Chemical formula

Chemical formula

[0453] It is recognized that the heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. The heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein and can include one or more of such substituents.

[0454] The term "oxo" represents a carbonyl oxygen. For example, cyclopentyl substituted with oxo is cyclopentanone.

[0455] The term "substituted" means that a particular group or moiety has one or more substituents. The term "unsubstituted" means that a particular group has no substituents. When the term "substituted" is used to refer to a structural system, it is assumed that the substitution occurs at a position allowed by any valence of the system. In certain embodiments, "substituted" means that a particular group or moiety has one, two, or three substituents. In other embodiments, "substituted" means that a particular group or moiety has one or two substituents. In yet other embodiments, "substituted" means that a particular group or moiety has one substituent.

[0456] All formulas described herein are intended to represent compounds of the structural formulas and certain variations 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, any formula shown herein is also intended to refer to hydrates, solvates or polymorphs of such compounds or mixtures thereof.

[0457] All formulas described herein are also intended to represent unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structure represented by the formulas shown herein, provided that one or more atoms are replaced with atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the 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), in kinetic studies (e.g., 2 H or 3 H), in detection or imaging techniques [e.g., positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays] or in the radiotherapy 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 replacing the non-isotopically labeled reagents with readily available isotopically labeled reagents in the preparation of the following schemes or examples and the implementation of the disclosed methods of manufacture.

[0458] Certain chemical substances of formulas (I) to (XII) can be represented in two or more tautomeric forms. Any and all alternative tautomers are included within the scope of these formulas, and it should not be inferred whether they exist with respect to the tautomeric forms in which the chemical substances are described. It is understood that certain chemical substances described herein can exist in various tautomeric forms. It is readily recognized by those skilled in the art that due to rapid interconversion, tautomers can generally be regarded as the same compound. Examples of tautomers include, but are not limited to, enol-keto tautomers, amine-imine tautomers, etc.

Chemical formula

[0459] The nomenclature “(atom) i- (atom) j ” (where j > i) is intended to refer to embodiments of the present invention in which, when applied to classes of substituents, each and all of the atomic members from i to j, including i and j, are independently recognized. By way of example, the term C 1- C3 refers independently to embodiments having 1 carbon member (C1), embodiments having 2 carbon members (C2), and embodiments having 3 carbon members (C3).

[0460] Any disubstituent referred to herein is intended to encompass various bonding possibilities when more than one location is allowed. For example, the disubstituent -J-K- (where J ≠ K) herein refers to a disubstituent in which J is bonded to the first substitution member and K is bonded to the second substitution member, and also refers to a disubstituent in which J is bonded to the second substitution member and K is bonded to the first substitution member.

[0461] It is recognized that some of the compounds described herein contain one or more positions at which they can exist as stereoisomers. For example, some of the compounds described herein contain one or more carbon atoms that can exist in one or more stereoisomeric configurations. It is recognized that carbon atoms described without any indication of stereoisomeric configuration and for which stereoisomeric configurations can exist include the disclosure of each of the possible stereoisomeric configurations. For example, a carbon atom having four groups that can be prioritized according to the Cahn-Ingold Prelog Rules known to those skilled in the art is described without a specific stereochemical definition as in the structure on the left below and is also understood to be described as both of the possible stereoisomers (S) and (R) shown below:

Chemical formula

[0462] The present invention includes compounds represented by formulas (I) to (XII), preferably pharmaceutically acceptable salts of the above and specific compounds exemplified herein, pharmaceutical compositions containing such salts, and methods of using such salts.

[0463] "Pharmaceutically acceptable salts" are intended to mean salts of the compounds of the herein shown free acids or bases which are non-toxic, biologically acceptable or otherwise biologically suitable for administration to the subject. See generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those which are pharmacologically effective and suitable for contact with the tissues of the 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 can thus react with several inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0464] 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.

[0465] Regarding compounds of formulas (I)-(XII) containing 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, etc. 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 mixture of the acids exemplified herein and, in view of the normal levels in the art, any other acid and mixtures thereof recognized as equivalent or acceptable alternatives and can be prepared by treatment therewith.

[0466] The present invention also relates to pharmaceutically acceptable prodrugs of the compounds of formulas (I)-(XII) and methods of treatment using such pharmaceutically acceptable prodrugs. The term "prodrug" refers to a precursor of a designated compound that, upon administration to a subject, yields the compound in vivo by chemical or physiological processes 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)-(XII)). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically acceptable 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.

[0467] The present invention also relates to pharmaceutically active metabolites of the compounds of formulas (I)-(XII) and the use of such metabolites in the methods of the present invention. A "pharmaceutically active metabolite" is a pharmacologically active product of the metabolism in vivo of a compound of formula (I)-(XII) or a salt thereof. Prodrugs and active metabolites of a compound 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,

[0468] Representative embodiments In certain embodiments, the present invention provides a compound of formula I

Chemical formula

[0469] (wherein R 1 , R 2 , R 3 , R 4 , A, B, L, m, n, p and q are as described herein.) or a pharmaceutically acceptable salt thereof. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p is -O-CR 6 R7 - Does not contain a fragment.

[0470] In certain embodiments, the present invention provides a compound of formula II

Chemical formula

[0471] (wherein R 1 , R 2 , R 3 , R 4 , A, B, L, Y, m, n, p, and q are as described herein.) or a pharmaceutically acceptable salt thereof. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p does not contain an -O-CR 6 R 7 -fragment that is covalently bonded directly to ring A.

[0472] In certain embodiments, the present invention provides a compound of formula III

Chemical formula

[0473] (wherein R 1 , R 2 , R 3 , R 4 , A, B, L, Z, Z 1 , m, n, p, and q are as described herein.) or a pharmaceutically acceptable salt thereof. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p does not contain an -O-CR 6 R 7 -fragment that is covalently bonded directly to ring A.

[0474] In certain embodiments, the present invention provides a compound of formula IV [Chemical formula]

[0475] (wherein R 2 , R 3 , R 4 , A, B, L, X 1 , X 2 , X 3 , Z, Z 1 , m, n, p and q are as described herein.) A compound of or a pharmaceutically acceptable salt thereof is provided. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p does not contain an -O-CR 6 R 7 -fragment that is covalently bonded directly to ring A.

[0476] In certain embodiments, the present invention provides a compound of formula V [Chemical formula]

[0477] (wherein R 1 , R 2 , R 3 , R 4 , A, B, L, m, n and p are as described herein.) A compound of or a pharmaceutically acceptable salt thereof is provided. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p does not contain an -O-CR 6 R 7 -fragment that is covalently bonded directly to ring A.

[0478] In certain embodiments, the present invention provides a compound of formula VI [Chemical formula]

[0479] (wherein R 1 、R 2 、R 3 、R 4 、A, B, L, Y, m, n and p are as described herein.) A compound of or a pharmaceutically acceptable salt thereof is provided. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p does not contain an -O-CR 6 R 7 -fragment that is covalently bonded directly to ring A.)

[0480] In certain embodiments, the present invention provides a compound of formula VII

Chemical formula

[0481] (wherein R 1 、R 2 、R 3 、R 4 、A, B, L, Z, Z 1 、m, n and p are as described herein.) A compound of or a pharmaceutically acceptable salt thereof is provided. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p does not contain an -O-CR 6 R 7 -fragment that is covalently bonded directly to ring A.)

[0482] In certain embodiments, the present invention provides a compound of formula VIII

Chemical formula

[0483] (wherein R 2 、R 3 、R4 , A, B, L, X 1 , X 2 , X 3 , Z, Z 1 , m, n and p are as described herein. ) provides a compound or a pharmaceutically acceptable salt thereof. In certain embodiments of this aspect, (L) p does not contain -NR 5 C(O)- that is covalently bonded directly to ring A. In certain embodiments of this aspect, (L) p does not contain an -O-CR 6 R 7 -fragment that is covalently bonded directly to ring A.

[0484] In certain embodiments, the present invention provides a compound of formula IX

Chemical formula

[0485] (wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , A, B, m, n, p1 and q are as described herein. ) provides a compound or a pharmaceutically acceptable salt thereof.

[0486] In certain embodiments, the present invention provides a compound of formula X

Chemical formula

[0487] [[ID= fifty-nine]](wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , A, B, Z, Z 1 , m, n, p1 and q are as described herein. ) provides a compound or a pharmaceutically acceptable salt thereof.

[0488] In certain embodiments, the present invention provides a compound of formula XI [Chemical formula]

[0489] (wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , A, B, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , Z, Z 1 , p1 and q are as described herein.) A compound or a pharmaceutically acceptable salt thereof is provided.

[0490] In certain embodiments, the present invention relates to formula XII [Chemical formula]

[0491] (wherein R 3 , R 4 , R 6 , R 7 , A, B, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , Z, Z 1 and q are as described herein.) A compound or a pharmaceutically acceptable salt thereof is provided.

[0492] In certain embodiments, ring B is a 5- to 10-membered heteroarylene or C6-C 10 arylene. In certain embodiments, ring B is a monocyclic or bicyclic C6-C 10 arylene or a monocyclic or bicyclic 5- to 10-membered heteroarylene.

[0493] In certain embodiments, ring A is a 5- to 10-membered heteroarylene. In certain embodiments, ring A is a 5- or 6-membered heteroarylene. In certain embodiments, ring A is a 5-membered heteroarylene. In certain embodiments, ring A is a 6-membered heteroarylene. In certain embodiments, ring A is a fused bicyclic 8- to 10-membered heteroarylene.

[0494] In certain embodiments, ring A is a 5- to 10-membered heteroarylene such as a monocyclic 5- or 6-membered heteroarylene or a bicyclic 8- to 10-membered heteroarylene, wherein each hydrogen atom in the 5- to 10-membered heteroarylene described herein is independently optionally 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 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, where R 1 is substituted, and here, 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 c )5], -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 , -NR 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 、 is substituted with -CN or -NO2.

[0495] In certain embodiments, ring A is pyrrolylene, isoxazolylene, isothiazolylene, pyrazolylene or imidazolylene, wherein each hydrogen atom in pyrrolylene, isoxazolylene, isothiazolylene, pyrazolylene and imidazolylene is independently optionally deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, a 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, a 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 , -NRC(O)R b , -NR a , -NRC(O)OR b , -NR a , -NRC(O)NR a R b , -NR a , -NRS(O)R b , -NR a , -NRS(O)₂R b , -NR a , -NRS(O)NR a R b , -NR a , -NRS(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 , R is replaced by -CN or -NO₂, where C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-7 membered heterocycloalkyl, C₆-C 1 , 6 10Each hydrogen atom in aryl or 5- to 10-membered heteroaryl may independently be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c 、-OC(O)R c 、-OC(O)NR c R d 、-OC(=N)NR c R d 、-OS(O)R c 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d 、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=N)NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=N)NR c R d 、-PR c R d 、-P(O)Rc 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 、 is substituted with -CN or -NO2.

[0496] In certain embodiments, ring A is pyridinylene, pyrazinylene, pyrimidinylene or pyridazinylene, where each hydrogen atom in pyridinylene, pyrazinylene, pyrimidinylene or pyridazinylene is independently optionally 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 aS(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 substituted R 1 and 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 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)Rc )(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 or -NO2 substituted.

[0497] In one embodiment, ring A is a 5- to 10-membered heteroarylene such as a monocyclic 5- or 6-membered heteroarylene or a bicyclic 8- to 10-membered heteroarylene, where the 5- to 10-membered heteroarylene described herein is optionally substituted with 1, 2, 3, 4, or 5 R 1 (m R 1 ), each of which is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -ORa 、 -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[[ID=�0]] 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, independently selected from the group consisting of -CN and -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in aryl or 5- to 10-membered heteroaryl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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)NRc 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 or -NO2 substituted. In certain embodiments, two Rs 1 together with the atoms to which they are attached form, together, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl formed when the two Rs 1 are joined together is independently optionally -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

[0498] In one embodiment, ring A is pyridinylene, pyrazinylene, pyrimidinylene or pyridazinylene, where each is optionally substituted with 1, 2, 3, 4 or 5 R 1 (m R 1 ), and each of which is 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 , -NRa 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, independently selected from the group consisting of, 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 may independently be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 、 -NR d 、 -N(C(O)R c )(C(O)R d )、 -NR c 、 -NR d 、 -NR c C(O)NR c R d 、 -NR c C(=N)NR c R d 、 -NR c 、 -NR 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 or -NO2. In certain embodiments, ring A is pyridinylene, pyrazinylene, pyrimidinylene or pyridazinylene, where two Rs in the pyridinylene, pyrazinylene, pyrimidinylene or pyridazinylene described herein 1 together with the atoms to which they are attached form C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, where two Rs 1 each hydrogen atom in the C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl formed together is independently optionally -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PRe R f 、 -P(O)R e R f 、 -P(O)₂R e R f 、 -P(O)NR e R f 、 -P(O)₂NR e R f 、 -P(O)OR e 、 -P(O)₂OR e 、 is substituted with -CN or -NO₂.

