Indazole-based macrocyclic compounds

Abstract

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

Description

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 608,035, filed December 8, 2023, the entire disclosure of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure relates to indazole macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat disease, such as cancer. BACKGROUND

[0003] Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning, G et al., The protein kinase complement of the human genome. Science. 2002, 298:1912-34). Dysregulation of kinase activity is associated with many diseases, including cancers, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chern. Res. 2003,36:462-469). The molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson, LJ et al., New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res. 2018, 78:15-29). The critical role of kinases in cancer and other diseases makes them attractive targets for drug inventions with 62 small molecule kinase inhibitors have been approved and 55 of them for cancer targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2021 Update. Pharmacol Res 2021, 165:105463). Although kinase inhibitors have achieved dramatic success in cancer targeted therapies, the development of treatment resistance has remained as a challenge for small molecule kinase inhibitors. Acquired secondary mutations within kinase domain during the treatment often lead to treatment resistance to kinase inhibitors (Pottier, C et al., Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers (Basel), 2020,12:731). Resistance can also arise from subpopulations of tolerant / persister cells that survive in the presence of the treatment. Different processes contribute to the emergence of tolerant persister cells, including pathway rebound through the release of negative feedback loops, transcriptional rewiring mediated by chromatin remodeling and autocrine / paracrine communication among 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, it is necessary to invent kinase inhibitors that can target not only the kinase oncogenic drivers, overcome most frequent resistance mutations, but also tolerant persister cancer cells for overcoming resistance, achieving better efficacy and longer disease control.

[0004] Non-small-cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide (World Health Organisation. Cancer Fact Sheet 2017). Activating EGFR mutations have been reported in approximately 10% to 15% of cases of adenocarcinoma 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 found in NSCLC tumors are short in-frame deletions in exon 19 (dell9) of the EGFR gene and L858R, a single missense mutation in exon 21 (Konduri, K. et al., EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. Cancer Discovery 2016, 6:601-11).

[0005] The anaplastic lymphoma kinase (ALK) is a member of the family of insulin-like tyrosine kinase receptors involved in the oncogenesis of several tumor types. Approximately 5% of patients with non-small cell lung cancer (NSCLC) harbor rearrangement 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 FDA as the standard of care in the first- and second-line treatment of ALK-rearranged NSCLC patients. However, as complete response to ALK inhibitors is rare, almost all patients with ALK-rearranged NSCLC inevitably acquire resistance to ALK inhibitors, resulting in tumor recurrence. Drug resistance mechanisms include ALK-independent and ALK-dependent processes. ALK-independent resistance mechanisms involve the activation of bypass pathways, such as EGFR, c-MET, KRAS, and AXL or transformation into 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). Although five ALK inhibitors have been approved, they have a limited clinical ability to overcome ALK-independent resistance mechanisms. Therefore, it is necessary to develop next generation multitargeted ALK inhibitors with ability targeting not only primary ALK fusions and ALK secondary resistance mutations, but also targeting mechanisms associated with tolerant persister cancer cells for better efficacy and longer duration of response.

[0006] The proviral integration for the Moloney murine leukemia virus (PIM) kinases are oncogenic serine / threonine kinases that phosphorylate a wide range of substrates that regulate several 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 numerous major oncogenic players, including stabilization of p53, synergism with c-Myc, and notable parallel signaling with PI3K / Akt. The aberrant PIM kinase activity plays an important role in resistance mechanisms of chemotherapy, radiotherapy, anti-angiogenic therapies and targeted therapies, providing a rationale for co-targeting treatment strategies for a more durable patient response (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).

[0007] Cdc-like kinases (CLKs) are evolutionary conserved dual-specificity kinases that are able to phosphorylate serine, threonine, and tyrosine residues. CLKs catalyze the phosphorylation of SR proteins, serine, and arginine-rich splicing factors 1-12 (SRSF1-12), which regulate 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 feature of cancer. High-frequency mutations of SF3B1 or SRSF2 have been described 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). In addition, mutations in splicing-related genes have also been found in various solid cancers, including lung, breast, and pancreatic cancers (Dvinge, H et al., RNA splicing factors as oncoproteins and tumour suppressors. Nat Rev Cancer 2016, 16: 413 - 430). The modulation of pre-mRNA splicing via inhibition of CLK kinases is an attractive anti-neoplastic strategy, especially for the cancers that exhibit aberrant pre-mRNA splicing.

[0008] Therefore, it is necessary to develop a new generation of multitargeted ALK inhibitors that are potent against oncogenic driver ALK fusions, and point mutations, other emerging and established ALK resistance mutations, as well as emerging resistance targets for tolerant / persistent cancer cells, e.g., PIM kinases and CLK kinases. SUMMARY

[0009] In one aspect, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof, R7

[0010] wherein R1, R2a, R2b, R3, R4, R5, R7, R8, A, B, L, m, n, p, and q are as described herein.

[0011] In one aspect, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,

[0012] wherein R1, R2a, R2b, R3, R4, R5, R7, R8, A, B, L, m, n, p, q and each “------” are as described herein.

[0013] In one aspect, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, III

[0014] wherein R2a, R2b, R3, R4, R5, R7, R8, A, B, L, X1, X2, X3, p, q, and each “------” are as described herein.

[0015] In one aspect, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, IV

[0016] wherein R2a, R3, R4, R5, R7, Rs, X1, X2, X3, Y1, Y2, A, B, L, p, q, and each ------ are as described herein.

[0017] In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.

[0018] In further aspects, the disclosure relates to a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0019] hi further aspects, the disclosure relates to a method of treating disease, such as cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I)-(TV), or a pharmaceutically acceptable salt thereof.

[0020] In further aspects, the disclosure relates to use of a compound of Formula (I)-(IV), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of disease, such as cancer, and the use of such compounds and salts for treatment of such diseases.

[0021] In further aspects, the disclosure relates to a method of inhibiting one or more of aberrant ALK, including oncogenic driver ALK fusions (e.g. EML4-ALK) and ALK resistance mutations, aberrant PIM kinases, and / or aberrant CLK kinases comprising contacting a cell comprising one or more of aberrant ALK, including one or more oncogenic driver ALK fusion and ALK resistance mutations, aberrant PIM kinases, and / or aberrant CLK kinases with an effective amount of at least one compound of Formula (I)-(IV), or a pharmaceutically acceptable salt thereof, and / or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.

[0022] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.

[0023] 1. A compound of the formula R7 I

[0024] or a pharmaceutically acceptable salt thereof, wherein “------” is optionally a carbon-carbon single bond or a carbon-carbon double bond

[0025] ring A is a 5- or 6-membered heteroarylene or Ce-Cio arylene;

[0026] ring B is a 5- or 6-membered heteroarylene;

[0027] each L is independently -O-, -S-, -S(O)-, -S(O)2-, -N(R6)C(O)-, -C(O)N(R6)-, -N(R6)-, -N(R6)S(O)-, -S(O)N(R6)-, -N(R6)S(O)2-, -S(O)2N(R6)-, or -C(R7)(RS)-, provided that (L)p does not comprise an O-O, S-O, or N-N bond, and the point of covalent attachment of (L)p to -NR3- does not form a -N-N- or a -O-N- bond;

[0028] each R1 and R2b, when present, is independently deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, 5-to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd) RdNRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2;

[0029] R2a is deuterium, halogen, Ci-G> alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2;

[0030] R3 is H, deuterium, CiGs alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2;

[0031] each R4 is independently deuterium, halogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cgalkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-G, alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0032] R5 is H, deuterium, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, -P(O)2ORc, or -S(O)2ORc;

[0033] each R6, when present, is independently H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is independently optionally substituted by -ORC, -0C(0)Rc, -0C(0)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -0S(0)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(0)NRcRd, -S(0)2NRcRd, -NRcRd, -NRcC(0)Rd, -N(C(0)Rc)(C(0)Rd), -NRcC(O)ORd, -NRcC(0)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(0)NRcRd, -NRcS(0)2NRcRd, -C(O)RC, -C(0)0Rc, -C(0)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(0)RcRd, -P(0)2RcRd, -P(0)NRcRd, -P(0)2NRcRd, -P(0)0Rc, -P(O)2ORc, -CN, or -NO2;

[0034] each R7 and R8, is independently H, deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Cs alkyl, C2-C& alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-G> alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or two of R7 and R8, taken together with the carbon or carbons to which they are attached, optionally combine to form a C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl formed when two of R7 and R8 are taken together is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0035] each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, Ci-Ce alkylene-Ce-C 10 aryl, 5- to 10-membered heteroaryl, and Ci-Ce alkylene-5- to 10-membered heteroaryl, or Ra and Rb or Rc and Rd or Re and Rf, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in G-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, Ce-Goaryl, G-Ce alky lene-Ce-Go aryl, 5- to 10-membered heteroaryl, or G-Ce alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, G-Ce haloalkyl, -OH, -OCi-Ce alkyl, -0C(0)-(H or Ci-C6 alkyl), -0C(0)N(H or G-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or Ci-C6 alkyl), -OS(O)2-(H or Ci-C6 alkyl), -OS(O)N(H or Ci-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or Ci-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or Ci-C6 alkyl), -S(O)(H or G-G alkyl), -S(O)2(H or Ci-C6 alkyl), -S(O)N(H or G-G, alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or G-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or G-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or Ci-C6 alkyl)C(O)-(H or Ci-C6 alkyl), -N(H or Ci-C6 alkyl)C(O)O(H or Ci-C6 alkyl), -N(H or Ci-C6 alkyl)C(O)N(H or G-C6 alkyl)2, -N(H or Ci-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or G-G alkyl)S(O)-(H or Ci-C6 alkyl), -N(H or Ci-C6 alkyl)S(O)2(H or Ci-C6 alkyl), -N(H or G-C6 alkyl)S(O)N(H or G-C6 alkyl)2, -N(H or G-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or Ci-C6 alkyl)S(O)2N(H or Ci-C6 alkyl)2, -N(H or Ci-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(0)-(H or G-G alkyl), -C(O)O(H or Ci-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or Ci-C6 alkyl)2, -P(C2-C6 alkylene), -P(0)(H or Ci-C6 alkyl)2, -P(O)(C2-C6 alkylene), -P(O)2(H or G-G alkyl)2, -P(O)2(C2-C6 alkylene), -P(0)N(H or G-G alkyl)2, -P(0)N(G-G alkylene), -P(0)2N(H or Ci-G alkyl)2, -P(O)2N(G-C6 alkylene), -P(0)0(H or G-C6 alkyl), -P(0)20(H or G-C6 alkyl), -CN, or -NO2;

[0036] m is 0, 1, 2, or 3;

[0037] n is 0, 1, or 2;

[0038] p is 3, 4, 5, 6, or 7; and

[0039] qis 0, l,or2;

[0040] wherein the compound is not of the formula

[0041] 2. The compound of clause 1, or a pharmaceutically acceptable salt thereof, having the formula II wherein each “------” is independently optionally a carbon-carbon single bond or a carbon carbon double bond, and ring A is a 5-membered heteroarylene.

[0042] 3. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, having the formula III R7 III

[0043] wherein

[0044] ring B is a 5-membered heteroarylene;

[0045] X1, X2, and X3 are each independently -O-, -S-, =C(H)-, =C(R])-, -N(H)-, -NCR1)-, or =N- and ring A is a 5-membered heteroarylene, provided that at least one of X1, X2, and X3 is not =C(H)-, or =C(R1)-; and

[0046] each “------” is independently optionally a carbon-carbon single bond or a carbon carbon double bond.

[0047] 4. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, having the formula III R7 IV

[0048] wherein

[0049] Y1 and Y2 are each independently -O-, -S-, =C(H)-, =C(R2b)-, -N(H)-, -N(R2b)-, or =N- and ring B is a 5-membered heteroarylene, provided that at least one of Y1 and Y2 is not =C(H)-, or =C(Rab)-; and “------” in ring A is optionally a carbon-carbon single bond or a carbon-carbon double bond, one “------” in ring B is a carbon-carbon single bond, and one “------” in ring B is a carbon-carbon double bond.

[0050] 5. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroarylene selected from the group consisting of wherein each “ represents a point of covalent attachment.

[0051] 6. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroarylene selected from the group consisting of wherein each “mw'" represents a point of covalent attachment.

[0052] 7. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroarylene selected from the group consisting of wherein each '-rwxs'' represents a point of covalent attachment.

[0053] 8. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenylene, and m is 0, 1, or 2.

[0054] 9. The compound of any one of clauses 1, 2, or 8, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenylene, and m is 0 or 1.

[0055] 10. The compound of any one of clauses 1, 2, 8, or 9, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenylene, m is 1, and R1 is methyl, ethyl, hydroxyethyl, F, Cl, or Br.

[0056] 11. The compound of any one of clauses 1, 2, or 8 to 10, or a pharmaceutically acceptable salt thereof, wherein ring A is wherein each “ vrwv'” represents a point of covalent attachment.

[0057] 12. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroarylene.

[0058] 13. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroarylene selected from the group consisting of wherein each “ represents a point of covalent attachment.

[0059] 14. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroarylene of the formula wherein each “'Aaat” represents a point of covalent attachment.

[0060] 15. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R3 is H, methyl, ethyl, isopropyl, or cyclopropyl.