[0499] In certain embodiments, ring A is pyrrolylene, isoxazolylene, isothiazolylene, pyrazolylene or imidazolylene, where each is optionally substituted with 1, 2, 3, 4 or 5 R 1 (m R's 1 ), and each of which is deuterium, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C 10 aryl, 5- 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)Rb , -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 and -NO2, independently selected from the group consisting of, 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 c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O)2R c , -OS(O)NR c R d , -OS(O)2NR c R d , -SR c , -S(O)R c , -S(O)2R c , -S(O)NR c R d , -S(O)2NR c R d , -NR c R d, -NR c C(O)R d , -N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)R c R d , -P(O)2R c R d , -P(O)NR c R d , -P(O)2NR c R d , -P(O)OR c , -P(O)2OR c , -CN or -NO2 substituted. In certain embodiments, two Rs in the pyrrolilenes, isoxazolilenes, isothiazolilenes, pyrazolilenes or imidazolilenes described herein 1 together with the atoms to which they are attached form C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, where two Rs 1 when forming together, each hydrogen atom in the C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl is independently optionally -OR e , -OC(O)R e , -OC(O)NRe R f 、 -OS(O)R e 、 -OS(O)₂R e 、 -OS(O)NR e R f 、 -OS(O)₂NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)₂R e 、 -S(O)NR e R f 、 -S(O)₂NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)₂R f 、 -NR e S(O)NR e R f 、 -NR e S(O)₂NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)₂R e R f 、 -P(O)NR e R f 、 -P(O)₂NR e R f 、 -P(O)OR e 、 -P(O)₂OR e 、 is substituted with -CN or -NO₂.

[0500] In one embodiment, ring A has the formula

Chemical formula

[0501] 〔wherein, Y is a single or double bond, -O-, -S-, =C(H)-, =C(R 1 ), -, -N(H)-, -N(R 1 ), or =N-, and each

Chemical formula

[0502] In certain embodiments, ring A has the formula

Chemical formula

[0503] 〔wherein, Z is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0504] In certain embodiments, ring A has the formula [Chemical formula]

[0505] [wherein,

[0506] X 1 , X 2 and X 3 are each independently -O-, -S-, =C(H)-, =C(R 1 ), -N(H)-, -N(R 1 ), - or =N-, provided that X 1 , X 2 and X 3 at least one of which is not =C(H)- or =C(R 1 );

[0507] Z is [Chemical formula] where * is a shared bond to (L) p and ** is Z1 is a covalent bond point to [Chem.] represents a covalent bond point to ring A, [Chem.] one bond is a single bond and one bond is a double bond **and [Chem.] represents the condition between the bond points of; Z 1 is [Chem.] wherein, *** is a covalent bond point to "=", **** is a covalent bond point to Z, [Chem.] represents a covalent bond point to ring A, [Chem.] one bond is a single bond and one bond is a double bond ****and [Chem.] represents the condition between the bond points of, provided that both Z and Z 1 are not nitrogen atoms. ] is. In certain embodiments, ring A is a 5- to 10-membered heteroarylene. In certain embodiments, ring A is a 5- or 6-membered heteroarylene

[0508] In certain embodiments, m is 0, 1, 2, 3, or 4. In certain embodiments, m is 0, 1, 2, or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 0 or 1. 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.

[0509] In certain embodiments, ring A is

Chemical formula

[0510] where each

Chemical formula

[0511] In certain embodiments, ring A is

Chemical formula

[0512] where each

Chemical formula

[0513] In certain embodiments, ring A is

Chemical formula

[0514] where each

Chemical formula

[0515] In certain embodiments, ring A is

Chemical formula

[0516] where each

Chemical formula

[0517] In certain embodiments, each R 1 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 , -NRa S(O)R b 、 -NR a S(O)2R b 、 -NR a S(O)NR a R b 、 -NR a S(O)2NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -PR a R b 、 -P(O)R a R b 、 -P(O)2R a R b 、 -P(O)NR a R b 、 -P(O)2NR a R b 、 -P(O)OR a 、 -P(O)2OR a 、 -CN or -NO2, 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 may independently be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 Rd , -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 or -NO2 substituted.

[0518] In certain embodiments, each R 1 is independently deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, -CN, -OR a or -C(O)NR a R band wherein each hydrogen atom in C1-C6 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl is independently, optionally, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O)2R c , -OS(O)NR c R d , -OS(O)2NR c R d , -SR c , -S(O)R c , -S(O)2R c , -S(O)NR c R d , -S(O)2NR c R d , -NR c R d , -NR c C(O)R d , -N(C(O)R c )(C(O)R d , -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c Rd 、 -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 、 is substituted with -CN or -NO₂.

[0519] In certain embodiments, each R 1 is independently deuterium, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, 3-7 membered heterocycloalkyl or -C(O)NR a R b wherein each hydrogen atom in C₁-C₆ alkyl, C₃-C₆ cycloalkyl, 3-7 membered heterocycloalkyl is independently deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -OR c 、 -OC(O)R c 、 -OC(O)NR c R d 、 -OC(=N)NR c R d 、 -OS(O)R c 、 -OS(O)₂R c 、 -OS(O)NR c R d 、 -OS(O)₂NR c R d 、 -SR c 、 -S(O)R c 、 -S(O)₂R c 、 -S(O)NR c R d 、 -S(O)₂NR c R d 、 -NR c R d 、 -NR c C(O)R d 、 -N(C(O)R c )(C(O)R d 、 -NR c C(O)OR d 、 -NR c C(O)NR c Rd ,-NR c C(=N)NR c R d ,-NR c S(O)R d ,-NR c S(O)2R d ,-NR c S(O)NR c R d ,-NR c S(O)2NR c R d ,-C(O)R c ,-C(O)OR c ,-C(O)NR c R d ,-C(=N)NR c R d ,-PR c R d ,-P(O)R c R d ,-P(O)2R c R d ,-P(O)NR c R d ,-P(O)2NR c R d ,-P(O)OR c ,-P(O)2OR c ,-CN or substituted with -NO2.

[0520] In certain embodiments, two Rs 1 are combined with the atoms to which they are attached to optionally form, together, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl formed when the two Rs 1 are combined together is independently optionally -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e, -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2.

[0521] In certain embodiments, ring A is [ka] [ka] [ka] [ka] a 5- to 10-membered heteroarylene selected from the group consisting of

[0522] wherein each

Chem.

[0523] In certain embodiments, ring A is

Chem.

[0524] wherein each

Chem.

[0525] In certain embodiments, ring A is a monocyclic or bicyclic C6-C 10 arylene. In certain embodiments, ring A is a monocyclic C6-C 10 arylene. In certain embodiments, ring A is a bicyclic C6-C 10 arylene.

[0526] In certain embodiments, ring A is a C6-C 10 monocyclic or bicyclic arylene, wherein each hydrogen atom in the C6-C 10 monocyclic or bicyclic arylene is independently optionally 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)2Ra , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)2NR a R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2 1 wherein the alkyl is substituted by C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Each hydrogen atom in aryl or 5- to 10-membered heteroaryl is independently, optionally, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O)2R c , -OS(O)NR c R d , -OS(O)2NR c R d , -SR c , -S(O)R c , -S(O)2R c , -S(O)NR c R d , -S(O)2NR c R d , -NR c R d , -NR c C(O)R d , -N(C(O)R c )(C(O)R d , -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR<% c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)Rc 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 、 is substituted with -CN or -NO2.

[0527] In certain embodiments, ring A is phenylene or naphthylene, where each hydrogen atom in the phenylene or naphthylene is independently optionally 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 、 -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 R 1 is substituted by, and here, 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 may independently be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 、 -NRc 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 or -NO2 substituted.

[0528] In one embodiment, ring A is a C6-C 10 monocyclic or bicyclic arylene, where each is optionally substituted with 1, 2, 3, 4 or 5 R 1 (m R 1 ), each of which is 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)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 、 -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, independently selected from the group consisting of, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10Each hydrogen atom in aryl or 5- to 10-membered heteroaryl may independently be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 , -NR d , -N(C(O)R c )(C(O)R d , -NR c , -NR d , -NR c , -NR c R d , -NR c , -NR c R d , -NR c , -NR d , -NR c , -NR d , -NR c , -NR c R d , -NR c , -NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)Rc 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 、 is substituted with -CN and -NO2.

[0529] In certain embodiments, ring A is phenylene or naphthylene, where each is optionally substituted with 1, 2, 3, 4, or 5 R 1 (m R 1 ), and each of which is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, 5- 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 The original text to be translated is as below which wraped by : 、 -NR a S(O)R b 、 -NR a S(O)2R b 、 -NR aS(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 [[ID=?]]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, independently selected from the group consisting of, 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 may optionally be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 It should be noted that there is an unclear "?" in the original text at line 28 which is maintained as it is in the translation. Also, the original text seems to have some formatting or content issues which are translated as accurately as possible while keeping the original structure.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 or -NO2 substituted.

[0530] In certain embodiments, ring A is C6-C 10 arylene and m is as defined herein. In certain embodiments, ring A is phenylene and m is as defined herein.

[0531] In certain embodiments, m is 0, 1, 2, 3 or 4. In certain embodiments, m is 0, 1, 2 or 3. In certain embodiments, m is 0, 1 or 2. In certain embodiments, m is 0 or 1. 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.

[0532] In certain embodiments, each R 1 is independently methyl, ethyl, F, Cl, Br, -CN,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0533] In certain embodiments, ring A is phenylene, m is 1, and R 1 is methyl, ethyl, F, Cl, Br, -CN,

Chemical formula

[0534] In one embodiment, ring A has the formula [Chem.] and wherein each

[0535] each [Chem.] represents a covalent bond point. In one embodiment, ring A has the formula [Chem.] and wherein each

[0536] each [Chem.] represents a covalent bond point.

[0537] In one embodiment, ring B is a 5-membered heteroarylene.

[0538] In one embodiment, ring B is pyrrolylene, isoxazolylene, isothiazolylene, pyrazolylene or imidazolylene, wherein each hydrogen atom in pyrrolylene, isoxazolylene, isothiazolylene, pyrazolylene and imidazolylene is independently optionally 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 , -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 , R is substituted with -CN or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 2 and is substituted, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10Each hydrogen atom in aryl or 5- to 10-membered heteroaryl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c 、-OC(O)R c 、-OC(O)NR c R d 、-OC(=N)NR c R d 、-OS(O)R c 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d 、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=N)NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=N)NR c R d 、-PR c R d 、-P(O)Rc 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 、 is substituted with -CN or -NO2.

[0539] In certain embodiments, ring B is pyrrolylene, isoxazolylene, isothiazolylene, pyrazolylene or imidazolylene, where each is optionally substituted with 1, 2, 3, 4 or 5 R 2 (n R 2 ), each of which is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, 5- 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)2Rb 、 -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, independently selected from the group consisting of, 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 may optionally be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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)NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)R c R d , -P(O)2R c R d , -P(O)NR c R d , -P(O)2NR c R d , -P(O)OR c , -P(O)2OR c , substituted with -CN and -NO2.

[0540] In some embodiments, n is 0, 1, 2, 3 or 4. In some embodiments, n is 0, 1, 2 or 3. In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0541] In certain embodiments, ring B is [Chemical formula] a 5-membered heteroarylene selected from the group consisting of

[0542] where each [Chemical formula] represents a covalent bond point.

[0543] In certain embodiments, ring B is [Chemical formula] a 5-membered heteroarylene selected from the group consisting of

[0544] where each [Chemical formula] represents a covalent bond point, and each R 2 is as described herein independently.

[0545] In certain embodiments, ring B is [Chemical formula] a 5-membered heteroarylene selected from the group consisting of

[0546] where each [Chemical formula] [[ID=og]] represents a covalent bond point.

[0547] In certain embodiments, ring B is [Chemical formula] a 5-membered heteroarylene selected from the group consisting of

[0548] where each [Chemical formula] represents a shared bonding point, and each R 2 is as described independently herein.

[0549] In one embodiment, each R 2 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 , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a Rb 、 -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, -7 membered heterocycloalkyl, C₆-C 10 aryl or 5-10 membered heteroaryl may independently be deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -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 、 -S(O)₂NR c R d 、 -NR c R s 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 、 -NRc 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 or -NO2 substituted. In certain embodiments, each R 2 is independently deuterium 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 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)Rd 、 -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 or -NO2 substituted. In certain embodiments, two Rs 2 together with the atom to which they are attached optionally form, together, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl formed when two Rs 1 together is independently optionally -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.

[0550] In one embodiment, ring B is

Chemical formula

[0551] Here, each

Chem.

[0552] In certain embodiments, q is 0, 1, or 2. In certain embodiments, q is 0 or 1. In certain embodiments, q is 0. In certain embodiments, q is 1.

[0553] In certain embodiments, R 3 is 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 , -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 may independently be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c 、 -OC(O)R c 、 -OC(O)NR c R d 、 -OC(=N)NR c R d 、 -OS(O)R c 、 -OS(O)2R c 、 -OS(O)NR c R d 、 -OS(O)2NR c R d 、 -SR c 、 -S(O)R c 、 -S(O)2R c 、 -S(O)NR c R d 、 -S(O)2NR c R d 、 -NR c R d 、 -NR c C(O)R d 、 -N(C(O)R c )(C(O)R d )、 -NR c C(O)OR d, -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)R c R d , -P(O)2R c R d , -P(O)NR c R d , -P(O)2NR c R d , -P(O)OR c , -P(O)2OR c , -CN or -NO2 substituted. In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is fluoro, chloro or bromo. In certain embodiments, two R 3 are taken together with the atom to which they are attached and optionally together form C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl formed when two R 1 are taken together is independently optionally -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 、 is substituted with -CN or -NO2.

[0554] In one embodiment, R 4 is H, deuterium, C1-C6 alkyl, -C(O)R c 、 -C(O)OR c 、 -C(O)NR c R d 、 -P(O)2R cR d 、 -P(O)2NR c R d 、 -P(O)2OR c or -S(O)2OR c is. In certain embodiments, R 4 is H or deuterium. In certain embodiments, R 4 is H. In certain embodiments, R 4 is C1-C6 alkyl. In certain embodiments, R 4 is methyl or ethyl.

[0555] In certain embodiments, each R 5 , when present, 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 -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O)2R c , -OS(O)NR c R d , -OS(O)2NR c R d , -SR c , -S(O)R c , -S(O)2R c , -S(O)NR c R d , -S(O)2NR c R d , -NR c R d , -NR c C(O)R d , -N(C(O)R c )(C(O)Rd )、 -NR c C(O)OR d 、 -NR c C(O)NR c R d 、 -NR c C(=N)NR c R d 、 -NR c S(O)R d 、 -NR c S(O)2R d 、 -NR c S(O)NR c R d 、 -NR c S(O)2NR c R d 、 -C(O)R c 、 -C(O)OR c 、 -C(O)NR c R d 、 -C(=N)NR c R d 、 -PR c R d 、 -P(O)R c R d 、 -P(O)2R c R d 、 -P(O)NR c R d 、 -P(O)2NR c R d 、 -P(O)OR c 、 -P(O)2OR c 、 -CN or -NO2 substituted. In certain embodiments, each R 5 is independently H, methyl, ethyl, -C(O)CH3 or -C(O)CH2CH3; or R 5 is R 6 and together with R forms a 3- to 7-membered heterocycloalkyl.

[0556] In certain embodiments, each R 5 is, when present, independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C(O)R a 、 3- to 7-membered heterocycloalkyl, C6-C 10Aryl or 5- to 10-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl is independently optionally -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)NRc 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 or -NO2 substituted. In certain embodiments, each R 5 is independently H, methyl, ethyl, -C(O)CH3 or -C(O)CH2CH3; or R 5 is R 6 together with R

[0557] In certain embodiments, each L is independently -C(R 6 )(R 7 )-, -C(O)-, -O- or -N(R 5 )-, provided that (L) p does not contain an -O-O- or -O-N(R 5 )- bond, and the covalent attachment point of (L) p to ring A does not form an -N-N- or -O-N- bond.

[0558] In certain embodiments, p is 3, 4, 5, 6, 7, 8, or 9. In certain embodiments, p is 4, 5, 6, 7, 8, or 9. In certain embodiments, p is 4, 5, 6, 7, or 8. In certain embodiments, p is 4, 5, 6, or 7. In certain embodiments, p is 5, 6, 7, or 8. In certain embodiments, p is 5, 6, or 7. In certain embodiments, p is 3, 4, 5, 6, or 7. In certain embodiments, p is 3, 4, 5, or 6. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In certain embodiments, p is 8. In certain embodiments, p is 9.

[0559] In certain embodiments, p1 is 2, 3, or 4. In certain embodiments, p1 is 2. In certain embodiments, p1 is 3. In certain embodiments, p1 is 4.

[0560] In certain embodiments, -(L) p - is -CR 6 R 7 -O(CR 6 R 7 )2O-, -CR 6 R 7 -O(CR 6 R 7 )3O-, -(CR 6 R 7 )C(O)N(R 5 )-(CR 6 R 7 )2-, -(CR 6 R 7 )N(R 5 )C(O)-(CR 6 R 7 )2-, -O(CR 6 R 7 )2N(R 5 )C(O)-(CR 6 R 7 )O-, -N(R 5 )-C(O)(CR 6 R 7 )2O(CR6 R 7 )2-, -CR 6 R 7 O(CR 6 R 7 )2O-(CR 6 R 7 )2, -O(CR 6 R 7 )2O(CR 6 R 7 )2-, -O(CR 6 R 7 )2O(CR 6 R 7 )2O-, -CR 6 R 7 O-CR 6 R 7 -C(O)N(R 5 )-(CR 6 R 7 )2-, -(CR 6 R 7 )3O(CR 6 R 7 )2-, -(CR 6 R 7 )2O(CR 6 R 7 )3-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )4O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )3O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )2O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )2-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )3O-, -CR 6 R 7 -N(R 5 )-(CR6 R 7 )3-, -O(CR 6 R 7 )2O(CR 6 R 7 )3-, -(CR 6 R 7 )2-N(R 5 )-(CR 6 R 7 )3-, -O(CR 6 R 7 )2-N(R 5 )-CR 6 R 7 -, -(CR 6 R 7 )2-N(R 5 )-(CR 6 R 7 )2-, -O-(CR 6 R 7 )2-, -O-(CR 6 R 7 )3-, -O-(CR 6 R 7 )4-, -O-(CR 6 R 7 )5-, -O-(CR 6 R 7 )2O-, -O-(CR 6 R 7 )3O-, -O-(CR 6 R 7 )4O- or -O-(CR 6 R 7 )5O- is included.

[0561] In one embodiment, -(L) p - is -CR 6 R 7 -O(CR 6 R 7 )2O-, -CR 6 R 7 -O(CR 6 R 7 )3O-, -(CR 6 R 7 )C(O)N(R 5 )-(CR 6 R 7 )2-, -(CR 6 R 7 )N(R 5)C(O)-(CR 6 R 7 )2-、-O(CR 6 R 7 )2N(R 5 )C(O)-(CR 6 R 7 )O-、-N(R 5 )-C(O)(CR 6 R 7 )2O(CR 6 R 7 )2-、-CR 6 R 7 O(CR 6 R 7 )2O-(CR 6 R 7 )2、-O(CR 6 R 7 )2O(CR 6 R 7 )2-、-O(CR 6 R 7 )2O(CR 6 R 7 )2O-、-CR 6 R 7 O-CR 6 R 7 -C(O)N(R 5 )-(CR 6 R 7 )2-、-(CR 6 R 7 )3O(CR 6 [[ID=7--]]R 7 )2-、-(CR 6 R 7 )2O(CR 6 R 7 )3-、-CR 6 R 7 -N(R 5 )-(CR 6 R 7 )4O-、-CR 6 R 7 -N(R 5 )-(CR 6 R<\ 7 )3O-、-CR 6 R 7 -N(R 5 )-(CR 6 R 7 )2O-、-CR 6 R 7 -N(R5 )-(CR 6 R 7 )2-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )3O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )3-, -O(CR 6 R 7 )2O(CR 6 R 7 )3-, -(CR 6 R 7 )2-N(R 5 )-(CR 6 R 7 )3-, -O(CR 6 R 7 )2-N(R 5 )-CR 6 R 7 -, -(CR 6 R 7 )2-N(R 5 )-(CR 6 R 7 )2-, -O-(CR 6 R 7 )2-, -O-(CR 6 R 7 )3-, -O-(CR 6 R 7 )4-, -O-(CR 6 R 7 )5-, -O-(CR 6 R 7 )2O-, -O-(CR 6 R 7 )3O-, -O-(CR 6 R 7 )4O- or -O-(CR 6 R 7 )5O-.

[0562] In one embodiment, -(L) p - is -CR 6 R 7 -O(CR 6 R 7 )2O-, -CR 6 R7 -O(CR 6 R 7 )3O-,-(CR 6 R 7 )C(O)N(R 5 )-(CR 6 R 7 )2-,-(CR 6 R 7 )N(R 5 )C(O)-(CR 6 R 7 )2-,-O(CR 6 R 7 )2N(R 5 )C(O)-(CR 6 R 7 )O-,-N(R 5 )-C(O)(CR 6 R 7 )2O(CR 6 R 7 )2-,-CR 6 R 7 O(CR 6 R 7 )2O-(CR 6 R 7 )2-,-O(CR 6 R 7 )2O(CR 6 R 7 )2O-,-CR 6 R 7 O-CR 6 R 7 -C(O)N(R 5 )-(CR 6 R 7 )2-,-(CR 6 R 7 )3O(CR 6 R 7 )2-,-(CR 6 R 7 )2O(CR 6 R 7 )3-,-CR 6 R 7 -N(R 5 )-(CR 6 R 7 )4O-,-CR 6 R 7 -N(R 5 )-(CR 6 R 7 )3O-,-CR6 R 7 -N(R 5 )-(CR 6 R 7 )2O-、-CR 6 R 7 -N(R 5 )-(CR 6 R 7 )2-、-CR 6 R 7 -N(R 5 )-(CR 6 R 7 )3O-、-CR 6 R 7 -N(R 5 )-(CR 6 R 7 )3-、-O(CR 6 R 7 )2O-CR 6 R 7 -、-O(CR 6 R 7 )2O(CR 6 R 7 )2-、-O(CR 6 R 7 )2O(CR 6 R 7 )3-、-(CR 6 R 7 )2-N(R 5 )-(CR 6 R 7 )3-、-O(CR 6 R 7 )2-N(R 5 )-CR 6 R 7 -、-(CR 6 R 7 )2-N(R 5 )-(CR 6 R 7 )2-、-O-(CR 6 R 7 )2-、-O-(CR 6 R 7 )3-、-O-(CR 6 R 7 )4-、-O-(CR 6 R 7 )5-、-O-(CR 6 R 7 )2O-、-O-(CR 6 R7 ) 3O-, -O-(CR 6 R 7 ) 4O- or -O-(CR 6 R 7 ) 5O-.

[0563] In certain embodiments, -(L) p - is -CR 6 R 7 -O(CR 6 R 7 ) 2O-, -CR 6 R 7 -O(CR 6 R 7 ) 3O-, -(CR 6 R 7 )C(O)N(R 5 )-(CR 6 R 7 ) 2-, -(CR 6 R 7 )N(R 5 )C(O)-(CR 6 R 7 ) 2-, -O(CR 6 R 7 ) 2N(R 5 )C(O)-(CR 6 R 7 )O-, -N(R 5 )-C(O)(CR 6 R 7 ) 2O(CR 6 R 7 ) 2-, -CR 6 R 7 O(CR 6 R 7 ) 2O-(CR 6 R 7 ) 2-, -O(CR 6 R 7 ) 2O(CR 6 R 7 ) 2O-, -CR 6 R 7 O-CR 6 R 7 -C(O)N(R 5 )-(CR 6 R 7 ) 2-, -(CR 6 R 7 ) 3O(CR 6 R7 )2-, -(CR 6 R 7 )2O(CR 6 R 7 )3-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )4O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )3O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )2O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )2-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )3O-, -CR 6 R 7 -N(R 5 )-(CR 6 R 7 )3-, -O(CR 6 R 7 )2O-CR 6 R 7 -, -O(CR 6 R 7 )2O(CR 6 R 7 )2-, -O(CR 6 R 7 )2O(CR 6 R 7 )3-, -(CR 6 R 7 )2-N(R 5 )-(CR 6 R 7 )3-, -O(CR 6 R 7 )2-N(R 5 )-CR 6 R 7 -, -(CR 6 R 7 )2-N(R5 )-(CR 6 R 7 )2-, -O-(CR 6 R 7 )2-, -O-(CR 6 R 7 )3-, -O-(CR 6 R 7 )4-, -O-(CR 6 R 7 )5-, -O-(CR 6 R 7 )2O-, -O-(CR 6 R 7 )3O-, -O-(CR 6 R 7 )4O- or -O-(CR 6 R 7 )5O-.

[0564] In certain embodiments, each R 5 is H, methyl, ethyl, -C(O)CH3 or -C(O)CH2CH3; or R 5 isR 6 and together with R forms a 3- to 7-membered heterocycloalkyl. In certain embodiments, each R 6 is H or C1-C6 alkyl; or R 6 isR 5 and together with R forms a 3- to 7-membered heterocycloalkyl. In certain embodiments, one R 6 is methyl and the remaining R 6 and R 7 are H.

[0565] In certain embodiments, each R 5 is independently H, methyl, ethyl, -C(O)CH3 or -C(O)CH2CH3; or R 5 when present, and R 6 or R 7 when present, together with one or more atoms to which they are attached, form a 3- to 7-membered heterocycloalkyl; wherein R 5 and R 6 or R 7When formed integrally, each hydrogen atom in a 3- to 7-membered heterocycloalkyl is independently optionally -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.

[0566] In one embodiment, R 6 and R 7 , when present, together with one or more atoms to which they are attached, form, together, a 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in the 3- to 7-membered heterocycloalkyl formed when R 6 and R 7 are taken together is independently optionally -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 [[ID=Z37]], -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.

[0567] In certain embodiments, -(L) p- is -O-(CH2)2O-CH2-, -OC(H)(CH3)-CH2-O-CH2-, -CH2O-(CH2)2O-, -C(H)(CH3)-O-(CH2)2O-, -CH2N(H)-(CH2)2O-, -CH2N(CH3)-(CH2)2O-, -CH2N(CH2CH3)-(CH2)2O-, -O(CH2)2N(H)CH2-, -O(CH2)2N(CH3)CH2-, -OCH2-C(H)(CH3)-N(CH(CH3)2)CH2-, -OCH2-C(H)(CH2F)-N(CH3)CH2-, -OCH2-C(H)(CH2CH3)-N(CH3)CH2-, -O(CH2)2N(C(O)CH3)CH2-, -OC(H)(CH3)CH2N(H)CH2-, -OC(H)(CH3)CH2N(CH3)CH2-, -OC(H)(CH2CN)CH2N(CH3)CH2-, -OC(H)(CH2CH3)CH2N(CH3)CH2-, -OC(H)(CH2F)CH2N(CH3)CH2-, -OC(H)(CHF2)CH2N(CH3)CH2-, -OC(H)(CH2OH)CH2N(CH3)CH2-, -OC(H)(CH3)C(O)N(CH3)CH2-, -OC(H)(cyclobutyl)CH2N(CH3)CH2-, -OC(H)(CH3)CH2N(CH2CH3)CH2-, -OC(H)(CH3)CH2N(CH(CH3)2)-CH2-, -OC(H)(CH3)CH2N(CH3)-C(H)(CH3)-, -OC(H)(CH3)CH2N(CH(oxetan-3-yl)-CH2-, -OC(H)(CH3)CH2N(cyclopropyl)-CH2-, -OCH2C(H)(CH3)N(cyclopropyl)-CH2-, -OC(H)(CH3)CH2N(C(O)CH3)CH2-, -O(C(H)(CH3))CH2N(C(O)CH2CH3)CH2-, -CH2N(H)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-C(H)(CH3)-CH2O-, -CH2N(CH3)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-(CH2)-(C(H)CH3)O-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, -O(CH2)3O-, -O(CH2)4O-, -O(CH2)5O-, -O-(C(H)(CH3)-(CH2)2O-, -O(CH2)2-C(H)(CH3)-O--O(CH2)2C(H)(CH3)CH2O-, -O(CH2)3C(H)(CH3)CH2O-, -O(CH2)2N(H)C(O)-(CH2)O-, -O(CH2)2N(CH3)C(O)-(CH2)O-, -O(CH2)2O(CH2)2O-, -OC(H)(CH3)CH2OCH2-, -O(CH2)2OCH2C(H)(CH3)O-, -O(CH2)2OC(H)(CH3)-CH2O-

Chem.