[0061] 16. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R4 is H, fluoro, chloro, or methyl.

[0062] 17. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R5 is H.

[0063] 18. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each L is independently -O-, -C(R7)(R8)-, or -N(R6)-, provided that (L)p does not contain an -O-O-, -N-O-, or -N-N- bond and the point of attachment of (L)p to -NR3- does not form an -O-N- or -N-N- bond.

[0064] 19. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein (L)p is -O(C(R7)(R8))2- or -O(C(R7)(R8))3-.

[0065] 20. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H, methyl, or ethyl.

[0066] 21. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R7 and R8 is independently H or methyl.

[0067] 22. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein (L)p is -O-C((H)(CH3))-CH2-.

[0068] 23. The compound of any one of the preceding clauses, selected from the group consisting of (25)-l-{(105,17£')-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;

[0069] (25)-2- {(105,17£)- 12-ethyl-6-(methoxymethy 1)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl | propan-1 -ol;

[0070] (25)-l-[(105,17E)-16-ethoxy-12-ethyl-6-(methoxymethyl)-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"- n] [ 1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0071] (25)-1 - [(105,17E)-16-ethoxy-6-(methoxymethyl)-8,1 O-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4", 3"-n] [ 1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0072] (25)-1-{ (105,17E)-6-(methoxymethyl)-8,10,12-trimethyl-16-[(propan-2-yl)oxy]- 2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4; / :3',4'-j:4”,3"-n\ [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0073] (25)-l-[(105,17E)-12-cyclopropyl-16-ethoxy-6-(methoxymethyl)-8,l O-dimethyl- 2,8,10,ll,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-zi][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0074] (25)-1 - {(105,17E)-6- [difluoro(methoxy)methyl] -12-ethyl- 8,1 O-dimethyl-16- [(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n\ [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;

[0075] (25)-1 - {(105,17E)-6- [(difluoromethoxy)methyl] -12-ethyl- 8,1 O-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3’,4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0076] (25)-1-{(105,17E)-6-(ethoxymethyl)-12-ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]- 2,8,10,11,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4", 3"- n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0077] (25)-l-{(105,17E)-6-[(cyclopropyloxy)methyl]-16-ethoxy-12-ethyl-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4", 3"- n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;

[0078] (25)-1 -| (105,17 / 7)-16-ethoxy-12-ethy 1-8,10-dimelhy 1-6- { [(propan-2-yl)oxy]methyl}- 2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4”, 3"- n] [ 1,4]oxazacyclopentadecin- 14-yl]propan-2-ol;

[0079] (25)-1 - {(105,17E)-6-[(difluoromethoxy)methyl]-16-ethoxy- 12-ethyl-8,10-dimethyl- 2,8,10,ll,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-ra][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0080] (25)-l-[(105,17E)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"- n] [1,4]oxazacyclopentadecin- 14-yl]propan-2-ol;

[0081] (25)-1-{(105, nEl-O^ethoxymethyll-^-ethyl^O-fluoro-SJO-dimethyl-lO-Kpropan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;

[0082] (25)-1 - {(105,17E)- 12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,!0,1 1,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0083] (25) -1 - {(105,17£)- 6- (ethoxymethyl) -12-ethy 1-19-fluoro- 8,10-dimethy 1-16-[(propan-2-yl)oxy]-2,8,10,ll,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3’,4,-j:4",3"-n\ [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0084] (2S)-l-[(105,17E)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-19-fluoro-8,10-dimethyl- 2,8,10,ll,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0085] (25)-l-L(105,17E)-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl- 2,8,10,ll,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n\ [1,4]oxazacyclopentadecin- 14-yl]propan-2-ol;

[0086] (105,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl- 2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4; / :3',4'-j:4”, 3"- n] [ 1,4]oxazacyclopentadecine;

[0087] (105,17E)-20-fluoro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-877-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine;

[0088] (25)-1-{(105,17E)- 12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,ll,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14-y 1} propan-2-ol;

[0089] (25)-l-[(105,17E)-16-ethoxy-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,ll,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4; / :3',4’-j:4”,3”-n] [ 1,4]oxazacyclopentadecin- 14-yl]propan-2-ol;

[0090] (105,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2,10,ll,12,13,14-hexahydro-8H- 3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine;

[0091] (105,17E)-20-chloro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl- 2,10,1 l,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4; / :3',4’-j:4”,3"-n\ [ 1,4]oxazacyclopentadecine;

[0092] (2S)-2-[(105,17E)-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2,8,10,ll,12,13-hexahydro- l47 / -3,5-ethenotripyrazolo|3,4; / :3',4'- / :4",3”- / ?|| 1,4|oxazacyclopentadecin-14-yl]propan-l-ol; and

[0093] (25)-2-[(10S,17E)-16-ethoxy-20-fluoro-6,8,10,12-tetramethyl-2,8,10,ll,12,13- hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3’,4'-j:4",3"- / 7][l,4]oxazacyclopentadecin-14-yl]propan-l-ol;

[0094] or a pharmaceutically acceptable salt thereof.

[0095] 24. A pharmaceutical composition comprising a compound of any one of the preceding clauses, and optionally one or more excipients.

[0096] 25. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of clauses 1 to 23, or a pharmaceutical composition of clause 24.

[0097] 26. A compound according to any one of clauses 1 to 23, for use in a method of treating disease in a subject.

[0098] 27. Use of a compound according to any one of clauses 1 to 23, in the manufacture of a medicament for the treatment of disease in a subject. DETAILED DESCRIPTION

[0099] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0100] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0101] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0102] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0103] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and / or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.

[0104] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0105] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0106] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD / Labs 2022.2.3 (Advanced Chemistry Development, Inc.) or ChemDraw Professional 22.2.0.3300 (PerkinElmer Informatics, Inc.).

[0107] As used herein and in connection with chemical structures depicting the various embodiments described herein,           and “«aaa” each represent a point of covalent attachment of the chemical group or chemical structure in which the identifier is shown to an adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure A-B, where A and B are joined by a covalent bond, in some embodiments, the portion u A — *" of A-B defined by the group or chemical structure A can be represented by         , !,*_**« " * ___---£ , or 5 , where each of            and “    ? ” represents a bond to A and the point of covalent bond attachment to B. Alternatively, in some embodiments, the portion "*__on of A-B defined by the group or chemical structure B can be represented by          , ___git       __gii                                   ___5 , or ?      , where each of            and “    ? represents a bond to B and the point of covalent bond attachment to A.

[0108] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. CHEMICAL DEFINITIONS

[0109] 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 some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C1-C20 alkyl or C1-C20 alkylene, C1-C12 alkyl orCi-C12 alkylene, or Ci-Ce alkyl or Ci-Ce 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 in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. 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 will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0110] The term “alkenyl” refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. The term “alkenylene” refers to a straight- or branched-chain di-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” or “alkenylene” to a specific range of atoms, such as C2-C20 alkenyl or C2-C20 alkenylene, C2-C12 alkenyl or C2-C12 alkenylene, or C2-C6 alkenyl or C2-C6 alkenylene. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-l-yl. Examples of alkenylene groups include ethenylene (or vinylene) (-CH=CH-), n-propenylene (-CH=CHCH2-), iso-propenylene (-CH=CH(CH3)-), and the like. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl or alkenylene group can be unsubstituted or substituted as described herein. An alkenyl or alkenylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0111] The term “alkynyl” refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. The term “alkynylene” refers to a straight- or branched-chain divalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” or “alkynylene” to a specific range of atoms, such as C2-C20 alkynyl or C2-C20 alkynylene, C2-C12 alkynyl or C2-C12 alkynylene, or C2-C6 alkynyl or C2-C6 alkynylene. Examples of alkynyl groups include acetylenyl (-C=CH) and propargyl (-CH2C=CH), but-3-yn-l,4-diyl (-C=C-CH2CH2-), and the like. It will be appreciated that an alkynyl or alkynylene group can be unsubstituted or substituted as described herein. An alkynyl or alkynylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0112] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle. The term “cycloalkylene” refers to a saturated or partially saturated, monocyclic or polycyclic divalent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” or “cycloalkylene” to a specific range of atoms, such as having 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include monovalent radicals of the following entities, while cycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moi eties: . In In particular, a cyclopropyl moiety can be depicted by the structural formula particular, a cyclopropylene moiety can be depicted by the structural formula It will be appreciated that a cycloalkyl or cycloalkylene group can be unsubstituted or substituted as described herein. A cycloalkyl or cycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0113] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.

[0114] The term “haloalkyl” refers to an alkyl group with 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 with one or more halo substituents. Examples of haloalkyl groups include -CF2-, -C(H)(F)-, -C(H)(Br)-, -CH2CF2-, and -CH2C(H)(F)-.

[0115] The term “aryl” refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. The term “arylene” refers to a divalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. In some embodiments, it can be advantageous to limit the number of atoms in an “aryl” or “arylene” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6-C14 aryl), monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (Ce-Cio aryl), divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (Ce-C14 arylene), divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (Ce-Cio arylene). Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. Examples, without limitation, of arylene groups are phenylene, naphthalenylene and anthracenylene. It will be appreciated that an aryl or arylene group can be unsubstituted or substituted as described herein. An aryl or arylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0116] The term “heterocycloalkyl” refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. The term “heterocycloalkylene” refers to a divalent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. In some embodiments, it can be advantageous to limit the number of atoms in a “heterocycloalkyl” or “heterocycloalkylene” to a specific range of ring atoms, such as from 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 6membered), 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 some embodiments, it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or “heterocycloalkylene” to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Polycyclic ring systems include fused, bridged, and spiro systems. The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities, while heterocycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:

[0117] A three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of threemembered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane. A five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-1H- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-lH-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, l,3-dioxolan-2-one, and oxazolidin-2-one. A six-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocycle groups include monovalent or divalent radicals of piperidine, morpholine, 4H-l,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, l,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring.

[0118] It will be appreciated that a heterocycloalkyl or heterocycloalkylene group can be unsubstituted or substituted as described herein. A heterocycloalkyl or heterocycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0119] The term “heteroaryl” refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle. The term “heteroarylene” refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. In some embodiments, it can be advantageous to limit the number of ring atoms in a “heteroaryl” or “heteroarylene” to a specific range of atom members, such as 5- to 10-membered heteroaryl or 5- to 10-membered heteroarylene. In some instances, a 5- to 10membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. In some instances, a 5- to 10-membered heteroarylene can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities, while examples of 5-to 10-membered heteroarylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:

[0120] In some embodiments, a “monocyclic” heteroaryl can be an aromatic five- or sixmembered heterocycle. A five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include mono-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-limiting examples of five-membered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of six-membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-h]thiophene, 17 / -pyrrolo[2,3- / ?]pyridine, 1H-benzo[d]imidazole, benzo[<i]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- / ?]thiophene, 1 H-pyrrolo[2,3- / >]pyridine, l / / -benzo[d]imidazole, benzo[d]oxazole, and benzo[d] thiazole.

[0121] In particular, a pyrazolyl moiety can be depicted by the structural formula particular, an example of a pyrazolylene moiety can be depicted by the structural formula n-nh

[0122] It will be appreciated that a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. A heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0123] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.

[0124] The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments, “substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent.

[0125] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.

[0126] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, nC, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 36C1, and 12SI, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or singlephoton emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. For example, certain chemical entities of Formula (1)-(111) may be isotopically labelled such that they include one or two deuterium l isotopes. Example isotopically labeled (e.g., deuterated) moieties of i'' include

[0127] wherein each “vruwc” represents a point of covalent attachment.

[0128] Certain chemical entities of Formula (I)-(IV) may be depicted in two or more tautomeric forms. Any and all alternative tautomers are included within the scope of these formulas, and no inference should be made as to whether the chemical entity exists as the tautomeric form in which it is drawn. It will be understood that certain chemical entities described herein can exist in different tautomeric forms. It will be readily appreciated by one of skill in the art that because of rapid interconversion, tautomers can generally be considered to be the same chemical compound. Examples of tautomers include but are not limited to enolketo tautomers, amine-imine tautomers, and the like. foirn KeUs few*            Lactam iWm 1 actin'; fern.' Amide farm Imidk add ifem Amine form Imine form

[0129] The nomenclature “(ATOM)i-(ATOM)j” with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this disclosure for which each and every one of the number of atom members, from i to j including i and j, is independently realized. By way of example, the term C1-C3 refers independently to embodiments that have one carbon member (Ci), embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3).

[0130] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -J-K-, where J # K, refers herein to such disubstituent with J attached to a first substituted member and K attached to a second substituted member, and it also refers to such disubstituent with J attached to the second substituted member and K attached to the first substituted member.

[0131] It will be appreciated that certain of the compounds described herein include one or more position that can exists as stereoisomers. For example, certain of the compounds described herein include one or more carbon atoms that can exist in one or more stereoisomeric arrangements. It will be appreciated that a carbon atom that can exist in stereoisomeric arrangements that is depicted without showing any stereoisomeric arrangement includes as a disclosure each of eh possible stereoisomeric arrangements. For example a carbon atom having four groups that can be prioritized according to the Cahn-Ingold Prelog Rules known to one of skill in the art will be understood herein as describing no particular stereochemical definition as in the structure on the left below, and also as describing both possible stereoisomers (S) and (R) as shown below Ra                Ra (S)              (R) where Ra > Rb > Rc > Rd according to the Cahn-Ingold Prelog Rules.

[0132] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(IV), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

[0133] A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, 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 that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0134] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0135] For a compound of Formula (I)-(IV) that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0136] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(IV), and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(IV)). A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985.

[0137] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(IV), and uses of such metabolites in the methods of the disclosure. A “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(IV) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991). REPRESENTATIVE EMBODIMENTS

[0138] In some embodiments, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,

[0139] wherein R1, R2a, R2b, R3, R4, R5, R7, R8, A, B, L, m, n, p, and q are as described herein.

[0140] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,

[0141] wherein R1, R2a, R2b, R3, R4, Rs, R7, R8, A, B, L, m, n, p, q and each “ ” are as described herein.

[0142] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, R7 R5 III

[0143] wherein R2a, R2b, R3, R4, R5, R7, R8, A, B, L, X1, X2, X3, p, q, and each “------” are as described herein.

[0144] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, R7 IV

[0145] wherein R2a, R3, R4, R5, R7, R8, X1, X2, X3, Y1, Y2, A, B, L, p, q, and each “------” are as described herein.

[0146] In some embodiments, each of the compounds encompassed within the structures of the formula (I)-(IV), having one, two, or more hydrogen atoms replaced by deuterium atoms. In some embodiments, each of the compounds encompassed within the structures of the formula (I)-(IV), having one or two hydrogen atoms replaced by a deuterium atom.

[0147] In some embodiments, ring A is a 5- to 10-membered heteroarylene. In some embodiments, ring A is a 5- or 6-membered heteroarylene. In some embodiments, ring A is a 5-membered heteroarylene. In some embodiments, ring A is a 6-membered heteroarylene.

[0148] In some embodiments, Ring A is a 5- or 6-membered heteroarylene, such as a monocyclic 5- or 6-membered heteroarylene, wherein each hydrogen atom in the 5- or 6-membered heteroarylene , as described herein, is independently optionally substituted by an R1 that is deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRh, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2.

[0149] In some embodiments, ring A is pyrrolylene, isoxazolylene, isothiazolylene, pyrazolylene, or imidazolylene, wherein each hydrogen atom in pyrrolylene, isoxazolylene, isothiazolylene, pyrazolylene, and imidazolylene, is independently optionally substituted by an R1 that is deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRh, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-Cealkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2.

[0150] Tn some embodiments, ring A is pyridinylene, pyrazinylene, pyrimidinylene, pyridazineylene, or triazinylene, wherein each hydrogen atom in pyridinylene, pyrazinylene, pyrimidinylene, pyridazineylene, and triazinylene, is independently optionally substituted by an R1 that is deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2.

[0151] In some embodiments, ring A is a 5- or 6-membered heteroarylene, such as a monocyclic 5- or 6-membered heteroarylene, wherein the 55- or 6-membered heteroarylene, as described herein, is optionally substituted with 1, 2, or 3 of R1 (m of R1), each of which is independently selected from the group consisting of deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, 5-to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, and -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2.

[0152] In some embodiments, ring A is pyrrolylene, isoxazolylene, isothiazolylene, pyrazolylene, or imidazolylene, wherein each is optionally substituted with 1, 2, or 3 of R1 (m of R1), each of which is independently selected from the group consisting of deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, G>-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalky 1, -ORC, -OC(O)RC, -OC(O)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, and -NO2.

[0153] In some embodiments, ring A is of the formula

[0154] wherein “------” is optionally a carbon-carbon single bond or a carbon-carbon double bond, each “ -ruxru- ” represents a point of covalent attachment, and R1 and m are as described herein. In some embodiments, ring A is of the formula

[0155] wherein “------” is optionally a carbon-carbon single bond or a carbon-carbon double bond, each “'Arw'” represents a point of covalent attachment, ring A is a 5-membered heteroarylene, and R1 and m are as described herein.

[0156] In some embodiments, ring A is of the formula

[0157] wherein “------” is optionally a carbon-carbon single bond or a carbon-carbon double bond, each "-ruxrcn” represents a point of covalent attachment, X1, X2, and X3 are each independently -O-, -S-, =C(H)-, =C(R’)-, -N(H)-, -N(R*)- or =N-, provided that at least one of X1, X2, and X3 is not =C(H)-, or =C(R1)-. ring A is a 5-membered heteroarylene, and R1 and m are as described herein.

[0158] In some embodiments, ring A is a pyridinylene, pyrazinylene, pyrimidinylene, pyridazineylene, or triazinylene, wherein each is optionally substituted with 1, 2, 3, 4, or 5 of R1 (m of R1), each of which is independently selected from the group consisting of deuterium, halogen, Ci-Ce alkyl, CACe alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, G>-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalky 1, -ORC, -OC(O)RC, -OC(O)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(0)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2.

[0159] In some embodiments, m is 0, 1,2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0160] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0161] wherein each “-aa / v'’- represents a point of covalent attachment, and each R1 is independently as described herein.

[0162] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0163] wherein each           represents a point of covalent attachment, and each R1 is independently as described herein.

[0164] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0165] wherein each “jwv'" represents a point of covalent attachment, and each R1 is independently as described herein.

[0166] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of NH

[0167] wherein each "-kw” represents a point of covalent attachment, and each R1 is independently as described herein.

[0168] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0169] wherein each “jwv'" represents a point of covalent attachment, and each R1 is independently as described herein.

[0170] hi some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0171] wherein each “jwv'" represents a point of covalent attachment, and R1 is as described herein.

[0172] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0173] wherein each          represents a point of covalent attachment, and each R1 is independently as described herein.

[0174] In some embodiments, each R1 is independently deuterium, halogen, or Ci-Ce alkyl, wherein each hydrogen atom in Ci-Ce alkyl is independently optionally substituted deuterium, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2. In some embodiments, R1 is each R1 is independently methyl, ethyl, F, Cl, Br, OH ; or          \' , wherein “ ' / vwv' ” represents a point of covalent attachment

[0175] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0176] wherein each          represents a point of covalent attachment.

[0177] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0178] wherein each          represents a point of covalent attachment.

[0179] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of

[0180] wherein each “. / wx / '" represents a point of covalent attachment.

[0181] In some embodiments, ring A is a Cs-Cio arylene and m is 0, 1, or 2.

[0182] In some embodiments, ring A is a Ce-Cw arylene, wherein the Ce-Cio arylene, as described herein, is optionally substituted with 1 or 2 of R1 (m of R1), each of which is independently selected from the group consisting of deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, 5-to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, and -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2.

[0183] In some embodiments, Ring A is phenylene or naphthylene, wherein each is optionally substituted with 1, 2, 3, or 4 of R1 (m of R1), each of which is independently selected from the group consisting of deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in G-G> alkyl, C2-C& alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORC, -0C(0)Rc, -OC(O)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(0)2NRcRd, -NRcRd, -NRcC(0)Rd, -N(C(0)Rc)(C(0)Rd), -NRcC(0)0Rd, -NRcC(0)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(0)Rd, -NRcS(0)2Rd, -NRcS(0)NRcRd, -NRcS(0)2NRcRd, -C(O)RC, -C(0)0Rc, -C(0)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(0)RcRd, -P(0)2RcRd, -P(0)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2.

[0184] In some embodiments, ring A is a G>-Go arylene, and m is as defined herein. In some embodiments, ring A is a phenylene, and m is as defined herein.

[0185] In some embodiments, ring A is a phenylene, wherein the phenylene, as described herein, is optionally substituted with 1 or 2 of R1 (m of R1), each of which is independently selected from the group consisting of deuterium, halogen, CiG alkyl, GG alkenyl, C2-Ce alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Go aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, and -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Cs alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, G-G> alkyl, CiG haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -CGNRd)NRcRd. -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2.

[0186] In some embodiments, ring A is a phenylene, m is 1, and R1 can be for example, halo (e.g., F, Cl or Br), Ci-Ce alkyl (e.g., methyl or ethyl) which may be optionally substituted (e.g., by hydroxy so as to form hydroxyethyl). In some embodiments, ring A is a phenylene and m is 0, 1, or 2. In some embodiments, ring A is a phenylene, m is 1, and R1 is methyl, ethyl, hydroxyethyl, F, Cl, or Br.

[0187] In some embodiments, ring A is

[0188] wherein each “vruw'” represents a point of covalent attachment.

[0189] Tn some embodiments, ring B is a 5- to 10-membered heteroarylene or a Ce-Cio arylene. In some embodiments, Ring B is mono- or bi-cyclic Cg-Cio arylene or mono- or bi-cyclic 5- to 10-membered heteroarylene.

[0190] In some embodiments, ring B is a 5- or 6-membered heteroarylene. In some embodiments, ring B is a 5- or 6-membered heteroarylene. In some embodiments, ring B is a 5-membered heteroarylene. In some embodiments, ring B is a 6-membered heteroarylene.

[0191] In some embodiments, Ring B is a 5- or 6-membered heteroarylene, such as a monocyclic 5- or 6-membered heteroarylene, wherein each hydrogen atom in the 5- or 6-membered heteroarylene, as described herein, is independently optionally substituted by an R2b that is deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2.

[0192] In some embodiments, ring B is isoxazolylene, isothiazolylene, or pyrazolylene, wherein each hydrogen atom in isoxazolylene, isothiazolylene, or pyrazolylene, and imidazolylene, is independently optionally substituted by an R2b that is deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORC, -0C(0)Rc, -0C(0)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -0S(0)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(0)2NRcRd, -NRcRd, -NRcC(0)Rd, -N(C(0)Rc)(C(0)Rd), -NRcC(0)0Rd, -NRcC(0)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(0)Rd, -NRcS(0)2Rd, -NRcS(0)NRcRd, -NRcS(0)2NRcRd, -C(O)RC, -C(0)0Rc, -C(0)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(0)RcRd, -P(0)2RcRd, -P(0)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2.

[0193] In some embodiments, ring B is isoxazolylene, isothiazolylene, or pyrazolylene, wherein each hydrogen atom in isoxazolylene, isothiazolylene, or pyrazolylene, is independently optionally substituted by an R2b that is deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, 5-to 10-membered heteroaryl, -ORa, -OC(O)Ra, -0C(0)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2.

[0194] In some embodiments, ring B is a 5- or 6-membered heteroarylene, such as a monocyclic 5- or 6-membered heteroarylene, wherein the 5- or 6-membered heteroarylene, as described herein, is optionally substituted with 1 or 2 of R2b (n of R2b), each of which is independently selected from the group consisting of deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cealkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, -ORa, -0C(0)Ra, -0C(0)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)0Rb, -NRaC(0)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(0)NRaRb, -NRaS(0)2NRaRb, -C(0)Ra, -C(O)ORa, -C(0)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(0)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, G-G> alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORC, -0C(0)Rc, -0C(0)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -0S(0)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(O)NRcRd, -S(0)2NRcRd, -NRcRd, -NRcC(0)Rd, -N(C(0)Rc)(C(0)Rd), -NRcC(0)0Rd, -NRcC(0)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(0)Rd, -NRcS(0)2Rd, -NRcS(0)NRcRd, -NRcS(0)2NRcRd, -C(O)RC, -C(0)0Rc, -C(0)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(0)RcRd, -P(0)2RcRd, -P(0)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2.

[0195] In some embodiments, ring B is isoxazolylene, isothiazolylene, or pyrazolylene, wherein each is optionally substituted with 1 or 2 of R2b (n of R2b), each of which is independently selected from the group consisting of deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, 5-to 10-membered heteroaryl, -ORa, -OC(O)Ra, -0C(0)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(O)ORb, -NRaC(0)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-G> alkenyl, G-G> alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(0)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(0)NRcRd, -NRcCGNRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2.

[0196] In some embodiments, ring B is of the formula y2-y1 7VW wherein Y1 and Y2 are each independently -0-, -S-, =C(H)-, =C(R2b)-, -N(H)-, -N(R2b)-, or =N-, one “------” in ring B is a carbon-carbon single bond, and one “------” in ring B is a carbon-carbon double bond.

[0197] . 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.

[0198] In some embodiments, ring B is a 5-membered heteroarylene selected from the group consisting of

[0199] wherein each “       ” represents a point of covalent attachment, and each R2a and R2b is independently as described herein.

[0200] In some embodiments, R2a is deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Cs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-G> alkyl, Ci-Ce haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -CGNRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2.

[0201] In some embodiments, R2a is halogen or Ci-Ce alkyl, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(0)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2. In some embodiments, R2a is methyl, ethyl, methylmethoxy, methylethoxy, methylisopropoxy, methylcyclopropoxy, methyl-difuoromethoxy, or difluoromethylmethoxy.

[0202] In some embodiments, R2b is deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2. In some embodiments, R2b is methyl or ethyl.

[0203] In some embodiments, ring B is a 5-membered heteroarylene selected from the group consisting of

[0204] wherein each "mm" represents a point of covalent attachment.

[0205] hi some embodiments, ring B is a 5-membered heteroarylene selected from the group consisting of

[0206] wherein each          represents a point of covalent attachment.