[0568] In certain embodiments, -(L) p- is -O-(CH2)2O-CH2-, -OC(H)(CH3)-CH2-O-CH2-, -CH2O-(CH2)2O-, -C(H)(CH3)-O-(CH2)2O-, -CH2N(H)-(CH2)2O-, -CH2N(CH3)-(CH2)2O-, -CH2N(CH2CH3)-(CH2)2O-, -O(CH2)2N(H)CH2-, -O(CH2)2N(CH3)CH2-, -OCH2-C(H)(CH3)-N(CH(CH3)2)CH2-, -OCH2-C(H)(CH2F)-N(CH3)CH2-, -OCH2-C(H)(CH2CH3)-N(CH3)CH2-, -O(CH2)2N(C(O)CH3)CH2-, -OC(H)(CH3)CH2N(H)CH2-, -OC(H)(CH3)CH2N(CH3)CH2-, -OC(H)(CH2CN)CH2N(CH3)CH2-, -OC(H)(CH2CH3)CH2N(CH3)CH2-, -OC(H)(CH2F)CH2N(CH3)CH2-, -OC(H)(CHF2)CH2N(CH3)CH2-, -OC(H)(CH2OH)CH2N(CH3)CH2-, -OC(H)(CH3)C(O)N(CH3)CH2-, -OC(H)(cyclobutyl)CH2N(CH3)CH2-, -OC(H)(CH3)CH2N(CH2CH3)CH2-, -OC(H)(CH3)CH2N(CH(CH3)2)-CH2-, -OC(H)(CH3)CH2N(CH3)-C(H)(CH3)-, -OC(H)(CH3)CH2N(CH(oxetan-3-yl)-CH2-, -OC(H)(CH3)CH2N(cyclopropyl)-CH2-, -OCH2C(H)(CH3)N(cyclopropyl)-CH2-, -OC(H)(CH3)CH2N(C(O)CH3)CH2-, -O(C(H)(CH3))CH2N(C(O)CH2CH3)CH2-, -CH2N(H)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-C(H)(CH3)-CH2O-, -CH2N(CH3)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-(CH2)-(C(H)CH3)O-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, -O(CH2)3O-, -O(CH2)4O-, -O(CH2)5O-, -O-(C(H)(CH3)-(CH2)2O-, -O(CH2)2-C(H)(CH3)-O-,-O(CH2)2C(H)(CH3)CH2O-, -O(CH2)3C(H)(CH3)CH2O-, -O(CH2)2N(H)C(O)-(CH2)O-, -O(CH2)2N(CH3)C(O)-(CH2)O-, -O(CH2)2O(CH2)2O-, -OC(H)(CH3)CH2OCH2-, -O(CH2)2OCH2C(H)(CH3)O-, -O(CH2)2OC(H)(CH3)-CH2O-

Chem.

[0569] In certain embodiments, -(L) p - is -CH2O-(CH2)2O-, -C(H)(CH3)-O-(CH2)2O-, -CH2N(H)-(CH2)2O-, -CH2N(CH3)-(CH2)2O-, -CH2N(CH2CH3)-(CH2)2O-, -O(CH2)2N(H)CH2-, -O(CH2)2N(CH3)CH2-, -O(CH2)2N(C(O)CH3)CH2-, -O(C(H)(CH3))CH2N(H)CH2-, -O(C(H)(CH3))CH2N(CH3)CH2-, -O(C(H)(CH3))CH2N(CH2CH3)CH2-, -O(C(H)(CH3))CH2N(C(O)CH3)CH2-, -O(C(H)(CH3))CH2N(C(O)CH2CH3)CH2-, -CH2N(H)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-(CH2)2(C(H)CH3)CH2O-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, -O(CH2)3O-, -O(CH2)4O-, -O(CH2)5O-, -O-(C(H)(CH3)-(CH2)2O-, -O(CH2)2-(C(H)(CH3)-O-, -O(CH2)3C(H)(CH3)CH2O-, -O(CH2)2N(H)C(O)-(CH2)O-, -O(CH2)2N(CH3)C(O)-(CH2)O-, -O(CH2)2O(CH2)2O-, -O(CH2)2OCH2C(H)(CH3)O-, -O(CH2)2OC(H)(CH3)-CH2O- or

Chem.

[0570] In certain embodiments, -(L) p - is -CH2O-(CH2)2O-, -C(H)(CH3)-O-(CH2)2O-, -CH2N(H)-(CH2)2O-, -CH2N(CH3)-(CH2)2O-, -CH2N(CH2CH3)-(CH2)2O-, -O(CH2)2N(H)CH2-, -O(CH2)2N(CH3)CH2-, -O(CH2)2N(C(O)CH3)CH2-, -O(C(H)(CH3))CH2N(H)CH2-, -O(C(H)(CH3))CH2N(CH3)CH2-, -O(C(H)(CH3))CH2N(CH2CH3)CH2-, -O(C(H)(CH3))CH2N(C(O)CH3)CH2-, -O(C(H)(CH3))CH2N(C(O)CH2CH3)CH2-, -CH2N(H)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-(CH2)2(C(H)CH3)CH2O-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, -O(CH2)3O-, -O(CH2)4O-, -O(CH2)5O-, -O-(C(H)(CH3)-(CH2)2O-, -O(CH2)2-(C(H)(CH3)-O-, -O(CH2)3C(H)(CH3)CH2O-, -O(CH2)2N(H)C(O)-(CH2)O-, -O(CH2)2N(CH3)C(O)-(CH2)O-, -O(CH2)2O(CH2)2O-, -O(CH2)2OCH2C(H)(CH3)O-, -O(CH2)2OC(H)(CH3)-CH2O- and

Chemical formula

[0571] In connection with any of the embodiments described herein, (L) p is -NR that covalently bonds directly to ring A 5 does not include -C(O)-. In connection with any of the embodiments described herein, (L) p is -O-CR that covalently bonds directly to ring A 6 R 7-Fragment-free. In connection with any of the embodiments described herein, (L) p -NR is covalently bonded directly to ring A 5 Does not contain C(O)-, (L) p -O-CR is covalently bonded directly to ring A 6 R 7 - Contains no fragments.

[0572] In certain embodiments, the present invention provides (11E)-1-methyl-1,18,19,21-tetrahydro-8H-10,7,4-(ethan[1]yl[1,2]diylidene)pyrazolo[3,4-f][1,4,12,13]benzodioxadiazacyclooctadecine;

[0573] (11E)-1-[(methanesulfonyl)methyl]-19,20-dihydro-1H,8H,18H-10,7,4-(ethane[1]yl[1,2]diylidene)pyrazolo[3,4-f][1,5,12,13]benzodioxadiazacyclooctadecine;

[0574] (11E)-1-methyl-18,19,20,21-tetrahydro-1H,8H-10,7,4-(ethane[1]yl[1,2]diylidene)pyrazolo[3,4-g][1,6,13,14]benzodioxadiazacyclononadecin;

[0575] (10R,16E)-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4',3'-m][1,8,5]benzdioxoazacyclooctadecin-25-one;

[0576] (10R,16E)-3-methyl-13-[(4-methylpiperazin-1-yl)methyl]-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4',3'-m][1,8,5]benzdioxoazacyclooctadecin-25-one;

[0577] (10R,16E)-13-[(Dimethylamino)methyl]-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoaazacyclooctadecin-25-one;

[0578] (10R,16E)-3-methyl-13-(1-methylpiperidin-4-yl)-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoaazacyclooctadecin-25-one;

[0579] (10R,16E)-13-(2-methoxypropan-2-yl)-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoaazacyclooctadecin-25-one;

[0580] (10R,16E)-3-methyl-13-(4-methylpiperazin-1-yl)-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoaazacyclooctadecin-25-one;

[0581] (10R,16E)-14-fluoro-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoaazacyclooctadecin-25-one;

[0582] (10R,16E)-14-(2-hydroxypropan-2-yl)-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoaazacyclooctadecin-25-one;

[0583] (10R,16E)-14-{(2S)-2-[(Methanesulfonyl)methyl]azetidin-1-yl}-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoazacyclooctadecin-25-one;

[0584] (10R,16E)-3-methyl-25-oxo-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoazacyclooctadecin-14-carbonitrile; and

[0585] (10R,16E)-3-methyl-3,5,6,9,10,19-hexahydro-8H-20,22-etheno-7,10-methanodipyrazolo[3,4-i:4’,3’-m][1,8,5]benzodioxoazacyclooctadecine;

[0586] A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof is provided.

[0587] 32. (18E)-8-methyl-N-(propan-2-yl)-8,9,11,12-tetrahydro-2H-3,5-ethenodipyrazolo[3’,4’:9,10;4’’,3’’:13,14][1,4]dioxacyclopentadecinol[5,6-b]pyridine-16-carboxamide;

[0588] (18E)-N,8-dimethyl-8,9,11,12-tetrahydro-2H-3,5-ethenodipyrazolo[3’,4’:9,10;4’’,3’’:13,14][1,4]dioxacyclopentadecinol[5,6-b]pyridine-16-carboxamide;

[0589] (18E)-N,N,8-Trimethyl-8,9,11,12-tetrahydro-2H-3,5-ethenodipyrazolo[3’,4’:9,10;4’’,3’’:13,14][1,4]dioxacyclopentadecano[5,6-b]pyridine-16-carboxamide;

[0590] (18E)-N-Ethyl-8-methyl-8,9,11,12-tetrahydro-2H-3,5-ethenodipyrazolo[3’,4’:9,10;4’’,3’’:13,14][1,4]dioxacyclopentadecano[5,6-b]pyridine-16-carboxamide;

[0591] (10S,18E)-8,10,16-Trimethyl-2,8,11,12-tetrahydro-10H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,5]dioxacyclopentadecano[7,6-b]pyridine;

[0592] (10S,18E)-17-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-3,5-ethenodipyrazolo[3,4-j:4’,3’-n]pyrido[4,3-f][1,4]oxazacyclopentadecine; and

[0593] (10S,18E)-16-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-3,5-ethenodipyrazolo[3,4-j:4’,3’-n]pyrido[3,2-f][1,4]oxazacyclopentadecine;

[0594] The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, selected from the group consisting of

[0595] 33. (17E)-8,14,16-Trimethyl-2,8,9,11,12,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[11,10-c:15,14-c’:6,7-c’’]tripyrazole;

[0596] 2-[(17E)-8,9,16-Trimethyl-8,9,11,12-tetrahydro-3,5-etheno[1,4]dioxacyclopentadecano[11,10-c:15,14-c’:6,7-c’’]tripyrazol-14(2H)-yl]ethan-1-ol;

[0597] (17E)-8,14,16-Trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0598] (17E)-19-Fluoro-8,14,16-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0599] (17E)-16-Ethyl-8,14-dimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0600] 1-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-2-methylpropan-2-ol;

[0601] 1-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]propan-2-one;

[0602] 2-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]ethan-1-ol;

[0603] (17E)-8,16-dimethyl-14-[2-(pyrrolidin-1-yl)ethyl]-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0604] (3S)-1-{2-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]ethyl}pyrrolidin-3-ol;

[0605] (17E)-16-ethyl-8,12,14-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0606] (10S,17E)-8,10,14,16-tetramethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0607] (10R,17E)-8,10,14,16-tetramethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0608] (12S,17E)-16-Ethyl-8,12,14-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0609] (12R,17E)-16-Ethyl-8,12,14-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0610] (10S,17E)-16-Ethyl-8,10,14-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0611] (10S,17E)-16-Cyclopropyl-8,10,14-trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0612] (17E)-16-(Methoxymethyl)-8,14-dimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0613] (17E)-8,14,16-Trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0614] 1-[(17E)-8,14,16-Trimethyl-2,8,10,11,13,14-hexahydro-12H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-12-yl]ethan-1-one;

[0615] (17E)-8,12,14,16-Tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0616] (17E)-6,8,12,14,16-Pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0617] (17E)-16-Ethyl-8,12,14-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0618] (17E)-7,14,16-Trimethyl-2,10,11,12,13,14-hexahydro-7H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0619] (17E)-7,12,14,16-Tetramethyl-2,10,11,12,13,14-hexahydro-7H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0620] 2-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0621] (17E)-8,14,16-Trimethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0622] (17E)-8,10,14,16-Tetramethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0623] 2-[(17E)-8,16-Dimethyl-2,8,9,10,11,12-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0624] 2-[(17E)-8,10,16-Trimethyl-2,8,9,10,11,12-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0625] 2-[(17E)-10-Ethyl-8,16-dimethyl-2,8,9,10,11,12-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0626] (19E)-8,13,16,18-Tetramethyl-2,11,12,13,14,16-hexahydro-8H,10H-3,5-etheno[1,7]dioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazole;