[0207] In some embodiments, R3 is H, deuterium, C -O,alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2. In some embodiments, R3 is H or Ci-Ce alkyl, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2. In some embodiments, R3 is H or Ci-Ce alkyl. In some embodiments, R3 is H or methyl. In some embodiments, R3 is H, methyl, ethyl, isopropyl, or cyclopropyl.

[0208] In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0209] In embodiments, the compound comprises a portion of the formula

[0210] wherein R4 and R5 are as defined herein, and each           represents a point of covalent attachment.

[0211] In some embodiments, each R4 is independently deuterium, halogen, Ci -Cs alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, 5-to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Cs alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cs alkyl, Ci-Cr, haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, each R4 is independently deuterium, halogen, or Ci-Ce alkyl. In some embodiments, each R4 is H, fluoro, chloro, or methyl.

[0212] In some embodiments, R5 is H, deuterium, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, -P(O)2ORc, or -S(O)2ORC. In some embodiments, R5 is H or deuterium. In some embodiments, R5 is H. In some embodiments, R5 is -C(O)RC, -C(O)ORC, -C(O)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, -P(O)2ORC, or-S(O)2ORc.

[0213] In embodiments, the compound comprises a portion of the formula

[0214] wherein each          represents a point of covalent attachment.

[0215] In some embodiments, each L is independently -O-, -S-, -S(O)-, -S(O)2-, -N(R6)C(O)-, -C(O)N(R6)-, -N(R6)-, -N(R6)S(O)-, -S(O)N(R6)-, -N(R6)S(O)2-, -S(O)2N(R6)-, or -C(R7)(R8)-, provided that (L)p does not comprise an O-O, S-O, or N-N bond. In some embodiments, each L is independently each L is independently -C(R7)(R8)-, -C(O)-, -O-, or -N(R6)-, provided that (L)p does not comprise a -O-O- or a -O-N(R6)- bond, and the point of covalent attachment of (L)p to -NR3- does not form a -N-N- or a -O-N- bond. In some embodiments, each L is independently -0-, -C(R7)(R8)-, or -N(R6)-, provided that (L)p does not contain an -O-O-, -N-0-, or -N-N- bond and the point of attachment of (L)p and -NR3- does not for an -O-N- or -NN- bond.

[0216] In some embodiments, p is 3, 4, 5, 6, or 7. In some embodiments, p is 3, 4, 5, or 6. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9.

[0217] In some embodiments,   -(L)p-   comprises   -(CR7R8)C(O)N(R6)-(CR7R8)2-, -(CR7R8)N(R6)C(O)-(CR7R8)2-,                        -N(R6)-C(O)(CR7R8)2O(CR7R8)2-, -CR7R8O(CR7R8)2O-(CR7R8)2,                                 -O(CR7R8)2O(CR7R8)2-, -CR7R8O-CR7R8-C(O)N(R6)-(CR7R8)2-,   -(CR7R8)3O(CR7R8)2-,   -(CR7R8)2O(CR7Rs)3-, -CR7R8-N(R6)-(CR7R8)2-, -CR7R8-N(R6)-(CR7R8)3-, -O(CR7R8)2O(CR7R8)3-, -(CR7R8)2- N(R6)-(CR7R8)3-, -(CR7R8)2-N(R6)-(CR7R8)2-, -O-(CR7R8)2-, -O-(CR7R8)3-, or -O-(CR7R8)4-.

[0218] In some embodiments, -(CR7R8)N(R6)C(O)-(CR7R8)2-, -CR7R8O(CR7R8)2O-(CR7R8)2, -CR7R8O-CR7R8-C(O)N(R6)-(CR7R8)2-, -(L)p- is -(CR7R8)C(O)N(R6)-(CR7R8)2-, -N(R6)-C(O)(CR7R8)2O(CR7R8)2-, -O(CR7R8)2O(CR7R8)2-, -(CR7R8)3O(CR7R8)2-,    -(CR7R8)2O(CR7R8)3-, -CR7R8-N(R6)-(CR7R8)2-, -CR7R8-N(R6)-(CR7R8)3-, -O(CR7R8)2O(CR7R8)3-, -(CR7R8)2-N(R6)-(CR7R8)3-, -(CR7R8)2-N(R6)-(CR7R8)2-, -O-(CR7R8)2-, -O-(CR7R8)3-, or -O-(CR7R8)4-.

[0219] In some embodiments, each R6, when present, is independently H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-Ce cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -ORC, -OC(O)RC, -OC(O)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(0)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(0)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2. In some embodiments, R6, when present, is H or Ci-Ce alkyl. In some embodiments, R6, when present, is H, methyl, or ethyl.

[0220] In some embodiments, each R7 and R8, is independently H, deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-Ce cycloalkyl, 3-to 7-membered heterocycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or two of R7 and R8, taken together with the carbon or carbons to which they are attached, optionally combine to form a C3-Cs cycloalkyl, 3- to 7membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or 3- to 7membered heterocycloalkyl formed when two of R7 and R8 are taken together is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, R7, when present, is H, Ci-Ce alkyl, -OH, or -OCH3. In some embodiments, R7, when present, is H, methyl, -OH, or -OCH3. In some embodiments, R8, when present, is H, Ci-Ce alkyl, -OH, or -OCH3. In some embodiments, R8, when present, is H, methyl, -OH, or -OCH3. In some embodiments, each R7 and R8, when present, is H. In some embodiments, each R7 and R8 is independently H or methyl.

[0221] In some embodiments, each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cs alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, Ci-Ce alkylene-Ce-C 10 aryl, 5- to 10-membered heteroaryl, and Ci-Ce alkylene-5- to 10-membered heteroaryl, or Ra and Rb or Rc and Rd or Re and Rf, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, Ci-Ce alkylene-Ce-Cio aryl, 5- to 10-membered heteroaryl, or CiG alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OCi-C6 alkyl, -OC(O)-(H or Ci-C6 alkyl), -OC(O)N(H or Ci-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or G-Ce alkyl), -OS(O)2-(H or Ci-C6 alkyl), -OS(O)N(H or Ci-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or Ci-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or Ci-C6 alkyl), -S(O)(H or Ci-C6 alkyl), -S(O)2(H or Ci-C6 alkyl), -S(O)N(H or Ci-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or Ci-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or Ci-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or Ci-C6 alkyl)C(O)-(H or Ci-C6 alkyl), -N(H or Ci-C6 alkyl)C(O)O(H or Ci-C6 alkyl), -N(H or Ci-C6 alkyl)C(O)N(H or Ci-C6 alkyl)2, -N(H or Ci-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or Ci-C6 alkyl)S(O)-(H or Ci-C6 alkyl), -N(H or Ci-C6 alkyl)S(O)2(H or Ci-C6 alkyl), -N(H or Ci-C6 alkyl)S(O)N(H or Ci-C6 alkyl)2, -N(H or Ci-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or Ci-C6 alkyl)S(O)2N(H or Ci-C6 alkyl)2, -N(H or C-G, alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or Ci-C6 alkyl), -C(O)O(H or Ci-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or Ci-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or Ci-C6 alkyl)2, -P(O)(C2-C6 alkylene), -P(O)2(Hor Ci-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(O)N(H or Ci-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 G-C6 alkyl), -P(O)2O(Hor Ci-C6 alkyl), -CN, or -NO2.

[0222] In some embodiments, R6, when present, is H or Ci-Ce alkyl. In some embodiments, R6, when present, is H, methyl, or ethyl. In some embodiments, R7, when present, is H, Ci-Ce alkyl, -OH, or -OCH3. In some embodiments, R7, when present, is H, methyl, -OH, or -OCH3. In some embodiments, R8, when present, is H, Ci-Ce alkyl, -OH, or -OCH3. In some embodiments, R8, when present, is H, methyl, -OH, or -OCH3. In some embodiments, each R7 and R8, when present, is H. In some embodiments, each R7 and R8 is independently H or methyl.

[0223] In some embodiments, -(L)p- is -CH2C(O)N(H)-(CH2)2O-, -CH2C(O)N(CH3)-(CH2)2O-,          -CH2C(O)N(CH2CH3)-(CH2)2O-,          -CH2N(H)C(O)-(CH2)2O-, -CH2C(O)N(CH3)C(O)-(CH2)2O-,   -CH2C(O)N(CH2CH3)C(O)-(CH2)2O-,    -C(O)N(H)- (CH2)2O(CH2)2-,    -N(H)-C(O)(CH2)2O(CH2)2-, -CH2O(CH2)3O-, -CH2O(CH2)2OCH2-, -(CH2)2O(CH2)2O-,    -CH2O-CH2-C(O)N(H)-(CH2)2-,    -CH2O(CH2)2C(O)N(H)-CH2-, -CH2O(CH2)2N(H)C(O)-, -CH2O(CH2)3N(H)C(O)-, -(CH2)2O(CH2)2N(H)C(O)-, -CH(CH3)-CH2O(CH2)2N(CH3)C(O)-,                        -CH(CH3)-CH2O(CH2)2N(H)C(O)-, -CH(OCH3)-CH2O(CH2)2N(CH3)C(O)-,            -CH(OCH3)-CH2O(CH2)2N(H)C(O)-, -O(CH2)2O(CH2)2N(H)C(O)-, -CH2O(CH2)2N(H)C(O)-CH2-, or -O-(CH2)3C(O)N(H)-.

[0224] In some embodiments, -(L)p- is -CH2C(O)N(H)-(CH2)2OCH2-, -C(O)N(H)-(CH2)2O(CH2)2-, -N(H)-C(O)(CH2)2O(CH2)2-, -CH2O(CH2)2O-(CH2)2, -O(CH2)2O(CH2)2O-, -CH2O-CH2-C(O)N(H)-(CH2)2-, -CH2O(CH2)2C(O)N(H)-CH2-, -CH2O(CH2)2N(H)C(O)-, -CH2O(CH2)3N(H)C(O)-, -(CH2)2O(CH2)2N(H)C(O)-, -CH(CH3)-CH2O(CH2)2N(CH3)C(O)-, -CH(CH3)-CH2O(CH2)2N(H)C(O)-,              -CH(OCH3)-CH2O(CH2)2N(CH3)C(O)-, -CH(OCH3)-CH2O(CH2)2N(H)C(O)-,                     -O(CH2)2O(CH2)2N(H)C(O)-, -CH2O(CH2)2N(H)C(O)-CH2-, or -O-(CH2)3C(O)N(H)-.

[0225] In some embodiments, -(L)P- comprises -CH2N(H)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, and -O(CH2)2O(CH2)2-.

[0226] In some embodiments, -(L)P- is -CH2N(H)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, and -O(CH2)2O(CH2)2-.

[0227] hi some embodiments, (L)p is -O(C(R7)(R8))2- or -O(C(R7)(R8))3-. In some embodiments, (L)p is -O-C((H)(CH3))-CH2-.

[0228] In some embodiments, the disclosure provides a compound selected from the group consisting of (2S)-l-{(10S,17£')-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4’-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0229] (25)-2- {(1 OS, 17E)- 12-ethyl-6-(methoxymethy 1)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-1 -ol;

[0230] (25)-l-[(105,17E)-16-ethoxy-12-ethyl-6-(methoxymethyl)-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"- n] [ 1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0231] (25)-1 - [(105,17E)-16-ethoxy-6-(methoxymethyl)-8,1 O-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4", 3"-n] [ 1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0232] (25)-1-{ (105,17E)-6-(methoxymethyl)-8,10,12-trimethyl-16-[(propan-2-yl)oxy]- 2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4; / :3',4'-j:4”,3"-n\ [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0233] (25)-l-[(105,17E)-12-cyclopropyl-16-ethoxy-6-(methoxymethyl)-8,l O-dimethyl- 2,8,10,ll,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-zi][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0234] (25)-1 - {(105,17E)-6- [difluoro(methoxy)methyl] -12-ethyl- 8,1 O-dimethyl-16- [(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n\ [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;

[0235] (25)-1 - {(105,17E)-6- [(difluoromethoxy)methyl] -12-ethyl- 8,1 O-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3’,4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0236] (25)-1 - {(105,17E)-6-(ethoxymethyl)-12-ethyl-8,1 O-dimethyl-16-[(propan-2-yl)oxy]- 2,8,10,11,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4", 3"- n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0237] (25)-1-{(105,17E)-6-[(cyclopropyloxy)methyl]-16-ethoxy-12-ethyl-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4", 3"- n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;

[0238] (25)-1 -| (105,17 / 7)-16-ethoxy-12-ethy 1-8,10-dimelhy 1-6- { [(propan-2-yl)oxy]methyl}- 2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4”, 3"- n] [ 1,4]oxazacyclopentadecin- 14-yl]propan-2-ol;

[0239] (25)-1 - {(105,17E)-6-[(difluoromethoxy)methyl]-16-ethoxy- 12-ethyl-8,10-dimethyl- 2,8,10,ll,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-ra][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0240] (25)-l-[(105,17E)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"- n] [1,4]oxazacyclopentadecin- 14-yl]propan-2-ol;

[0241] (25)-1-{(IOSJ7E)-6-(ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;

[0242] (25)-1 - {(105,17E)- 12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,!0,1 1,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0243] (25) -1 - {(105,17£)- 6- (ethoxymethyl) -12-ethy 1-19-fluoro- 8,10-dimethy 1-16-[(propan-2-yl)oxy]-2,8,10,ll,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3’,4,-j:4",3"-n\ [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0244] (2S)-l-[(105,17E)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-19-fluoro-8,10-dimethyl- 2,8,10,ll,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0245] (25)-l-L(105,17E)-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl- 2,8,10,ll,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n\ [1,4]oxazacyclopentadecin- 14-yl]propan-2-ol;

[0246] (105,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl- 2,10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4; / :3',4'-j:4”, 3"- n] [ 1,4]oxazacyclopentadecine;

[0247] (105,17E)-20-fluoro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-877-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine;

[0248] (25)-1-{(105,17E)- 12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,ll,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14-y 1} propan-2-ol;

[0249] (25)-l-[(105,17E)-16-ethoxy-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl- 2,8,10,ll,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4; / :3',4’-j:4”,3”- n] [ 1,4]oxazacyclopentadecin- 14-yl]propan-2-ol;

[0250] (105,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2,10,ll,12,13,14-hexahydro-8H- 3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine;

[0251] (105,17E)-20-chloro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl- 2,10,1 l,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4; / :3',4’-j:4”,3"-n\ [ 1,4]oxazacyclopentadecine;

[0252] (2S)-2-[(105,17E)-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2,8,10,ll,12,13-hexahydro- l47 / -3,5-ethenotripyrazolo|3,4; / :3',4'- / :4",3”- / ?|| 1,4|oxazacyclopentadecin-14-yl]propan-l-ol; and

[0253] (25)-2-[(10S,17E)-16-ethoxy-20-fluoro-6,8,10,12-tetramethyl-2,8,10,ll,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3’,4'-j:4",3"-77][l,4]oxazacyclopentadecin-14-yl]propan-l-ol;

[0254] or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, the compound is not the compound is not of the formula HN-N                 HN-N 5 or

[0256] The following represent illustrative embodiments of compounds of Formula (T): Ex# Structure Name 1 J / \ >    OH II ) /           L / \ S— N * \        JL Jn QiT^Y HN'N           I (25)-1 - {(1 OS, 17£)-12-ethyl-6-(methoxymethy 1)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4; / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl}propan-2-ol 2 N-n"         \ / 0H L       rN' II / N HN-N          1 (25)-2- {(105,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l 1,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4; / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-l-ol 3 nY           / 0h A / A / / —\ l      rN' A.       II N HN-N (25)-1 - [(105,17£)-16-ethoxy- 12-ethyl- 6-(methoxymethyl)-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4; / :3',4'-j:4",3"- n] [ 1,4]oxazacyclopentadecin-14-yl]propan-2-ol Ex# Structure Name 4 n^ Y^N'^ / 0H ^o^j / ( r\ Y   r" A-        / / ,N / / HN-N (25)-1 - [(105,17E> 16-ethoxy-6-(methoxymethyl)-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14 / / -3,5- ethenotripyrazolo[3,4- / :3',4’- / 4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl]propan-2-ol 5 N-l / Y^N^ / 0H /   r~\ [ rN' / V        / / / N QzY HN-N          ' (25)-1-{ (105,17E)-6- (methoxymethyl)-8,10,12-trimethyl- 16-[(propan-2-yl)oxy]- 2,8,10,11,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4’-j:4",3”- w][ 1,4]oxazacyclopentadecin-14- yl}propan-2-ol 6 n-n^ X^n Y oh Y r" (Io / HN-N (25)-1 - [(105,17£)-12-cyclopropyl-16-ethoxy-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14 / / - 3,5 -ethenotripy razolo [3,4- / : 3', 4 ’ -j:4",3"-w][l,4]oxazacyclopentadecin-14-yl]propan-2-ol 7 N- /             / 0H HN-N          ' (25)-1-{( 105,17E / -6- [difluoro(methoxy)methyl] -12-ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4’-j:4",3”- n] [ 1,4]oxazacyclopentadecin-14-yl}propan-2-ol 8 nY           ,oh 'X^YLYo7 I r\ F Jk Yz> Ox'^Y HN-N          1 (25)-1 -{(105,17E)-6- [ (difluoromethoxy )methyl] -12-ethy 1-8,10-dimethyl-16- [(propan-2-yl)oxy ] -2,8,10,11,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [1,4]oxazacyclopentadecin-14-yl}propan-2-ol 9 N~ /         __ / °H \zCXlXo /   / \ Y rN' Qa\ HN-N          \ (25)-1 - {(105,17E)-6-(ethoxymethy 1)-12-ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,ll,12,13-hexahydro-14 / / -3,5 -ethenotripyrazolo[3,4- / : 3 ',4'- / 4",3"-M][l,4]oxazacyclopentadecin-14-yl}propan-2-ol Ex# Structure Name 10 N-l /             PH __ / VAAo  ( / \ v y rN' / ¼ JL zN Qm / at / / HN-N (25)-l-{(105,17E)-6- [(cyclopropyloxy)methyl] -16-ethoxy- 12-ethyl-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4; / ':3',4’-j:4",3"- / 71 [ 1,4]oxazacyclopentadecin-14-yl}propan-2-ol 11 O I / -7 ' > O^Z _ o-4 A < 2X I (25)-1 - [(105,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-6-{ [(propan-2-yl)oxy]methyl {-2,8,10,11,12,13-hexahydro-1477-3,5- ethenotripyrazolo[3,4- / :3',4’-j:4",3"-n} [ 1,4]oxazacyclopentadecin-14-yl]propan-2-ol 12 N-N^             OH Fv°^\^o I rA F A JC / N O<#Y / HN-N (25)-l-{(105,17E)-6- [ (difluoromethoxy )methyl]-16-ethoxy- 12-ethyl-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-147 / -3,5-ethenotripyrazolo[3,4- / :3',4’-j:4",3”- n] [ 1,4]oxazacyclopentadecin-14-yl}propan-2-ol 13 O I Z—     / > z^ /    O-^Z Xz-Z C Z^L ZE (25)-1 - [(105,17E)-16-ethoxy-6- (ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl-2,8,10,11,12,13- hexahydro-1477-3,5- ethenotripyrazolo|3,4; / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14- yl]propan-2-ol 14 nY            / 0H X-O^JLz^O (   / C L rN' aAA HN-N          1 (25)-1 - {(105,17E)-6-(ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,ll,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4’-j:4",3"-m] [ 1,4]oxazacyclopentadecin-14-yl}propan-2-ol 15 nY ^^n^ PH ( rA l       rN' xV^Y HN-N          1 (25)-1 - {(105,17E)-12-ethyl- 19-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[ (propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro- 1477-3,5-ethenotripyrazolo[3,4; / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl}propan-2-ol Ex# Structure Name 16 O I   Z—     '   > V / —z (25)-1 - {(105,17E)-6-(ethoxymethyl)-12-ethyl-19-fluoro- 8,10-dimethyl-16-[ (propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4’- / 4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl}propan-2-ol 17 N—,0H HN-N (25)-1 - [(105,17£)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,ll,12,13-hexahydro-14 / / -3,5- ethenotripyrazolotS^^S'^'-j^’’^"-n] [ 1,4]oxazacyclopentadecin-14-yl]propan-2-ol 18 \ O zy    o-^z V^z—z ___ / ° i (25)-1 - [(105,17£)-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14 / / - 3,5 -ethenotripy razolo [ 3,4- / : 3' ,4' - / 4",3"-;i][l,4]oxazacyclopentadecin-14-ylJpropan-2-ol 19 / x . n-n ^x^Az^'o (   / l rN' IXty f'a; ii HN-N (105,17E)-20-fluoro-6- (methoxy methyl) - 8,10,12,14,16-pentamethyl-2,10,11,12,13,14- hexahydro-8 / / -3,5- ethenotripyrazolo[3,4- / :3',4’-j:4",3”-n] [ 1,4]oxazacyclopentadecine 20 / X / x n-n f Y^O I Z l       rN' A.       II / N (YY f        it HN-N (105,17E)-20-fluoro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-8 / / -3,5-ethenotripyrazolo[3,4- / :3',4’- / 4",3"-n} [ 1,4]oxazacyclopentadecine 21 n-i /                / 0H ( r\ T rN' fvYy HN-N          1 (25)-1 - {(105,17E)- 12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l 1,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4; / 3',4'- / 4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl}propan-2-ol Ex# Structure Name 22 N-1 /               ,0H .. HN-N (2S)-1 - [(1 OS, 17E)-16-ethoxy- 12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14 / 7-3,5 -ethenotripy razolo [ 3,4-f: 3 ’, 4’ -y:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol 23 / \ n-n l       rN' A-      11 / N Ci^A / 7 HN-N (1 OS, 17E)-20-chloro-6,8,10,12,14,16- hexamethyl-2,10,11,12,13,14- hexahydro-877-3,5- ethenotripyrazolo[3,4- / :3’,4’-j:4",3”- n] [ 1,4]ox azacy cl open tadeci ne 24 \ O - c \=\ A2 1 )—     / > \__ / —z (10S,17E)-20-chloro-6- (methoxy methyl) - 8,10,12,14,16-pentamethyl-2,10,11,12,13,14- hexahydro-8H-3,5- ethenotripyrazolo[3,4- / :3',4'-j:4",3"- n] [ 1,4]oxazacyclopentadecine 25 Ny       \ / 0H T    rN' HN-N (2S)-2- [(1 OS, 17£)-16-ethoxy- 12-ethyl-20-fluoro-6,8,10-trimethyl- 2,8,10,11,12,13-hexahydro-14H-3,5- ethenotripyrazolotSA^S'A'-j^"^"-n] [1,4]oxazacyclopentadecin-14-yl]propan-l-ol 26 l   7—'     /   > —z A z: (2S)-2- [(1 OS, 17£)-16-ethoxy-20-fluoro-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4; / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl]propan-l-ol and pharmaceutically acceptable salts thereof.

[0257] Those skilled in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected. PHARMACEUTICAL COMPOSITIONS

[0258] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the disclosure are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.

[0259] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.

[0260] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the disclosure may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0261] For oral administration, the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Example liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are example disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0262] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0263] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0264] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multidose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 pg / kg / minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0265] For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier. The inventive compositions may be formulated for rectal administration as a suppository.

[0266] For topical applications, the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery.

[0267] As used herein, the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.

[0268] The term “subject” refers to a mammalian patient in need of such treatment, such as a human.

[0269] Example diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation. As used herein, the term “cancer” includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER+ breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CML), acute myeloid leukemia (AML), congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, skin cutaneous melanoma, head and neck squamous cell carcinoma, pediatric glioma prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial cancer. In some embodiments, cancer includes, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.

[0270] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target ALK. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit diseases, such as cancers driven by the activity of ALK. In some embodiments, the compounds described herein can target ALK in an oncogenic driver fusion, such as EML4-ALK. In some embodiments, the compounds described herein can target ALK fusion having one or more resistance mutations.

[0271] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target PIM kinases. In some embodiments, the compounds described herein can target PIM kinase activity to overcome resistance mechanisms of chemotherapy, radiotherapy, anti-angiogenic therapies and targeted therapies. In some embodiments, methods of treating a target cancer, such as AML, are described.

[0272] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target CLK kinases. In some embodiments, the compounds described herein can target CLK kinase activity to treat diseases, such as cancers, through modulation of pre-mRNA splicing via inhibition of CLK kinase activity. In some embodiments, methods of treating a target cancer, such as myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, AML, lung cancer, breast cancer, and pancreatic cancer are described.

[0273] In the inhibitory methods of the disclosure, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to a mutation of ALK, PIM, and / or CLK as described herein.

[0274] In treatment methods according to the disclosure, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment, such as those described herein having a disease, such as cancer, including those associated with aberrant ALK, including oncogenic driver fusions (such as EML4-ALK) and ALK resistance mutations, aberrant PIM kinases, and / or aberrant CLK kinases. Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An example dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).

[0275] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis. DRUG COMBINATIONS

[0276] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure.

[0277] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the disclosure, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. For cancer indications, additional such agents include, but are not limited to, kinase inhibitors, such as ALK inhibitors (e.g., crizotinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids. CHEMICAL SYNTHESIS METHODS

[0278] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I)-(IV).