[0627] 2-[(19E)-8,13,18-Trimethyl-2,8,11,12,13,14-hexahydro-10H,16H-3,5-etheno[1,7]dioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazol-16-yl]ethan-1-ol;

[0628] (19E)-8,16,18-Trimethyl-2,11,12,16-tetrahydro-8H,10H-3,5-ethenotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,7,4]dioxoazacycloheptadecin-13(14H)-one;

[0629] (19E)-8,12,16,18-Tetramethyl-2,11,12,16-tetrahydro-8H,10H-3,5-ethenotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,7,4]dioxoazacycloheptadecin-13(14H)-one;

[0630] (13R,19E)-8,13,16,18-Tetramethyl-2,10,11,13,14,16-hexahydro-8H-3,5-etheno[1,4,7]trioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazole;

[0631] (13S,19E)-8,13,16,18-Tetramethyl-2,10,11,13,14,16-hexahydro-8H-3,5-etheno[1,4,7]trioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazole;

[0632] 2-[(19E)-8,13,18-Trimethyl-2,8,10,11,13,14-hexahydro-16H-3,5-etheno[1,4,7]trioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazol-16-yl]ethan-1-ol;

[0633] (19E)-8,13,18-Trimethyl-16-[2-(pyrrolidin-1-yl)ethyl]-2,10,11,13,14,16-hexahydro-8H-3,5-etheno[1,4,7]trioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazole;

[0634] (3S)-1-{2-[(17E)-16-Ethyl-8-methyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecin[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]ethyl}pyrrolidin-3-ol;

[0635] (19E)-22-Fluoro-8,16,18-trimethyl-2,10,11,13,14,16-hexahydro-8H-3,5-etheno[1,4,7]trioxacycloheptadecin[12,13-c:17,16-c’:8,9-c’’]tripyrazole;

[0636] 3-[(17E)-16-Ethyl-8-methyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecin[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-N,N-dimethylpropan-1-amine;

[0637] (rac)-4-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecin[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]pyrrolidin-3-ol;

[0638] (rac)-4-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-1-methylpyrrolidin-3-ol;

[0639] (3R,4S)-4-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]oxolan-3-ol;

[0640] (3S,4R)-4-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]oxolan-3-ol;

[0641] (rac)-2-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]cyclobutan-1-ol;

[0642] (rac)-4-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]piperidin-3-ol;

[0643] (rac)-4-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-1-methylpiperidin-3-ol;

[0644] (rac)-1,5-Anhydro-3-O-2,3-dideoxy-3-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-L-threo-pentitol;

[0645] (rac)-1,5-Anhydro-2,4-dideoxy-2-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]-L-threo-pentitol;

[0646] (12R,17E)-8,10,12,14,16-Pentamethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0647] (12S,17E)-8,10,12,14,16-Pentamethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0648] (rac)-(3S,4S)-1-Methyl-4-[(17E)-8,10,16-trimethyl-2,8,9,10,11,12-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]pyrrolidin-3-ol;

[0649] (11S,17E)-8,11,14,16-Tetramethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0650] (17E)-8,9,16-Trimethyl-14-[2-(pyrrolidin-1-yl)ethyl]-2,8,9,11,12,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecino[11,10-c:15,14-c’:6,7-c’’]tripyrazole;

[0651] [(10S,17E)-8,10,14-Trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c’:6,7-c’’]tripyrazol-16-yl]methanol;

[0652] N 1 -{(1s,3s)-3-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]cyclobutyl}-N 1 ,N2,N2-Trimethylethane-1,2-diamine;

[0653] (11S,17E)-8,10,11,14,16-Pentamethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0654] N2-{(1s,3s)-3-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,14H-3,5-etheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14-yl]cyclobutyl}-N 1 ,N 1-Dimethylethane-1,2-diamine;

[0655] (10R,15E)-3,12,14-Trimethyl-5,6,9,10,12,18-hexahydro-3H,8H-19,21-etheno-7,10-methanotripyrazolo[3,4-i:3’,4’-m:4’’,3’’-q][1,8,4]dioxoazacyclooctadecin-24-one;

[0656] (17E)-16-Ethyl-8,10,14-trimethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0657] (17E)-10-Ethyl-8,14,16-trimethyl-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0658] 2-[(10S,17E)-8,10,16-Trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]ethan-1-ol;

[0659] 2-[(10S,17E)-19-Fluoro-8,10,12,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]ethan-1-ol;

[0660] (17E)-8,10,16-Trimethyl-14-(1-methylpyrrolidin-3-yl)-2,9,10,11,12,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0661] 2-[(10S,17E)-16-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]ethan-1-ol;

[0662] (10S,17E)-8,10,12,14,16-Pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0663] (10R,19E)-8,16,18-Trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0664] (2S)-1-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]propan-2-ol;

[0665] 2-[(10S,17E)-19-Chloro-8,10,12,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]ethan-1-ol;

[0666] (2R)-1-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0667] 2-[(10S,17E)-16-Ethyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0668] 2-[(10S,17E)-12-Ethyl-8,10,16-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0669] (10S,17E)-8,10,12,14-Tetramethyl-16-[(piperidin-4-yl)oxy]-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0670] 2-[(10R,19E)-18-Ethoxy-8-methyl-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine-16(8H)-yl]ethan-1-ol;

[0671] 2-[(10S,17E)-6,8,10,12,16-Pentamethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0672] (10S,17E)-8,10,14,16-Tetramethyl-12-(oxetan-3-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0673] 2-[(10S,17E)-16-Ethoxy-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0674] (10S,17E)-16-{[1-(Methanesulfonyl)piperidin-4-yl]oxy}-8,10,12,14-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0675] (10S,13R,17E)-8,10,12,13,14,16-Hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0676] (10S,13S,17E)-8,10,12,13,14,16-Hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0677] 2-{(10S,17E)-8,10,12-Trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0678] (10S,17E)-8,10,12,14-Tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-ol;

[0679] (10S,17E)-16-[(azetidin-3-yl)oxy]-8,10,12,14-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0680] (10S,17E)-16-{[1-(methanesulfonyl)azetidin-3-yl]oxy}-8,10,12,14-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0681] 2-[(10S,17E)-16-Ethoxy-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0682] 2-[(17E)-10-Cyclobutyl-8,12,16-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0683] (10S,17E)-8,10,12,14-Tetramethyl-16-{[(3S)-pyrrolidin-3-yl]oxy}-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0684] (10S,17E)-16-{[(3S)-1-(Methanesulfonyl)pyrrolidin-3-yl]oxy}-8,10,12,14-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0685] (2S)-2-[(10S,17E)-16-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0686] (10S,17E)-16-Ethoxy-8,10,14-trimethyl-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0687] (10S,17E)-8,10,14-Trimethyl-2,11,12,14-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole-16-carbonitrile;

[0688] (10S,17E)-8,10,12,14-Tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-16-carbonitrile;

[0689] (10R,19E)-18-Ethoxy-8,16-dimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0690] (10S,17E)-12-Cyclopropyl-8,10,14,16-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0691] (10S,17E)-8,10,12,14-Tetramethyl-16-(2,2,2-trifluoroethoxy)-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0692] {[(10S,17E)-8,10,12,14-Tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-16-yl]oxy}acetonitrile;

[0693] (10S,17E)-10,14,16-Trimethyl-8-[(methylsulfanyl)methyl]-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0694] (10S,17E)-12-Ethyl-8,10,14,16-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0695] 2-[(10S,17E)-16-Ethoxy-8-ethyl-10,12-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]ethan-1-ol;

[0696] 2-{(10S,17E)-8-Ethyl-10,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl}ethan-1-ol;

[0697] (2R)-2-[(10S,17E)-16-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol;

[0698] 2-[(10S,17E)-16-Ethoxy-19-fluoro-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0699] 2-[(10S,17E)-16-{[1-(Methanesulfonyl)piperidin-4-yl]oxy}-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0700] (10S,19E)-8,16,18-Trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0701] 2-[(10S,17E)-16-Ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0702] 2-[(10S,17E)-16-Ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0703] 2-{(10S,17E)-19-Fluoro-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0704] 2-[(10S,17E)-16-{[(3S)-1-(Methanesulfonyl)pyrrolidin-3-yl]oxy}-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0705] 2-[(10S,17E)-16-Bromo-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0706] 2-{(10S,17E)-16-[(Azetidin-3-yl)oxy]-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0707] (10S,17E)-14-(2-Hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-ol;

[0708] (10S,17E)-16-{[3-(Methanesulfonyl)cyclobutyl]oxy}-8,10,12,14-tetramethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0709] (10S,19E)-18-Ethoxy-8,16-dimethyl-2,8,11,12,15,16-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine-13(10H)-one;

[0710] (10R,19E)-18-Ethoxy-8,16-dimethyl-2,8,11,12,15,16-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine-13(10H)-one;

[0711] 2-[(10R,19E)-18-Ethoxy-22-fluoro-8-methyl-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine-16(8H)-yl]ethan-1-ol;

[0712] 2-{(11S,17E)-8,11-Dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl}ethan-1-ol;

[0713] 2-{(10R,17E)-8,10-Dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0714] 2-{(11S,17E)-19-Fluoro-8,11-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0715] 2-{(10R,17E)-19-Fluoro-8,10-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0716] 2-[(10R,17E)-12-Cyclopropyl-16-ethoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0717] 2-[(10R,17E)-16-Ethoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0718] 2-[(11S,17E)-12-Cyclopropyl-16-ethoxy-8,11-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0719] 2-[(10R,19E)-22-Fluoro-8-methyl-18-[(propan-2-yl)oxy]-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecin-16(8H)-yl]ethan-1-ol;

[0720] (2S)-2-{(10S,17E)-19-Fluoro-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-1-ol;

[0721] 2-{(11S,17E)-6,8,11-Trimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0722] 2-{(10R,17E)-6,8,10-Trimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0723] {(10S,17E)-14-(2-Hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-yl}oxyacetonitrile;

[0724] 2-[(10R,17E)-12-Cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0725] 2-[(11S,17E)-12-Cyclopropyl-16-ethoxy-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0726] (10S,17E)-16-Ethoxy-12-ethyl-19-fluoro-8,10,14-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0727] (2S)-2-{(10R,17E)-8,10-Dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-1-ol;

[0728] (10S,17E)-14-(2-Hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-16-carbonitrile;

[0729] (10S,17E)-12-Ethyl-8,10,14-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-16-ol;

[0730] (10S,17E)-19-Fluoro-14-(2-hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-16-ol;

[0731] 2-[(10S,17E)-19-Fluoro-8,10,12-trimethyl-16-(2,2,2-trifluoroethoxy)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl]ethan-1-ol;

[0732] 2-{(10R,17E)-12-Cyclopropyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl}ethan-1-ol;

[0733] 2-{(11S,17E)-12-Cyclopropyl-8,11-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,;4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0734] (2S)-2-[(10S,17E)-16-Ethoxy-19-fluoro-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0735] (2S)-2-[(10S,17E)-16-Ethoxy-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[;3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0736] 2-{(10S,17E)-12-Ethyl-19-fluoro-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0737] 1-[(10R,17E)-16-Ethoxy-14-(2-hydroxyethyl)-8,10-dimethyl-2,8,10,11,13,14-hexahydro-12H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-12-yl]ethan-1-one;

[0738] Ethyl [(10S,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]acetate;

[0739] (2S)-2-{[(10S,17E)-12-ethyl-19-fluoro-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0740] (10S,17E)-14-(2-hydroxyethyl)-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,12,13,14-tetrahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-11(10H)-one;

[0741] 2-[(10S,17E)-16-{[1-(methanesulfonyl)azetidin-3-yl]oxy}-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0742] 1-[(10S,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]-2-methylpropan-2-ol;

[0743] 2-{(10S,13R,17E)-8,10,12,13-Tetramethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0744] 2-{(10S,13S,17E)-8,10,12,13-Tetramethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0745] 2-{(17E)-10-(Fluoromethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0746] 2-{(17E)-11-(Fluoromethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0747] (2S)-1-{(10R,17E)-12-Ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-2-ol;

[0748] (2S)-2-[(11S,17E)-16-Ethoxy-19-fluoro-8,11-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0749] (2S)-2-[(10R,17E)-16-Ethoxy-19-fluoro-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0750] (2S)-2-{(11S,17E)-19-Fluoro-8,11-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-1-ol;

[0751] (2S)-2-{(10R,17E)-19-Fluoro-8,10-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-1-ol;

[0752] 2-{(10S,17E)-12-Ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}acetamide;

[0753] (10S,17E)-19-Fluoro-14-(2-hydroxyethyl)-8,10,12-trimethyl-2-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-ol;

[0754] 2-[(8aR,19E)-1-(Cyclopropylmethoxy)-22-fluoro-9,11-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0755] (10R,18E)-17-Ethoxy-8,15-dimethyl-2,8,11,12,14,15-hexahydro-10H-3,5-etheno-10,13-methanotripyrazolo[3,4-g:3’,4’-k:4’’,3’’-o][1,5]oxazacyclohexadecine;

[0756] {(17E)-14-(2-Hydroxyethyl)-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,10,11,12,13,14-hexahydro-7H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-7-yl}acetonitrile;

[0757] (17E)-16-Ethoxy-8,14-dimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno-10,12-methanotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin;