[0279] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art: g grams eq equivalents mmol millimoles mL milliliters MHz megahertz PPm parts per million 6 chemical shift s singlet d doublet t triplet q quartet quin quintet br broad m multiplet Hz hertz THF tetrahydrofuran °C degrees Celsius RT Room Temperature PE petroleum ether EA or EtOAc ethyl acetate Rf retardation factor N normal J coupling constant dmso-< / 6 deuterated dimethyl sulfoxide n-BuOH n-butanol t-BuOH Tert-Butanol AcOH Acetic Acid DMAc N, A-Dimethylacetamide DIEA or DIPEA or Hunig's Base n,n-diisopropylethylamine TMSC1 trimethylsilyl chloride min minutes hr hours Me methyl Et ethyl i-Pr isopropyl TLC thin layer chromatography M molar Compd# compound number MS mass spectrum m / z mass-to-charge ratio Ms methanesulfonyl Boc tert-butyloxycarbonyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride Tos or Ts toluenesulfonyl DMAP 4- (dimethy lamino)pyridine mM millimolar uM or |1M micromolar ATP adenosine triphosphate IC50 half maximal inhibitory concentration U / mL units of activity per milliliter KHMDS potassium bis(trimethylsilyl)amide DIAD diisopropyl azodicarboxylate MeCN (ACN) Acetonitrile MeTHF 2-methyltetrahydrofuran MOM methoxymethyl DCM dichloromethane DMF A,A-di methyl formamide DPPA diphenyl phosphoryl azide DBU l,8-diazabicyclo[5.4.0]undec-7-ene DHP Dihydropyran THP tetrahydropyranyl SEM [2-(Trimethylsilyl)ethoxy]methyl acetal Hex hexanes Pd(dppf)Ch [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) PPh3 Triphenyl phosphine p-TSA or TsOH Para-Tolylsulfonic acid Pd(amphos)C12 Dichlorobis [di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) mCPBA Meta-Chloroperoxy benzoic acid TBAF Tetrabutylammonium fluoride TBAC Tetrabutylammonium chloride BPD or B2pini 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)-l,3,2-dioxaborolane or Bis(pinacolato)diboron MTBE Methy rm-Butyl Ether NBS N-bromosuccinimide NIS N-iodosuccinimide T3P Propylphosphonic anhydride HATU 1 -[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate t-BuBrettPhos Pd G3 [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylpheny])phenyl]phosphane DBAD Di-tert-butyl azodicarboxylate TEA triethylamine Pd(OAc)2 palladium (II) acetate LAH or LiAlH4 Lithium aluminum hydride

[0280] Preparation of Intermediates

[0281] Preparation of (lR)-2-(tert-butoxycarbonylamino)-l-methyl-ethyl methanesulfonate (1-1-1). Ms2O, TEA NHBoc        '•< NHBoc OH             DCM       0Ms 1-1-1

[0282] To a solution of commercially available te / T-butyl N-[(2R)-2-hydroxypropyl]carbamate (10.0 g, 57.0 mmol, 1 eq) in DCM (20 mL) was added methylsulfonyl methanesulfonate (14.9 g, 85.6 mmol, 1.5 eq) and TEA (171 mmol, 23.8 mL, 3 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the reaction mixture was quenched by addition H2O (30 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with a saturated solution of NaCl (50 mL), filtered and concentrated under reduced pressure to give [(lR)-2-(tert-butoxycarbonylamino)-l-methyl-ethyl] methanesulfonate (12.0 g, 47.3 mmol, 83% yield) as a white solid. LI-1 was used without further purification.

[0283] Preparation of (R)-N-ethyl-2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (1-2-1). i \ / NH2                   tea,tfaa MeOH OH H         DCM H0 4--F F F Step 1                             Step 2            |21

[0284] Step 1. To a solution of commercially available (R)-2-methyloxirane (10 g, 172.18 mmol, 1 eq) in MeOH (100 mL) was added ethanamine (2 M, 258 mL, 3 eq). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was concentrated to give (R)-l-(ethylamino)propan-2-ol (8.13 g, 78.8 mmol, 46% yield) as a brown solid. 'H NMR (400 MHz, CDCI3) d = 3.84 - 3.70 (m, 1H), 2.74 - 2.55 (m, 3H), 2.45 - 2.34 (m, 2H), 1.16 - 1.05 (m, 6H).

[0285] Step 2. To a solution of (2R)-l-(ethylamino)propan-2-ol (8.13 g, 78.8 mmol, 1 eq) in DCM (80 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (24.8 g, 118 mmol, 16.4 mL, 1.5 eq) and TEA (39.9 g, 394 mmol, 5 eq) at 0 °C, then the mixture was stirred at 0 °C for 1 h. On completion, the reaction mixture was partitioned between DCM (100 mL x 3) and water (100 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:1) to give (R)-N-ethyl-2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (7.92 g, 39.8 mmol, 50% yield) as a white solid. LCMS: (M+l: 200.1).

[0286] Preparation of (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N-methylacetamide (1-3-1). / NH2 MeOH Step 1 TEA, TFAA DCM Step 2 1-3-1

[0287] 1-3-1 was prepared following the method described for the preparation of 1-2-1, using methanamine instead of ethanamine in Step 1. 'HNMR (400 MHz, CDCI3) 5 = 4.05 - 3.96 (m, 1H), 3.38 (d, J= 3.6 Hz, 1H), 3.34 - 3.24 (m, 2H), 3.16 (d, 7=1.6 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H).

[0288] Preparation of 5-bromo-l-tetrahydropyran-2-yl-3-vinyl-indazole (1-1-4) Br. H i2, t-BuOK. THF Step 1 DHP. TosOH -------► toluene Step 2 THP BF?K Pd(dppf)Cl2, NajCOa, dioxane / HyO Step 3 1-1-4

[0289] Step 1. To a solution of commercially available 5-bromo-lH-indazole (5.00 g, 25.3 mmol, 1 eq) in THF (50 mL) was added t-BuOK (5.70 g, 50.7 mmol, 2 eq) at 0°C followed by addition of a solution of b (7.08 g, 27.9 mmol, 1.1 eq) in THF (50 mL). The reaction mixture was stirred at 25°C for 12 hrs. On completion, the residue was diluted with water and then extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 5-bromo-3-iodo-lH-indazole (8.10 g, 98.8% yield) as brown solid. ’H NMR (400 MHz, DMSO-de) 5 = 13.69 (s, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.55 - 7.53 (m, 2H). LCMS: (M+l: 324.4).

[0290] Step 2. To a mixture of 5-bromo-3-iodo-IH-indazole (8.10 g, 25.0 mmol, 1 eq) and TosOH (863 mg, 5.02 mmol, 0.2 eq) in toluene (200 mL) was added DHP (5.27 g, 62.7 mmol, 2.5 eq). The reaction mixture was stirred at 90°C for 12 hr. On completion, the residue was diluted with water and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 5-bromo-3-iodo-1-tetrahydropyran-2-yl-indazole (8.30 g, 81.2% yield) as yellow solid. *H NMR (400 MHz, DMSO-d6) 8 = 7.75 - 7.70 (m, 1H), 7.62 - 7.58 (m, 2H), 5.83 (dd, 7 = 2.0, 9.6 Hz, 1H), 3.89 - 3.82 (m, 1H), 3.75 - 3.67 (m, 1H), 2.35 - 2.29 (m, 1H), 2.01 - 1.93 (m, 2H), 1.74- 1.67 (m, 1H), 1.59 - 1.53 (m, 2H). LCMS: (M+l: 408.7).

[0291] Step 3. To a mixture of 5-hromo-3-iodo-l -tetrahydropyran-2-yl-indazole (8.30 g, 20.3 mmol, 1 eq) and potassium trifluoro(vinyl)borate (2.73 g, 20.3 mmol, 1 eq) in dioxane (80 mL) and H2O (12 mL) were added Pd(dppf)Ch (1.49 g, 2.04 mmol, 0.1 eq) and Na2COa (6.48 g, 61.1 mmol, 3 eq). The reaction mixture was stirred at 80°C for 12 hrs under N2. On completion, the residue was diluted with water and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 5-bromo-l-tetrahydropyran-2-yl-3-vinyl-indazole (6.00 g, 19.5 mmol, 95.7% yield) as white solid. ’H NMR (400 MHz, DMSO-76) 6 = 8.24 (s, 1H), 7.73 (d, 7 = 8.8 Hz, 1H), 7.57 (d, 7 = 8.8 Hz, 1H),7.O1 (dd,7= 11.6, 17.6 Hz, 1H), 6.14 (d, 7= 18.0 Hz, 1H), 5.85 (d, 7=9.6 Hz, 1H), 5.53 (d, 7= 11.6 Hz, 1H), 3.88 (d, 7= 11.6 Hz, 1H), 3.78 -3.69 (m, 1H), 2.43 - 2.31 (m, 1H), 2.06 - 1.91 (m, 2H), 1.79 - 1.66 (m, 1H), 1.58 (s, 2H).

[0292] Preparation of 5-bromo-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (1-2-4) Br                             Br HN-N step 1          HN-N          Step 2 I-2-2 Br                                          Br N-N          Pd(dppf)CI2, Na2CO3 N-N THP                dioxane / H2O        THP I-2-3                       Step 3                   I-2-4

[0293] 1-2-4 was prepared from commercially available 5-bromo-6-fluoro-lH-indazole following the method described in Steps 1-3 used for the preparation of 1-1-4, using NaOH as the base and DMF as the solvent in Step 1. !H NMR (400 MHz, CDCh) 8 = 8.09 (d, 7 = 6.4 Hz, 1H), 7.36 (d, 7= 8.8 Hz, 1H), 6.96 (dd,7=11.2, 18.0 Hz, 1H), 6.05 (dd,7 = 0.8, 18.0 Hz, 1H), 5.64 - 5.53 (m, 2H), 4.07 - 4.00 (m, 1H), 3.80 - 3.68 (m, 1H), 2.55 - 2.43 (m, 1H), 2.18 -2.04 (m, 2H), 1.81 - 1.68 (m, 3H).

[0294] Preparation of 5-bromo-7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (1-3-4). Br HN-N l2, t-BuOK DMF Step 1 I-3-2 DHP, TosOH dioxane Step 2 ^BF3 K+ 1a Pd(dppf)CI2, Cs2CO3 dioxane / H2O Step 3                   I-3-4

[0295] 1-3-4 was prepared from commercially available 5-bromo-7-fluoro-lH-indazole following the method described in Steps 1-3 used for preparation of 1-1-4, using DMF as the solvent in Step 1, using dioxane as the solvent in step 2, and using CS2CO3 as the base in Step 3. ]H NMR (400 MHz, DMSO-J6) 5 = 8.11 (s, 1H), 7.59 (d, J = 11.2 Hz, 1H), 7.01 (dd, 7 = 11.2, 17.9 Hz, 1H), 6.17 (d, 7= 18.0Hz, 1H), 5.83 - 5.73 (m, 1H), 5.57 (d, 7= 11.6 Hz, 1H), 3.95 - 3.87 (m, 1H), 3.69 - 3.61 (m, 1H), 2.42 - 2.34 (m, 1H), 2.05 (d, 7= 10.4 Hz, 2H), 1.78 -1.68 (m, 1H), 1.55 (d, 7= 3.2 Hz, 2H). LCMS: (M+l :325.0).

[0296] Preparation of 5-bromo-7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (1-4-4). Br HN-N l2, t-BuOK THF Step 1 I-4-2 DHP, PPTS DCM Step 2 I-4-3 ^BF3 K+ Pd(dppf)CI2, Na2CO3 Dioxane / H2O Step 3

[0297] 1-4-4 was prepared from commercially available 5-bromo-7-chloro-lH-indazole following the method described in Steps 1-3 used for preparation of 1-1-4, using PPTS as the catalyst and DCM as the solvent in Step 2. LCMS: (M+23: 364.8)

[0298] Preparation of 3-isopropoxy-lH-pyrazole-5-carboxylate (1-1-5) 1-1-5

[0299] To a solution of commercially available ethyl 3-hydroxy-lH-pyrazole-5-carboxylate (10.0 g, 64.0 mmol, 1 eq) in DMF (100 mL) was added K2CO3 (26.5 g, 192 mmol, 3 eq) and 2-iodopropane (21.8 g, 128 mmol, 2 eq). The mixture was stirred at 12 °C for 12 h. On completion, the reaction mixture was partitioned between ethyl acetate (300 mL x 3) and water (300 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether / Ethyl acetate=10:l to 10:1) to give ethyl 3-isopropoxy-lH-pyrazole-5-carboxylate (6.00 g, 30.3 mmol, 47% yield) as a white solid. LCMS: (M+l: 199.1).

[0300] Preparation of tert-butyl-dimethyl-[(lS)-2-[5-(bromomethyl)-4-iodo-3-isopropoxy- pyrazol-1 -y 1 ]-1 -methyl-ethoxy]silane (I-1 -9) 1: To

[0301] Step a solution of commercially available (2S)-2-[tert- butyl(dimethyl)silyl]oxypropan-l-ol (4.49 g, 23.6 mmol, 2 eq) and ethyl 3-isopropoxy-lH-pyrazole-5-carboxylate (1-1-5, 2.34 g, 11.81 mmol, 1 eq) in 2-Me THF (4 mL) was added PPI13 (6.81 g, 25.9 mmol, 2.2 eq) and D1AD (5.25 g, 25.9 mmol, 2.2 eq). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether / Ethyl acetate= 8:1 to 8:1) to give ethyl 2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-isopropoxy-pyrazole-3- carboxylate (1-1-6, 4.43 g, crude) as a white solid. LCMS: (M+l: 371.1). The product (1-1-6) was used in the next step without further purification.

[0302] Step 2: To a solution of ethyl 2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-isopropoxy-pyrazole-3-carboxylate (1-1-6,4.29 g, 11.6 mmol, 1 eq) in THF (40 mL) was added LiAlH4 (2.5 M, 6.95 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, portions of water (0.6 mL), 15% NaOH (0.6 mL) and water (2.0 mL) were added successively, and the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 6:1 to 6:1) to give [2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-isopropoxy-pyrazoL3-yl] methanol (1-1-7, 2.26 g, 6.88 mmol, 59% yield) as abrown solid. LCMS: (M+l: 329.1). The product (1-1-7) was used in the next step without further purification.

[0303] Step 3: To a solution of [2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-isopropoxy-pyrazol -3-yl]methanol (1-1-7,2.06 g, 6.27 mmol, 1 eq) in ACN (20 mL) was added N1S (2.12 g, 9.41 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was partitioned between ethyl acetate (25 mL x 3) and water (25 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 6:1 to 6:1) to give [2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-4-iodo-5-isopropoxy-pyrazol-3-yl]methanol (1-1-8, 2.79 g, 6.13 mmol, 98% yield) as a purple oil. LCMS: (M+l: 455.4). The product (1-1-8) was used in the next step without further purification.

[0304] Step 4: To a solution of [2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-4-iodo-5-isopropoxy-pyrazoL3-yl]methanol (1-1-8, 1.00 g, 2.20 mmol, 1 eq) in DCM (10 mL) was added PPI13 (692 mg, 2.64 mmol, 1.2 eq), then CBr4 (876 mg, 2.64 mmol, 1.2 eq) was added at 0°C under N2 atmosphere. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 6:1 to 6:1) to give [(lS)-2-[5-(bromomethyl)-4-iodo-3-isopropoxy-pyrazol-l-yl]-l-methyl-ethoxy]-tert-butyl-dimethyl-silane (1-1-9, 1.06 g, 2.05 mmol, 93% yield) as abrown oil. LCMS: (M+l: 519.0).

[0305] Preparation of (S)-5-(bromomethyl)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo- IH-pyrazole (1-2-9) NIS, ACN Step 3 NIS, PPh3 DCM Step 4 1-2-8

[0306] Step 1. To a solution of commercially available ethyl 3-ethoxy-lH-pyrazole-5-carboxylate (1-2-5, 1.17 g, 6.35 mmol, 1 eq), and commercially available (S)-2-((tert-butyldimethylsilyl)oxy)propan-l-ol (1.81 g, 9.53 mmol, 1.5 eq) in 2-MeTHF (20 mL) was added PPI13 (3.67 g, 14.0 mmol, 2.2 eq). The mixture was stirred at 25 °C for 0.5 h, then DIAD (2.83 g, 14.0 mmol, 2.2 eq) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was then concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:EA= 10:1) to give ethyl (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-lH-pyrazole-5-carboxylate (1-2-6, 1.96 g, crude) as a yellow oil. LCMS: (M+E357.2).

[0307] Step 2. To a solution of ethyl (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-lH-pyrazole-5-carboxylate (1-2-6, 1.76 g, 4.94 mmol, 1 eq) in THF (18 mL) was added LAH (2.5 M, 2.96 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was sequentially quenched with water (0.3 mL), 15% NaOH (0.3 ml) and water (0.9 mL). The combined organic phase was dried over NazSO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: THF= 4:1) to give (S)-(l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-lH-pyrazol-5-yl)methanol (1-2-7, 1.46 g, crude) as a yellow oil. LCMS: (M+l:315.3).

[0308] Step 3. To a solution of (S)-(l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-lH-pyrazol-5-yl)methanol (1-2-7, 1.26 g, 4.01 mmol, 1 eq) in ACN (13 mL) was added NIS (992 mg, 4.41 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched with sat. Na3SO3 (20 mL) at 0 °C and extracted with ethyl acetate (15 mL x 3), and the combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (Si02, PE:     THF=10:l) to give (S)-(l-(2-((tert- butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methanol (1-2-8, 2.05 g, crude) as ayellow oil. LCMS: (M+l:441.1).

[0309] Step 4. To a solution of (S)-(l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methanol (1-2-8, 15.0 g, 34.1 mmol, 1 eq,) in DCM (150 mL) was added NIS (15.3 g, 68.1 mmol, 2 eq) and PPI13 (13.4 g, 51.1 mmol, 1.5 eq) under N2, then the mixture was stirred at 0 °C for 2 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA= 1:0 to 10:1) to give (S)-5-(bromomethyl)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-lH-pyrazole (1-29, 15.0 g, 27.3 mmol, 80 % yield) as a yellow solid. LCMS: (M+l: 551.0).

[0310] Preparation of 5-(bromomethyl)-4-iodo-1,3-dimethyl-IH-pyrazole (1-3-9).

[0311] Step 1. To a solution of ethyl l,3-dimethyl-lH-pyrazole-5-carboxylate (10.0 g, 59.5 mmol, 1.0 eq) in ACN (100 mL) was added NIS (14.7 g, 65.4 mmol, 1.1 eq). The mixture was stirred at 60 °C for 16 hr. On completion, the mixture was quenched with sat. Na2SOs (500 mL) and extracted with ethyl acetate (250 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 4-iodo-l,3-dimethyl-lH-pyrazole-5-carboxylate (17 g, crude) as a colorless oil. LCMS: (M+l:295.2).

[0312] Step 2. To a solution of ethyl 4-iodo-l,3-dimethyl-lH-pyrazole-5-carboxylate (8.00 g, 27.2 mmol, 1.0 eq) in MeOH (150 mL) was added LiBH4 (14.8 g, 680 mmol, 25 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hr. The mixture was then quenched with water (200 mL) and concentrated in vacuum to give a residue. To the residue, water (100 mL) was added and extracted with ethyl acetate (60 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was triturated with PE / EA - (10:1) at 25 °C for 10 min to give (4-iodo-l,3-dimethyl-lH-pyrazol- 5-yl)methanol (6.30 g, 22.5 mmol, 83% yield) as a white solid. LCMS: (M+l:252.9).

[0313] Step 3. To a solution of (4-iodo-l,3-dimethyl-lH-pyrazol-5-yl)methanol (4 g, 15.9 mmol, 1.0 eq) in DCM (40 mL) was added PBn (4.73 g, 17.5 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was adjusted to pH = 7~8 with sat. NaHCOs. Then, water (100 mL) was added and extracted with ethyl acetate (100 mL x 3), and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 5 / 1 to 1 / 1) to give 5-(bromomethyl)-4-iodo-l,3-dimethyl-l H-pyrazole (2.70 g, 8.57 mmol, 54% yield) as a white solid. ]H NMR (400 MHz, CDCL-^ / ) 5 = 4.46 (s, 2H), 3.91 (s, 3H), 2.23 (s, 3H); LCMS: (M+L316.8).

[0314] Preparation of (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-1 H-pyrazole (1-4-9). 1-1-8                                             I-4-9 A mixture of (S)-(l-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-lH-pyrazol-5-yl)methanol (13.0 g, 28.6 mmol, 1 eq, 1-1-8), and PPhs (11.3 g, 42.9 mmol, 1.5 eq) in DCM (130 mL) was degassed and purged with N2 3 times, and then NIS (12.9 g, 57.2 mmol, 2 eq) was added into the mixture. The mixture was stirred at 0 °C for 2 hr under N2 atmosphere. On completion, the reaction mixture was quenched by addition to saturated solution of NaHCOs (100mL) at 0 °C, diluted with H2O (400 mL) and extracted with EA (300 mL, 100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 10:1) to give (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-l H-pyrazole (12.0 g, 21.3 mmol, 74% yield) as a white solid. 'H NMR (400 MHz, DMSO-de) 5 = 4.80 (td, 7= 6.0, 12.0 Hz, 1H), 4.53 - 4.37 (m, 2H), 4.24 - 4.14 (m, 1H), 4.14 - 4.05 (m, 1H), 3.99 - 3.92 (m, 1H), 1.34 (dd, J= 4.4, 5.6 Hz, 6H), 1.22 (d, J= 6.4 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 3H), -0.17 (s, 3H). LCMS: (M+l: 565.1).

[0315] Preparation of (S)-l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-5-(iodomethyl) -1 H-pyrazole (I- 5 -9). PPh3, DIAD, THF                , , „ Step 2 3’       ’                            1-5-6                               1-5-7 Step 1 I-5-8                                           I-5-9

[0316] Step 1. To a solution of ethyl 3-ethoxy-lH-pyrazole-5-carboxylate (1.65 kg, 6.63 mol, 1 eq) in THF (16.5 L) was added (R)-l-((tert-butyldimethylsilyl)oxy)propan-2-ol (1.58 kg, 8.29 mol, 1.25 eq), PPh3 (2.61 kg, 9.94 mol, 1.5 eq) and DIAD (2.01 kg, 9.94 mol, 1.93 L, 1.5 eq) at 0 °C under Ns. The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuum and triturated with MTBE (5 L) 5 times to remove triphenylphosphine oxide. The mixture was filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiOs, Petroleum ether / Ethyl acetate = 1:0 to 20:1) to give ethyl (S)-l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-lH-pyrazole-5-carboxylate (7.16 kg, 10.0 mol, 76% yield, 50% purity) as a yellow oil. ’H NMR (400 MHz, CDCh-d) 5 6.15 (s, 1H), 5.45 - 5.37 (m, 1H), 4.30 (d, J = 7.0 Hz, 2H), 4.18 - 4.10 (m, 2H), 3.82 - 3.76 (m, 1H), 3.74 - 3.57 (m, 1H), 1.42 - 1.34 (m, 9H), 0.79 (s, 9H), -0.03 - -0.13 (m, 6H). LCMS: (M+l :357.6).

[0317] Step 2. To a solution of ethyl (S)-l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-lH-pyrazole-5-carboxylate (1.79 kg, 5.02 mol, 1 eq) in THF (8 L) at 0 °C, was added LAH (2.5 M, 2.01 L, 1 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. On completion, the reaction mixture was slowly quenched with 190 mL (0 °C) water, followed by addition of 15% sodium hydroxide (190 ml) and water (190 ml x 3). The mixture was then filtered. The combined organic layer was washed with brine (1500 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give (S)-(l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-lH-pyrazol-5-yl)methanol (1.35 kg, 4.29 mol, 85.5% yield) as a yellow oil. LCMS: (M+l:315.4).

[0318] Step 3. To a solution of (S)-(l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-lH-pyrazol-5-yl)methanol (1.35 kg, 4.29 mol, 1 eq) in ACN (9.5 L) was added NIS (1.03 kg, 4.59 mol, 1.07 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was quenched dropwise with sodium sulfite aqueous solution (9.5 L), then was concentrated and extracted with EA (2000 mL x 3). The combined organic layer was washed with brine (2000 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (PE : EA = 25:1-5:1) to give (S)-(l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methanol (700 g, 1.59 mol, 37% yield) as a white solid. LCMS: (M+l:441.4).

[0319] Step 4. A solution of (S)-(l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methanol (1.00 kg, 2.27 mol, 1 eq) and NIS (1.02 kg, 4.54 mol, 2 eq) in DCM (7 L) was degassed and purged with N2 3 times. PPI13 (893 g, 3.41 mol, 1.5 eq) was dissolved in DCM (800 mL) and slowly added to the reaction solution at 0 °C, and the mixture was stirred at 25 °C for 1 h under N2. On completion, the mixture was poured into saturated sodium sulfite (7000 mL) aqueous solution, and the aqueous phase was extracted with DCM (2000 mL x 3). The combined organic phase was washed with brine (2000 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (0-90% Petroleum ether / Ethyl acetate) to afford (S)-l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-lH-pyrazole (905 g, 1.55 mol, 95% yield, 94% purity) as yellow oil. LCMS: (M+l:551.1)

[0320] Preparation of Final Macrocycles

[0321] Preparation of (2S)-l-{(10S',17£')-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3’,4’-j:4",3”-n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol (Ex. 1) SteP 1                   1-1-10 NaH, DMF Step 3 THP' 1-1-12

[0322] Step 1: A mixture of commercially available 5-(methoxymethyl)-2-methyl-pyrazol-3-ol (1.16 g, 8.14 mmol, 1 eq), 5-bromo-l-tetrahydropyran-2-yl-3-vinyl-indazole (3.00 g, 9.77 mmol, 1.2 eq), tBubrettPhos Pd G3 (1-1-4, 695 mg, 813 pmol, 0.1 eq), K2CO3 (3.37 g, 24.4 mmol, 3 eq) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 130 °C for 0.5 hours under N2 atmosphere. On completion, the reaction mixture was quenched by addition H2O (20 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with saturated solution of NaCl (30 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 10:1) to give 5-(methoxymethyl)-2-methyl-4-(l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3-ol (1-1-10, 500 mg, 1.33 mmol, 16% yield) was a white solid. ’H NMR (400 MHz, CDCI3) 8 = 8.02 - 7.72 (m, 1H), 7.66 - 7.31 (m, 1H), 7.06 - 6.76 (m, 1H), 5.70 - 5.34 (m, 2H), 4.36 - 3.91 (m, 3H), 3.81 - 3.63 (m, 1H), 3.40 -3.26 (m, 4H), 2.58 - 2.34 (m, 2H), 2.22 - 1.91 (m, 2H), 1.83 - 1.51 (m, 3H)._LCMS: (M+l: 369.0).

[0323] Step 2. To a solution of 5-(methoxymethyl)-2-methyl-4-(l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3-ol (1-1-10, 300 mg, 814 pmol, 1 eq), [(lR)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate (1-1-1, 412 mg, 1.63 mmol, 2 eq) in DMF (5 mL) was added K2CO3 (337 mg, 2.44 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was quenched by addition H2O (15 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with saturated solution of NaCl (20 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:1) to give tert-butyl N-[(2S)-2-[5-(methoxymethyl)-2-methyl-4-(l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3-yl]oxypropyl]carbamate (1-1-11, 180 mg, 342 pmol, 42% yield) as a white solid. LCMS: (M+l: 526.3).