[0758] 2-[(10S,17E)-16-Ethoxy-19-fluoro-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0759] 2-[(8aR,9R,19E)-1-Ethoxy-9,11-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0760] 2-[(8aR,9S,19E)-1-Ethoxy-9,11-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0761] 2-[(19E)-18-Ethoxy-8,21-dimethyl-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecin-16(8H)-yl]ethan-1-ol;

[0762] 2-[(8aR,9R,19E)-1-Ethoxy-22-fluoro-9,11-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0763] 2-[(8aR,9S,19E)-1-Ethoxy-22-fluoro-9,11-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0764] 2-[(19E)-18-Ethoxy-22-fluoro-8,21-dimethyl-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecin-16(8H)-yl]ethan-1-ol;

[0765] 2-{(10S,17E)-8-Cyclopropyl-10,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0766] (10S,13S,19E)-18-Ethoxy-8,13,16-trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0767] (10R,13R,19E)-18-Ethoxy-8,13,16-trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0768] (10R,13S,19E)-18-Ethoxy-8,13,16-trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0769] (10S,13R,19E)-18-Ethoxy-8,13,16-trimethyl-2,8,10,11,12,13,15,16-octahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecine;

[0770] 2-{(10R,17E)-19-Fluoro-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-14-yl}ethan-1-ol;

[0771] 2-[(8aR,9S,19E)-9,11-Dimethyl-1-[(propan-2-yl)oxy]-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecine-3(4H)-yl]ethan-1-ol;

[0772] 2-[(8aR,9R,19E)-9,11-Dimethyl-1-[(propan-2-yl)oxy]-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecine-3(4H)-yl]ethan-1-ol;

[0773] 2-[(19E)-8,21-Dimethyl-18-[(propan-2-yl)oxy]-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecin-16(8H)-yl]ethan-1-ol;

[0774] 2-[(8aR,9R,19E)-22-Fluoro-9,11-dimethyl-1-[(propan-2-yl)oxy]-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0775] 2-[(8aR,9S,19E)-22-Fluoro-9,11-dimethyl-1-[(propan-2-yl)oxy]-7,8,8a,9,11,17-hexahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0776] 2-[(19E)-22-Fluoro-8,21-dimethyl-18-[(propan-2-yl)oxy]-2,10,11,12,13,15-hexahydro-3,5-etheno-10,14-methanotripyrazolo[3,4-h:3’,4’-l:4’’,3’’-p][1,6]oxazacycloheptadecin-16(8H)-yl]ethan-1-ol;

[0777] 2-{(10R,17E)-10-(Hydroxymethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0778] 2-[(11S,17E)-16-Ethoxy-11-ethyl-8,12-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0779] 2-[(10S,17E)-16-Ethoxy-10-ethyl-8,12-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0780] 2-[(10S,17E)-16-(Methoxymethyl)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0781] 1-{(10S,17E)-12-Ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}-2-methylpropan-2-ol;

[0782] 1-{(10S,17E)-12-Ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-2-one;

[0783] (10R,17E)-14-(2-Hydroxyethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-10-carbonitrile;

[0784] 2-{(10S,17E)-8,10,12-Trimethyl-16-[(methylamino)methyl]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0785] 2-{(10S,17E)-16-[(dimethylamino)methyl]-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol:

[0786] (2R)-2-{[(10S,17E)-19-Fluoro-14-(2-hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-yl]oxy}propanenitrile;

[0787] (2S)-2-{[(10S,17E)-19-Fluoro-14-(2-hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-yl]oxy}propanenitrile;

[0788] 2-[(4aS,7aS,13E)-12-Ethoxy-3,6,8-trimethyl-4a,5,6,7,7a,8,9,16-octahydro-17,19-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[3,4-b][1,4]oxazacyclopentadecin-10(3H)-yl]ethan-1-ol;

[0789] 2-[(4aR,7aR,13E)-12-Ethoxy-3,6,8-trimethyl-4a,5,6,7,7a,8,9,16-octahydro-17,19-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[3,4-b][1,4]oxazacyclopentadecin-10(3H)-yl]ethan-1-ol;

[0790] {[(8aR,19E)-3-(2-Hydroxyethyl)-9,11-dimethyl-3,4,7,8,8a,9,11,17-octahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-1-yl]oxy}acetonitrile;

[0791] {[(8aR,9R,19E)-3-(2-Hydroxyethyl)-9,11-dimethyl-3,4,7,8,8a,9,11,17-octahydro-6H-14,16-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-1-yl]oxy}acetonitrile;

[0792] 2-{(10S,17E)-10-(Difluoromethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0793] 2-{(10R,17E)-10-(Difluoromethyl)-8,12-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0794] 2-{(10S,17E)-8,10-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0795] 2-[(10R,17E)-16-ethoxy-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0796] (4aS,7aS,13E)-12-ethoxy-3,8,10-trimethyl-3,4a,5,6,7,7a,8,9,10,16-decahydro-17,19-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[3,4-b][1,4]oxazacyclopentadecine;

[0797] (4aR,7aR,13E)-12-ethoxy-3,8,10-trimethyl-3,4a,5,6,7,7a,8,9,10,16-decahydro-17,19-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n]pyrrolo[3,4-b][1,4]oxazacyclopentadecine;

[0798] (2S)-1-{(10S,17E)-12-Ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-2-ol;

[0799] 2-{(11R,17E)-19-Fluoro-8,11-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0800] 2-{(10S,17E)-19-Fluoro-8,10-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}ethan-1-ol;

[0801] 2-[(11R,17E)-16-Ethoxy-19-fluoro-8,11-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0802] 2-[(10S,17E)-16-Ethoxy-19-fluoro-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0803] {(10S,17E)-19-Fluoro-14-(2-hydroxyethyl)-8,10,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-16-yl}oxyacetonitrile;

[0804] 2-[(10R,17E)-12-Ethyl-19-fluoro-16-methoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0805] (2S)-2-[(10R,17E)-16-Ethoxy-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0806] 2-[(10S,17E)-16-Ethoxy-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0807] (2S)-2-[(10R,17E)-12-Ethyl-19-fluoro-16-methoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0808] (10S,17E)-16-Ethoxy-12-ethyl-14-(2-hydroxyethyl)-8,10-dimethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-6-carbonitrile;

[0809] 2-[(10S,17E)-16-Ethoxy-6-ethynyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0810] 2-[(10S,17E)-12-Ethyl-19-fluoro-16-methoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0811] 2-[(10S,17E)-16-(Ethylamino)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0812] (2S)-1-{(10S,17E)-12-Ethyl-19-fluoro-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl}propan-2-ol;

[0813] 2-[(10S,17E)-6-Amino-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0814] (2S)-2-[(10S,17E)-12-Ethyl-19-fluoro-16-methoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0815] 2,2’-[(10S,17E)-10,12-Dimethyl-16-[(propan-2-yl)oxy]-10,11,12,13-tetrahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-8,14(2H)-diyl]di(ethan-1-ol);

[0816] (17E)-16-Ethyl-8,14-dimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0817] 2-[(17E)-8,16-Dimethyl-2,10,11,13-tetrahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14(8H)-yl]-N-ethylacetamide;

[0818] (17E)-8,14-Dimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole-16-carbonitrile;

[0819] (17E)-8,14,16-Trimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0820] (10S,17E)-8,10,14-Trimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0821] (10S,17E)-8,10,14-Trimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole-16-carbonitrile;

[0822] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[6,5-d][1,2]oxazole-16-carbonitrile;

[0823] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[6,5-d][1,2]thiazole-16-carbonitrile;

[0824] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[5,6-c][1,2]oxazole-16-carbonitrile;

[0825] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[5,6-c][1,2]thiazole-16-carbonitrile; and

[0826] (10S,17E)-16-Ethyl-8,10,14-trimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0827] A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

[0828] 34. (17E)-8,15,16-Trimethyl-2,8,9,11,12,15-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[11,10-c:15,14-c’:6,7-c’’]tripyrazole;

[0829] (17E)-8,15,16-Trimethyl-2,11,12,15-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0830] 1-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]propan-2-one;

[0831] 1-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]-2-methylpropan-2-ol;

[0832] 2-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]ethan-1-ol;

[0833] (17E)-8,16-dimethyl-15-[2-(pyrrolidin-1-yl)ethyl]-2,11,12,15-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0834] (10S,17E)-8,10,15,16-tetramethyl-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0835] (17E)-8,15,16-trimethyl-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0836] 1-[(17E)-8,15,16-trimethyl-2,8,10,11,13,15-hexahydro-12H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-12-yl]ethan-1-one;

[0837] (17E)-8,12,15,16-tetramethyl-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0838] 1-[(10S,17E)-8,10,15,16-Tetramethyl-2,8,10,11,13,15-hexahydro-12H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-12-yl]ethan-1-one;

[0839] (10S,17E)-8,10,12,15,16-Pentamethyl-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0840] 2-[(10S,17E)-8,10,16-Trimethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]ethan-1-ol;

[0841] 2-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]ethan-1-ol;

[0842] (10S,17E)-12-Ethyl-8,10,15,16-tetramethyl-2,10,11,12,13,15-hexahydro-8H-III-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0843] 1-[(10S,17E)-8,10,15,16-Tetramethyl-2,8,10,11,13,15-hexahydro-12H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-12-yl]propan-1-one;

[0844] 2-[(19E)-8,13,18-Trimethyl-2,8,11,12,13,14-hexahydro-10H,17H-3,5-etheno[1,7]dioxacycloheptadecano[12,13-c:17,16-c’:8,9-c’’]tripyrazol-17-yl]ethan-1-ol;

[0845] (13E)-3-Methyl-3,5,6,7,8,16-hexahydro-9,12-(azeno)-17,19-ethenodipyrazolo[3,4-l:4’,3’-p][1,6]oxazacycloheptadecine;

[0846] (18E)-8-Methyl-2,8,10,11,12,13-hexahydro-3,5-ethenotripyrazolo[1,5-f:3’,4’-j:4’’,3’’-n][1,6]oxazacyclopentadecine;

[0847] (17E)-15-(2-Methoxyethyl)-8,16-dimethyl-2,11,12,15-tetrahydro-8H,10H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[0848] 2-[(17E)-8,9,16-Trimethyl-8,9,11,12-tetrahydro-3,5-etheno[1,4]dioxacyclopentadecano[11,10-c:15,14-c’:6,7-c’’]tripyrazol-15(2H)-yl]ethan-1-ol;

[0849] (rac)-4-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]piperidin-3-ol;

[0850] (rac)-4-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]-1-methylpiperidin-3-ol;

[0851] (17E)-8,9,16-Trimethyl-15-[2-(pyrrolidin-1-yl)ethyl]-2,8,9,11,12,15-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[11,10-c:15,14-c’:6,7-c’’]tripyrazole;

[0852] (rac)-1,5-Anhydro-2,3-dideoxy-3-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]-L-threo-pentitol;

[0853] 1,5-Anhydro-2,4-dideoxy-2-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]-L-threo-pentitol;

[0854] (10S,17E)-8,10,12,16-Tetramethyl-15-[2-(pyrrolidin-1-yl)ethyl]-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0855] (10S,17E)-8,10,12,16-Tetramethyl-15-[2-(4-methylpiperazin-1-yl)ethyl]-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0856] (20E)-8,18-Dimethyl-2,8,11,12-tetrahydro-10H-3,5-ethenodipyrazolo[3’’,4’’:10’,11’;4’’’,3’’’:14’,15’][1,5]dioxacyclopentadecinol[6’,7’:3,4]pyrazolo[1,5-a]pyrazin-19(18H)-one;

[0857] (10S,17E)-8,10,12,16-Tetramethyl-15-[2-(morpholin-4-yl)ethyl]-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0858] 4-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine-15-yl]butan-2-ol;

[0859] N 1 -{(1s,3s)-3-[(17E)-8,16-Dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecinol[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]cyclobutyl}-N 1 ,N2,N2-Trimethylethane-1,2-diamine;

[0860] 2-Methyl-4-[(10S,17E)-8,10,12,16-tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]butan-2-ol;

[0861] 2-Methyl-1-[(10S,17E)-8,10,12,16-tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]propan-2-ol;

[0862] N2-{ (1s,3s)-3-[(17E)-8,16-dimethyl-2,8,11,12-tetrahydro-10H,15H-3,5-etheno[1,5]dioxacyclopentadecin[10,11-c:15,14-c’:6,7-c’’]tripyrazol-15-yl]cyclobutyl}-N 1 ,N 1 -dimethyl ethane-1,2-diamine;

[0863] (17E)-8,10,16-Trimethyl-15-(1-methylpyrrolidin-3-yl)-2,9,10,11,12,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:4’,3’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0864] (10R,17E)-8,10,12,16-Tetramethyl-15-[2-(pyrrolidin-1-yl)ethyl]-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0865] (2S)-1-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]propan-2-ol;

[0866] (10S,17E)-8,10,12,14,15-Pentamethyl-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[4,3-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0867] (2R)-1-[(10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-15H-3,5-ethenotripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-15-yl]propan-2-ol;

[0868] (10S,17E)-8,10,12,14,16-Pentamethyl-2,10,11,12,13,16-hexahydro-8H-3,5-ethenotripyrazolo[4,3-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0869] (10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[3,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0870] ((10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0871] (10S,17E)-8,10,12,16-Tetramethyl-2,8,10,11,12,13-hexahydro-3,5-ethenodipyrazolo[3,4-j:4’,3’-n][1,2]thiazolo[3,4-f][1,4]oxazacyclopentadecine;

[0872] (10S,20E)-18-[2-(Methanesulfonyl)ethyl]-8,10,12-trimethyl-2,8,10,11,12,13,16,17,18,19-decahydro-3,5-ethenopyrazino[1’,2’:1,5]pyrazolo[3,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0873] (10S,17E)-16-Cyclopropyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0874] (10S,17E)-16-Ethyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0875] (10S,17E)-8,10,12-Trimethyl-16-(propan-2-yl)-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0876] (10S,17E)-8,10,12-Trimethyl-16-(propan-2-yl)-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0877] (10S,17E)-16-Ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-3,5-etheno[1,2]oxazolo[5,4-f]dipyrazolo[3,4-j:4’,3’-n][1,4]oxazacyclopentadecine;

[0878] (10R,17E)-8,10,14,15-Tetramethyl-12-(propan-2-yl)-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[4,3-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0879] (10S,17E)-8,10,14,15-Tetramethyl-12-(propan-2-yl)-2,10,11,12,13,15-hexahydro-8H-3,5-ethenotripyrazolo[4,3-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine;

[0880] (10S,17E)-8,10,16-Trimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecino[7,6-d][1,2]oxazole;

[0881] (10S,17E)-8,10-Dimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecino[7,6-d][1,2]oxazole-16-carbonitrile;

[0882] (10S,17E)-8,10,16-Trimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecino[7,6-d][1,2]thiazole;

[0883] (10S,17E)-8,10-Dimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[7,6-d][1,2]thiazole-16-carbonitrile;

[0884] (10S,17E)-8,10,16-Trimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]oxazole;

[0885] (10S,17E)-8,10-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][(1,2]oxazole-16-carbonitrile;

[0886] (10S,17E)-8,10,16-Trimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]thiazole;

[0887] (10S,17E)-8,10-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]oxazole-16-carbonitrile;

[0888] (10S,17E)-8,10-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]thiazole-16-carbonitrile;

[0889] (17E)-8,16-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]oxazole;

[0890] (17E)-8,16-Dimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[7,6-d][1,2]oxazole; and

[0891] (17E)-8,16-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]thiazole;

[0892] The compound of item 1 or 2 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0893] The following shows representative embodiments of the compounds of formulas (I) to (XII): [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

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

Table 45

Table 46

Table 47

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

Table 65

Table 66

Table 67

Table 68

Table 69

Table 70

Table 71

Table 72

Table 73

Table 74

Table 75

Table 76

Table 77

Table 78

[0894] One of ordinary skill in the art will recognize that the species listed or described herein are not exhaustive and that additional species falling within the scope of these defined terms may be selected.

[0895] Another embodiment Certain compounds of the present invention are also described in the following additional embodiments. One of ordinary skill in the art will understand that the additional embodiments described herein are consistent with the embodiments described throughout this disclosure. The additional embodiments describe certain aspects within the scope of the general teachings of this disclosure and are described in a similar manner.

[0896] In certain embodiments, the present invention provides a compound of Formula IA [Chemical formula]

[0897] (wherein R 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , A A , B A , m A , n A , p A and q A are as described herein.) or a pharmaceutically acceptable salt thereof. <9010394> In certain embodiments, the present invention provides a compound of Formula IIA [Chemical formula]

[0899] (wherein R 1A , R 2A , R 3A , R 4A , R 5A , R6A , R 7A , R 8A , A A , B A , Z A , Z 1A , m A , n A , p A , q A and " --- " are as described in this specification.) A compound of formula or a pharmaceutically acceptable salt thereof is provided.

[0900] In certain embodiments, the present invention provides a compound of formula IIIA [Chemical Formula]

[0901] (wherein R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , A A , B A , X 1A , X 2A , X 3A , Z A , Z 1A , Y 1A , Y 2A , Y 3A , p A , q A and " --- " are as described in this specification.) A compound of formula or a pharmaceutically acceptable salt thereof is provided.

[0902] In certain embodiments, the present invention provides a compound of formula IVA [Chemical Formula]

[0903] (wherein R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , A A , BA , X 1A , X 2A , X 3A , Z A , Z 1A , Y 1A , Y 2A , Y 3A and q A is as described herein.) or a pharmaceutically acceptable salt thereof.

[0904] In a further aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (IA)-(IVA) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive.

[0905] In a further aspect, the present invention relates to a compound of formula (IA)-(IVA) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0906] 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 (IA)-(IVA) or a pharmaceutically acceptable salt thereof.

[0907] In a further aspect, the present invention relates to the use of a compound of formula (IA)-(IVA) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease such as cancer and the use of such a compound and salt for the treatment of such a disease.

[0908] In a further aspect, the present invention relates to a method of inhibiting ALK, the method comprising contacting a cell comprising one or more of ALK with an effective amount of at least one compound of formula (IA)-(IVA) 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.

[0909] Further embodiments, features, and advantages of the present invention will become apparent from the following detailed description and practice of the present invention. The compounds of the present invention can be described as embodiments of any of the following numbered clauses. It is understood that any of the embodiments described herein can be used in combination with any other embodiment described herein, provided the embodiments are not mutually inconsistent.

[0910] 1. Formula IA

Chemical formula

[0911] 〔Wherein,

[0912] Ring A A And ring B A Are each independently a 5-membered heteroarylene;

[0913] Each R 1A , R 2A And R 8A When present, are 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 , -NRa 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, 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 may independently be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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)NRc 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 、 is substituted with -CN or -NO2;

[0914] Each R 1A and R 5A or R 6A can, together with one or more atoms to which they are attached, optionally combine to form C3 - C6 cycloalkyl or 3 - 7 membered heterocycloalkyl, where R 1A and R5A or R 6A When two of them are integrally formed, each hydrogen atom in C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl may independently be optionally -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)ORe 、 -P(O)2OR e 、 is substituted with -CN or -NO2;

[0915] Each R 3A 、 R 4A 、 R 5A and R 6A 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 Rb , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)2NR a R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom of the aryl and 5- to 10-membered heteroaryl is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)NR e R f, -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN or substituted with -NO2; or R 3A , R 4A , R 5A and R 6A of two of them, together with one or more carbons to which they are attached, optionally combine to form C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, where R 3A , R 4A , R 5A and R 6A when two of them combine to form C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl, each hydrogen atom in the C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl is independently optionally -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NRe C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0916] R 7A are independently H, deuterium, and -C(O)R c , -C(O)OR c , -C(O)NR c R d , -S(O)NR c R d , -P(O)2R c R d , -P(O)2NR c R d or -P(O)2OR c and;

[0917] Each R a , R b , R c , R d , R e and R fis independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl, and C1-C6 alkylene-5- to 10-membered heteroaryl, or R a and R b or R c and R d or R e and R f and R, together with the atoms to which they are attached, form a 3- to 7-membered heterocycloalkyl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, C1-C6 alkylene-C6-C 10Each hydrogen atom in aryl, 5- to 10-membered heteroaryl or C1-C6 alkylene-5- to 10-membered heteroaryl is independently, if desired, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2,-P(O)(C2-C6 alkylene), -P(O)2(H or C1-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6 alkyl), -CN or -NO2 substituted;

[0918] m A is 0, 1, 2 or 3;

[0919] n A is 0, 1, 2 or 3;

[0920] p A is 2, 3 or 4; and

[0921] q A is 0, 1 or 2. ]]

[0922] A compound of or a pharmaceutically acceptable salt thereof.

[0923] 2. Formula IIA

Chem.

[0924] 〔Wherein,

[0925] 「 --- 」 is optionally a carbon-carbon single bond or a carbon-carbon double bond;

[0926] Z A is

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0927] 3. Formula IIIA

Chemical formula

[0928] 〔In the formula,

[0929] X 1A , X 2A and X 3Aare independently of each other -O-, -S-, =C(H)-, =C(R 1A )-, -N(H)-, -N(R 1A )- or =N-, and ring A A is a 5-membered heteroarylene, provided that X 1A , X 2A and X 3A at least one of which is not =C(H)- or =C(R 1A );

[0930] Y 1A , Y 2A and Y 3A are independently -O-, -S-, =C(H)-, =C(R 2A )-, -N(H)-, -N(R 2A )- or =N-, and ring B is a 5-membered heteroarylene, provided that Y 1A , Y 2A and Y 3A at least one of which is not =C(H)- or =C(R 2A ); and

[0931] " --- " is optionally a carbon-carbon single bond or a carbon-carbon double bond;

[0932] Z A is

Chem.

Chem.

Chem.

Chem.

[0933] 4. Formula IVA [ka]

[0934] [During the ceremony,

[0935] " --- " is optionally a carbon-carbon single bond or a carbon-carbon double bond;

[0936] Z A teeth [ka] where * is the point of covalent attachment to the ether and ** is the Z 1A is the point of covalent attachment to [ka] is ring B A represents a covalent bond point to the ring atom of, [Chemical formula] one bond is a single bond and one bond is a double bond **and [Chemical formula] represents the condition between the bond points of; Z 1A is [Chemical formula] wherein, *** is a covalent bond point to indazole and **** is a covalent bond point to Z A is a covalent bond point to, [Chemical formula] is ring B A represents a covalent bond point to the ring atom of, [Chemical formula] one bond is a single bond and one bond is a double bond ****and [Chemical formula] represents the condition between the bond points of; and ring B A is a 5-membered heteroarylene.] A compound according to any one of embodiments 1 to 3 having or a pharmaceutically acceptable salt thereof.

[0937] 5. X 2A is -O-, -S-, -N(H)-, -N(R 1A )- or =N-, X 1A and X 3A are independently of each other -O-, -S-, =C(H)-, =C(R 1A )-, -N(H)-, -N(R 1A )- or =N-, ring A A is a 5-membered heteroarylene; and

[0938] Y2A is -O-, -S-, -N(H)-, -N(R 2A )- or =N-, and Y 1A and Y 3A are independently of each other -O-, -S-, =C(H)-, =C(R 2A )-, -N(H)-, -N(R 2A )- or =N-, and ring B A is a 5-membered heteroarylene,

[0939] a compound according to any one of embodiments 1 to 3.

[0940] 6. Ring A A is

Chem.

[0941] where each

Chem.

[0942] a compound according to any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof.

[0943] 7. Ring A A is

Chem.

[0944] where each

Chem.

[0945] 8. Ring A A is [Chem.] a 5-membered heteroarylene selected from the group consisting of,

[0946] wherein each [Chem.] represents a covalent bond point, a compound of any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof.

[0947] 9. Ring B A is [Chem.] a 5-membered heteroarylene selected from the group consisting of,

[0948] wherein each [Chem.] represents a covalent bond point, and each R 2 is as described herein, a compound of any one of the previous embodiments or a pharmaceutically acceptable salt thereof.

[0949] 10. Ring B A is [Chem.] a 5-membered heteroarylene selected from the group consisting of,

[0950] wherein each [Chem.] represents a covalent bond point, a compound of any one of the previous embodiments or a pharmaceutically acceptable salt thereof.

[0951] 11. [Chem.]

[0952] is ethylene, propylene or butylene, wherein each hydrogen atom in ethylene, propylene and butylene 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 , -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 Rb 、 -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 、 substituted with -CN or -NO2, each

Chemical formula

[0953] 12. One R 3A is 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 eR 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 or two Rs 3A and / or R 4A together with one or more carbons to which they are attached, optionally combine to form C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl formed by the combination of two Rs 3A and / or R 4A is independently optionally -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, and any remaining R 3A and R 4A is H, a compound of any of the previous embodiments or a pharmaceutically acceptable salt thereof.

[0954] 13. One R 3A is 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 , -NR f C(O)R e , -NR f C(O)OR e , -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, and any remaining R 3A and R 4A is H, a compound of any of the previous embodiments or a pharmaceutically acceptable salt thereof.

[0955] 14. A compound of any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein one R 3A is C1-C6 alkyl.

[0956] 15. A compound of any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein one R 3A is methyl, and any remaining R 3A and R 4AA compound of any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein [the relevant group] is H.

[0957] 16. R 5A and R 6A A compound of any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein [the relevant group] is H.

[0958] 17. R 7A A compound of any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein [the relevant group] is H.

[0959] 18. q A A compound of any of the previous claims or a pharmaceutically acceptable salt thereof, wherein q is 0.

[0960] 19.

Chemical Structure

[0961] or a pharmaceutically acceptable salt thereof.

[0962] 20. A pharmaceutical composition comprising a compound of the previous embodiment and optionally one or more additives.

[0963] 21. A method of treating a disease in a subject, comprising administering a therapeutically effective amount of a compound of any of Embodiments 1 to 19 or the pharmaceutical composition of Embodiment 20.

[0964] 22. A compound according to any of Embodiments 1 to 19 for use in a method of treating a disease in a subject.

[0965] 23. Use of a compound according to any of Embodiments 1 to 19 in the manufacture of a medicament for the treatment of a disease in a subject.

[0966] In one embodiment, ring A A is a 5-membered heteroarylene.

[0967] In certain embodiments, ring A A is a 5-membered heteroarylene, where each R 1A when present, independently represent deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a Rb 、 -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 may independently be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 Rd , -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 or -NO2 substituted; each R 1A and R 5A or R 6A or R, together with one or more atoms to which they are attached, may optionally combine to form C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl formed by the combination of two R 1A and R 5A or R 6A is independently optionally 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 , NRC(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.

[0968] In certain embodiments, ring A A 's R 1A and R 5A or R 6A together with one or more atoms to which they are attached can optionally combine to form C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl formed by the combination of two R 1A and R 5A or R 6A is independently optionally 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 、 is substituted with -CN or NO2.

[0969] In one embodiment, ring A A is pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene, where each is independently optionally substituted with 1, 2 or 3 R 1A (m R's 1A) is replaced by each of which 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 , -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 Rb 、 -P(O)OR a 、 -P(O)₂OR a 、 selected from the group consisting of -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 c 、 -OC(O)R c 、 -OC(O)NR c R d 、 -OC(=N)NR c R d 、 -OS(O)R c 、 -OS(O)₂R c 、 -OS(O)NR c R d 、 -OS(O)₂NR c R d 、 -SR c 、 -S(O)R c 、 -S(O)₂R c 、 -S(O)NR c R d 、 -S(O)₂NR c R d 、 -NR c R d 、 -NR c C(O)R d 、 -N(C(O)R c )(C(O)R d 、 -NR c C(O)OR d 、 -NR c C(O)NR c R d 、 -NR c C(=N)NR c R d 、 -NR c S(O)R d 、 -NR c S(O)₂R d 、 -NR c S(O)NR c R d 、 -NR c S(O)₂NR c R d, -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)R c R d , -P(O)2R c R d , -P(O)NR c R d , -P(O)2NR c R d , -P(O)OR c , -P(O)2OR c , -CN or -NO2 substituted.

[0970] In one embodiment, ring A A is of the formula

Chemical formula

[0971] 〔wherein, " --- " is optionally a carbon-carbon single bond or a carbon-carbon double bond, and each

Chemical formula

Chemical formula

[0972] 〔wherein, " --- " is optionally a carbon-carbon single bond or a carbon-carbon double bond, and each

Chemical formula

[0973] In certain embodiments, ring A A is of the formula

Chemical formula

[0974] 〔wherein, " --- " is optionally a carbon-carbon single bond or a carbon-carbon double bond, each

Chemical formula

[0975] In certain embodiments, m A is 0, 1, 2, or 3. In certain embodiments, m A is 0, 1, or 2. In certain embodiments, m A is 0 or 1. In certain embodiments, m A is 0. In certain embodiments, m A is 1. In certain embodiments, m Ais 2. In certain embodiments, m A is 3.

[0976] In certain embodiments, ring A A is

Chem.

[0977] wherein each

Chem.

[0978] In certain embodiments, ring A A is

Chem.

[0979] wherein each

Chem.

[0980] In certain embodiments, R 1A is C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is independently optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 , -NR d , -N(C(O)R c )(C(O)R d , -NR c , -NR d , -NR c , -NR c R d , -NR c , -NR c R d , -NR c , -NR d , -NR c , -NR d , -NR c , -NR c R d , -NR c , -NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)R c R d , -P(O)2R c R d , -P(O)NR c R d , -P(O)2NR c R d , -P(O)OR c , -P(O)2OR c is substituted with -CN or -NO2.

[0981] In one embodiment, ring A A is [Chemical formula] a 5-membered heteroarylene selected from the group consisting of

[0982] where each [Chemical formula] represents a covalent bond point.

[0983] In one embodiment, ring B A is a 5-membered heteroarylene.

[0984] In one embodiment, ring B A is a 5-membered heteroarylene, where each R 2A , 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 aS(O)R b 、 -NR a S(O)2R b 、 -NR a S(O)NR a R b 、 -NR a S(O)2NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -PR a R b [[ID=The original text to be translated is as below which wraped by : 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 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 、-NRc 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 or -NO2 substituted.

[0985] In one embodiment, ring B A is of the formula

Chemical formula

[0986] 〔Wherein each

Chemical formula

[0987] where Z A is [Chemical formula] where * is the point of covalent bond to the ether and ** is the point of covalent bond to Z 1A is the point of covalent bond to Z, [Chemical formula] represents the point of covalent bond to the ring atoms of ring B A ; [Chemical formula] where one bond is a single bond and one bond is a double bond ** and [Chemical formula] represents the condition between the bonding points of ; Z 1A is [Chemical formula] where *** is the point of covalent bond to the indazole and **** is the point of covalent bond to Z A is the point of covalent bond to Z, [Chemical formula] represents the point of covalent bond to the ring atoms of ring B A ; [Chemical formula] where one bond is a single bond and one bond is a double bond **** and [Chemical formula] represents the condition between the bonding points of. ] is.

[0988] In certain embodiments, ring B A is of the formula

Chem.

[0989] wherein each

Chem.

[0990] In one embodiment, ring B A is of the formula

Chem.

[0991] wherein each

Chem.

[0992] In one embodiment, Z 1A is N. In one embodiment, Z 1A is C.

[0993] In one embodiment, ring B A is pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene, where each may optionally be substituted with one, two or three R 2A (n A number of R 2A ) and each of which is 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 Rb , -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, independently selected from the group consisting of, 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 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)Rd 、 -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 、 is substituted with -CN or -NO2.

[0994] In one embodiment, n A is 0, 1, 2 or 3. In one embodiment, n A is 0, 1 or 2. In one embodiment, n A is 0 or 1. In one embodiment, n A is 0. In one embodiment, n A is 1. In one embodiment, n A is 2. In one embodiment, n A is 3.

[0995] In one embodiment, ring B A is

Chemical Structure

[0996] where each

Chemical Structure

[0997] In certain embodiments, ring B A teeth [ka] is a 5-membered heteroarylene selected from the group consisting of

[0998] Here, each [ka] represents a covalent bond point.

[0999] In some embodiments, R 7A are independently H, deuterium, and -C(O)R c , -C(O)OR c , -C(O)NR c R d , -S(O)NR c R d , -P(O)2R c R d , -P(O)2NR c R d or -P(O)2OR c is.

[1000] In some embodiments, R 7A are independently H.

[1001] In certain embodiments, the indazole optionally contains 0, 1, or 2 R 8A (q R 8A ), each of which is independently substituted with deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NRa R b 、 -OS(O)R a 、 -OS(O)₂R a 、 -SR a 、 -S(O)R a 、 -S(O)₂R a 、 -S(O)NR a R b 、 -S(O)₂NR a R b 、 -OS(O)NR a R b 、 -OS(O)₂NR a R b 、 -NR a R b 、 -NR a C(O)R b 、 -NR a C(O)OR b 、 -NR a C(O)NR a R b 、 -NR a S(O)R b 、 -NR a S(O)₂R b 、 -NR a S(O)NR a R b 、 -NR a S(O)₂NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -PR a R b 、 -P(O)R a R b 、 -P(O)₂R a R b 、 -P(O)NR a R b 、 -P(O)₂NR a R b 、 -P(O)OR a 、 -P(O)₂OR a 、 -CN or -NO₂, selected from the group consisting of, where C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3-7 membered heterocycloalkyl, C₆-C 10Each hydrogen atom in aryl or 5- to 10-membered heteroaryl may independently be deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O)2R c , -OS(O)NR c R d , -OS(O)2NR c R d , -SR c , -S(O)R c , -S(O)2R c , -S(O)NR c R d , -S(O)2NR c R d , -NR c R d , -NR c C(O)R d , -N(C(O)R c )(C(O)R d , -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)Rc 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 、 is substituted with -CN or -NO2.

[1002] In certain embodiments, each R 8A , when present, is independently hydrogen.

[1003] In certain embodiments, q A is 0, 1, or 2. In certain embodiments, q A is 0 or 1. In certain embodiments, q A is 0. In certain embodiments, q A is 1. In certain embodiments, q A is 2.

[1004] In certain embodiments, [Chemical formula] is ethylene, propylene, or butylene, where each hydrogen atom in ethylene, propylene, and butylene is independently optionally 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 substituted, and each

Chemical formula

[1005] In certain embodiments, p A is 2, 3, or 4. In certain embodiments, p A is 2 or 3. In certain embodiments, p A is 2. In certain embodiments, p A is 3. In certain embodiments, p A 00 is 4.

[1006] In some embodiments, one R 3A is C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f, -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2 substituted or two Rs 3A and / or R 4A together with one or more carbons to which they are attached, optionally combine to form C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, where two Rs 3A and / or R 4A each hydrogen atom in the C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl formed by combination is independently optionally -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 、 -CN or -NO₂ substituted, and any remaining R 3 and R 4 is H.

[1007] In one embodiment, one R 3A is 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 、 -NRe S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2 substituted, and any remaining R 3 and R 4 is H.

[1008] In certain embodiments, one R 3A is C1-C6 alkyl. In certain embodiments, one R 3A is methyl, and any remaining R 3A and R 4A is H.

[1009] In certain embodiments, R 5A and R 6A is H.

[1010] In certain embodiments, the present invention is

[1011] (17E)-16-Ethyl-8,14-dimethyl-2,8,10,11,13,14-hexahydro-3,5-ethano[1,4]dioxacyclopentadecino[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[1012] 2-[(17E)-8,16-Dimethyl-2,10,11,13-tetrahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazol-14(8H)-yl]-N-ethylacetamide;

[1013] (17E)-8,14-Dimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole-16-carbonitrile;

[1014] (17E)-8,14,16-Trimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[1015] (10S,17E)-8,10,14-Trimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole;

[1016] (10S,17E)-8,10,14-Trimethyl-2,8,10,11,13,14-hexahydro-3,5-etheno[1,4]dioxacyclopentadecano[10,11-c:15,14-c’:6,7-c’’]tripyrazole-16-carbonitrile;

[1017] (10S,17E)-8,10,16-Trimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[7,6-d][1,2]oxazole;

[1018] (10S,17E)-8,10-Dimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[7,6-d][1,2]oxazole-16-carbonitrile;

[1019] (10S,17E)-8,10,16-Trimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[7,6-d][1,2]thiazole;

[1020] (10S,17E)-8,10-Dimethyl-2,10,11,13-tetrahydro-8H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[7,6-d][1,2]thiazole-16-carbonitrile;

[1021] (10S,17E)-8,10,16-Trimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]oxazole;

[1022] (10S,17E)-8,10-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]oxazole-16-carbonitrile;

[1023] (10S,17E)-8,10,16-Trimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]thiazole;

[1024] (10S,17E)-8,10-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]oxazole-16-carbonitrile;

[1025] (10S,17E)-8,10-Dimethyl-2,8,10,11-tetrahydro-13H-3,5-ethenodipyrazolo[3’,4’:10,11;4’’,3’’:14,15][1,4]dioxacyclopentadecano[6,7-c][1,2]thiazole-16-carbonitrile;

[1026] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[6,5-d][1,2]oxazole-16-carbonitrile;

[1027] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[6,5-d][1,2]thiazole-16-carbonitrile;

[1028] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[5,6-c][1,2]oxazole-16-carbonitrile;

[1029] (10S,17E)-10,14-Dimethyl-10,11,13,14-tetrahydro-2H-3,5-ethenodipyrazolo[4’,3’:13,14;4’’,3’’:9,10][1,4]dioxacyclopentadecano[5,6-c][1,2]thiazole-16-carbonitrile;

[1030] Provided is a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[1031] Pharmaceutical composition For treatment purposes, the pharmaceutical compositions containing the compounds described herein may further contain one or more pharmaceutically acceptable additives. Pharmaceutically acceptable additives are substances that are non-toxic and biologically suitable in other respects 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 compositions of the present invention are sterile compositions. The pharmaceutical compositions can be manufactured using mixing techniques known or available to those skilled in the art.

[1032] Sterile compositions are also contemplated by the present invention and include compositions that comply with the authorities of the country or region regulating such compositions.

[1033] The pharmaceutical compositions and compounds described herein can be formulated by conventional methods known in the various fields of dosage form manufacture as solutions, emulsions, suspensions or dispersions in a suitable pharmaceutical solvent or carrier or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution or capsules together with a solid carrier. 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 compositions are formulated for intravenous or oral administration.

[1034] For oral administration, the compounds of the present invention can be provided in solid forms such as tablets or capsules, or as solutions, emulsions or suspensions. For the manufacture of oral compositions, the compounds of the present invention can be formulated to provide a dosage, for example, of about 0.1 mg to 1 g per day or about 1 mg to 50 mg per day or about 50 to 250 mg per day or about 250 mg to 1 g per day. Oral tablets contain the active ingredient mixed with compatible pharmaceutically acceptable additives such as diluents, disintegrants, binders, lubricants, sweeteners, flavorants, colorants 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 may include starch and gelatin. Lubricants, if present, may be magnesium stearate, stearic acid or talc. Optionally, the tablets may be coated with substances such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract or may be coated with an enteric coating.

[1035] Capsules for oral administration include hard and soft gelatin capsules. For the manufacture of hard gelatin capsules, the active ingredient can be mixed with a solid, semi-solid or liquid diluent. Soft gelatin capsules can be mixed with the active ingredient and 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.

[1036] The liquid for oral administration may be in the form of a suspension, solution, emulsion or syrup or may be lyophilized or provided as a dry product for reconstitution with water or other suitable medium before use. Such liquid compositions may optionally contain suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous media such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, optionally, pharmaceutically acceptable additives such as flavoring or coloring agents.

[1037] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal or subcutaneous routes, the agent of the invention can be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonic or in a parenterally acceptable oil. Suitable aqueous media include Ringer's solution and isotonic sodium chloride. Such forms can be provided in unit dosage forms such as ampoules or disposable injection devices, multi-dose forms such as vials that can aspirate appropriate doses or in solid forms or pre-concentrates that can be used in the manufacture of injectable formulations. Examples of infusion doses are in the range of about 1 to 1000 μg / kg / min of the agent mixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[1038] For nasal, inhalation or oral administration, the pharmaceutical composition of the invention can be administered using, for example, a spray formulation that also contains a suitable carrier. The composition of the invention can be formulated for rectal administration as a suppository.

[1039] For topical administration, the compound of the invention is preferably formulated as a cream or ointment or similar medium suitable for topical administration. For topical administration, the compound of the invention can be mixed with a pharmaceutical carrier at a drug-to-medium concentration of about 0.1% to about 10%. Other modes of administration of the agent of the ...

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