[0324] Step 3. To a solution of tert-butyl N-[(2S)-2-[5-(methoxymethyl)-2-methyl-4-(l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3-yl]oxypropyl]carbamate (I-1-11, 170 mg, 323 pmol, 1 eq) in DMF (3 mL) was added NaH (38.8 mg, 970 nmol, 60% purity, 3 eq). The mixture was stirred at 0 °C for 0.5 hours. Then tert-butyl-dimethyl-[(lS)-2-[5- (bromomethyl)-4-iodo-3-isopropoxy-pyrazol-l-yl]-l-methyl-ethoxy]silane (1-1-9, 167 mg, 323 pmol, 1 eq) was added to the mixture above. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched by addition H2O (10 mL) and extracted with EA (5 mL x 3). The combined organic layers were washed with NaCl (10 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3:1) to give tert-butyl N-[[4-iodo-5-isopropoxy-2-[(2S)-2-[tert-butyl(dimethyl)silyl] oxypropyl]pyrazol-3-yl] methyl]-N-[(2S)-2-[5-(methoxymethyl)-2-methyl-4-(l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3-yl]oxypropyl]carbamate (1-1-12,130 mg, 135 pmol, 41% yield) as a white solid. LCMS: (M+l: 962.5).

[0325] Step 4. A mixture of tert-butyl N-[[4-iodo-5-isopropoxy-2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl] pyrazol-3-yl]methyl] -N-[(2S)-2-[5-(methoxymethyl)-2-methyl-4-( 1 -tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3-ylJoxypropyl]carbamate (11-12, 110 mg, 114 pmol, 1 eq), Pd(OAc)2 (5.13 mg, 22.8 pmol, 0.2 eq), TBAC (31.7 mg, 114 pmol, 1 eq) and NaHCOs (24.0 mg, 285 pmol, 2.5 eq) in DMF (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 2 hours under N2 atmosphere. On completion, the reaction mixture was quenched by addition H2O (5 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with saturated solution of NaCl (10 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:1) to give tert-butyl (105,17E)-14-[(25)-2-{ [tert-butyl(dimethyl)silyl]oxy }propyl]-6-(methoxymethyl)-8,10-dimethyl-2-(oxan-2-yl)-16- [(propan-2-yl)oxy] -2,8,10,11,13,14-hexahydro-1277-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine-l 2-carboxylate (1-1-13, 40.0 mg, 47.9 pmol, 41% yield) as a white solid. LCMS: (M+l: 834.7).

[0326] Step 5: To a solution of tert-butyl (IO5,l7E)-l4-|(25)-2-{| / ert-butyl(dimethyl)silyl]oxy}propyl]-6-(methoxymethyl)-8,10-dimethyl-2-(oxan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,l l,13,14-hexahydro-12H-3,5-ethenotripyrazolo[3,4; / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine-12-carboxylate (1-1-13, 40.0 mg, 47.9 pmol, 1 eq) in DCM (2 mL) was added HCl / dioxane (0.5 mL, 1 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated under reduced pressure to give (25)-1-{(105,17E)-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol (1-1-14, 20.0 mg, 37.3 pmol, 77% yield) as a white solid. LCMS: (M+l: 536.3).

[0327] Step 6. To a solution of (25)-l-{(105,17E)-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,ll,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4’-j:4",3"- n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (1-1-14, 20.0 mg, 37.3 pmol, 1 eq) in MeOH (2 mL) was added AcOH (2.24 mg, 37.3 pmol, 1 eq), acetaldehyde (1.64 mg, 37.3 pmol, 1 eq) and NaBH(OAc)3 (7.91 mg, 37.3 pmol, 1 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent. The crude product was purified by reversed-phase column chromatography: CD02-Waters Xbidge BEH C18 150*25*10 um; mobile phase: [water(NH3H2O)-ACN]gradient: 34%-64% B over 10 min to give (25)-l-{(105,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l 1,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3”-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (Ex. 1, 2.69 mg, 4.77 pmol, 12.78% yield) as a white solid. The analytical data for Ex. 1 is provided in Table 1.

[0328] Preparation of (25)-l-[(10>S’,17£')-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,lL12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol (Ex. 18): / —\  O HO   N—\ / CF: 1-2-1 X DBAD, PPh3, dioxane Step 2 O t-BuBrettphos Pd G3 K2CO3, 2-MeTHF 70 °C, 16 h Step 1 K2CO3, DMF Step 4 N—N THP 1-2-11

[0329] Step 1. To a solution of 5-bromo-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (5.00 g, 15.4 mmol, 1 eq) and commercially available 3-(methoxymethyl)-l-methyl-lH-pyrazol-5-ol (2.51 g, 17.9 mmol, 1.15 eq) in 2-MeTHF (70 mL) was added potassium carbonate (4.25 g, 30.8 mmol, 2 eq), and the mixture was stirred at 20 °C for 15 min. The resulting mixture was vacuum degassed and backfilled with N2 three times; then t-BuBrettphos Pd G3 (1.31 g, 1.54 mmol, 0.1 eq) was added to the mixture, and the mixture was vacuum degassed and backfilled with N2 three times and stirred at 70° C for 16 h. On completion, the mixture was filtered, and the filter cake was washed with EA (50 mL), then the mixed solution was extracted with ethyl acetate (50 mL x 2) and water (100 mL). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The aqueous phase was adjusted to pH 3~5 with citric acid and extracted with DCM (20 mL x3). The combined organic phase was washed with brine (20 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a 3-(methoxymethyl)-l-methyl-lH-pyrazol-5-ol (8.00 g, 12.4 mmol, 40% yield, 60% purity) as brown gum. LCMS: (M+l: 387.2).

[0330] Step 2. A mixture of 4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-ol (7.33 g, 11.4 mmol, 1 eq), (R)-N-ethyL 2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (1-2-1, 3.40 g, 17.1 mmol, 1.5 eq), and PPI13 (4.48 g, 17.1 mmol, 1.5 eq) in dioxane (70 mL) was degassed and purged with N2 3 times, and then to the mixture was added DBAD (5.24 g, 22.8 mmol, 2 eq) under N2 atmosphere at 0 °C. The mixture was then stirred at 20 °C for 2 h under N2 atmosphere. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give N-ethyl-2,2,2-trifluoro-N-((2S)-2-((4-(6-fluoro-l-(tetr ahydro-2H-pyran-2-yl)-3-vinyl- 1H-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)oxy)propyl)acetamide (5.00 g, 8.81 mmol, 77% yield) as a brown oil. !H NMR (400 MHz, DMSO-Je) 5 = 8.00 (d, J = 6.8 Hz, 1H), 7.69 - 7.53 (m, 1H), 6.98 (dd, J= 11.6, 18.0 Hz, 1H), 6.07 (d, J= 18.0 Hz, 1H), 5.81 (s, 1H), 5.54 (d, 7 = 11.6 Hz, 1H), 4.31 - 4.09 (m, 3H), 3.96 - 3.85 (m, 1H), 3.81 - 3.71 (m, 1H), 3.67 - 3.62 (m, 3H), 3.46 (s,4H), 3.15-3.10 (m, 3H), 2.45 - 2.30 (m, 1H),2.O9- 1.90 (m, 2H), 1.82- 1.67 (m, 1H), 1.59 (d, 7 = 3.6 Hz, 2H), 1.14-1.04 (m, 3H), 1.02-0.95 (m, 3H).

[0331] Step 3. To a solution of N-ethyl-2,2,2-trifluoro-N-((2S)-2-((4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1 H-indazol-5-yl)-3-(methoxymethyl)-1 -methyl-1 H-pyrazol-5-yl)oxy)propyl)acetamide (4.50 g, 7.93 mmol, 1 eq) in THF (40 mL) and H2O (8 mL) was added LiOH.H2O (1.66 g, 39.6 mmol, 5 eq). The mixture was stirred at 20 °C for 3 h. On completion, the reaction mixture was filtered, and the filtrate was separated, then the water phase was partitioned between ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=LO to 0:1) to give (2S)-N-ethyl-2-((4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)oxy)propan-l-amine (6.33 g, 11.8 mmol, 74% yield, 88% purity) as a brown oil. LCMS: (M+l: 472.4).

[0332] Step 4. To a solution of (2S)-N-ethyl-2-((4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)oxy)propan-l-amine (2.00 g, 4.24 mmol, 1 eq,) and (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-5-(iodomethyl)-lH-pyrazole (1.40 g, 2.54 mmol, 0.6 eq) in DMF (20 mL) was added K2CO3 (1.76 g, 12.7 mmol, 3 eq). The mixture was stirred at 60 °C for 2 hr. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=2:l to 1:1) to give (2S)-N-((l-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1 H-indazol-5-yl)-3-(methoxymethyl)-1 -methyl-1 H-pyrazoL5-yl)oxy)propan-1 -amine (1.40 g, 1.57 mmol, 36% yield) as a white solid. LCMS: (M+l: 894.5).

[0333] Step 5. A mixture of (2S)-N-((l-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1 H-indazol-5-yl)-3-(methoxymethyl)-1 -methyl-1 H-pyrazol-5-yl)oxy)propan-1 -amine (1.25 g, 1.40 mmol, 1 eq), TBAC (388 mg, 1.40 mmol, 1 eq), Pd(OAc)2 (31.3 mg, 0.140 mmol, 0.1 eq) and NaHCOs (293 mg, 3.50 mmol, 2.5 eq) in DMF (13 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 130 °C for 2 h under N2 atmosphere. On completion, the mixture was diluted with water (35 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOr, Petroleum ether / Ethyl acetate=2:l to 1:1) to give (105,17^)-14-((25)-2-((^^-butyl(dimethyl)silyl]oxy (propyl]-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-2-(oxan-2-yl)-2,10,l l,12,13,14-hexahydro-8Z / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine (1.00 g, 1.31 mmol, 93% yield) as a yellow solid. LCMS: (M+l: 766.6).

[0334] Step 6. To a solution of (105,17E)-14-((25)-2-{[rert-butyl(dimethyl)silyl]oxy(propyl]-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-2-(oxan-2-yl)-2,10,ll,12,13,14-hexahydro-8Z / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"- / r](l,4]oxazacyclopentadecine (950 mg, 1.24 mmol, 1 eq) in MeOH (10 mL) was added cone. HC1 (12M, 20.7 mmol, 2 mL, 16.6 eq). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2,DCM / MeOH=10:l to 1:1) to give (25)-1-[(105,17E)- 16-ethoxy- 12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl- 2,8,10,ll,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4; / :3',4’-j:4”,3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol (274.93 mg, 0.455 mmol, 36.71% yield, 94% purity) as a white solid (Ex. 18). Analytical data for Ex. 18 can be found in the table below.

[0335] Preparation of (105,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl- 2,10,ll,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3”- n][l,4]oxazacyclopentadecine (Ex. 19). LiOH*H2O THF / H2O Step 3 1-3-12 K2CO3, DMF Step 4 1-3-13

[0336] Step 1. A mixture of commercially available 3-(methoxymethyl)-l-methyl-lH-pyrazol-5-ol (2.99 g, 21.0 mmol, 1.2 eq), 5-bromo-7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (5.70 g, 17.5 mmol, 1 eq,), K2CO3 (7.27 g, 52.6 mmol, 3 eq), and tBuBrettPhosPdG3 (899 mg, 1.05 mmol, 0.06 eq) in dioxane (57 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 130 °C for 1 h under N2 atmosphere. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (0-10% MeOH in DCM) to give 4- (7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-ol (6.20 g, 16.0 mmol, 92% yield) as a brown solid. LCMS: (M+l :387.2).

[0337] Step 2. A mixture of 4-(7-fluoro-l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)-5-(methoxymethy])-2-methyl-pyrazol-3-ol (1.00 g, 2.59 mmol, 1 eq), (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N-methylacetamide (718 mg, 3.88 mmol, 1.5 eq), and PPI13 (1.36 g, 5.18 mmol, 2 eq) in dioxane (20 mL) was degassed and purged with N2 3 times. DBAD (1.19 g, 5.18 mmol, 2 eq) was added into the mixture at 0 °C, and then the mixture was stirred at 25 °C for 2 h under N2 atmosphere. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=2:l to 1:1) to give 2,2,2-trifluoro-N-((2S)-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)oxy)propyl)-N-methylacetamide (2.40 g, 1.34 mmol, 51% yield, 31% purity) as a yellow solid. LCMS: (M + 1 =554.3).

[0338] Step 3. To a solution of 2,2,2-trifluoro-N-((2S)-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)oxy)propyl)-N-methylacetamide (2.30 g, 4.16 mmol, 1 eq) in THF (20 mL) and H2O (4 mL) was added LiOH.H2O (871 mg, 20.7 mmol, 5 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2,DCM / MeOH=4:1 to 1:1) to give (2S)-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1 H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1 H-pyrazoL5-yl)oxy)-N-methylpropan-1-amine (750 mg, 1.56 mmol, 37.% yield, 95% purity) as a yellow solid. LCMS: (M+l =458.3).

[0339] Step 4. To a solution of (2S)-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)oxy)-N-methylpropan-l-amine (650 mg, 1.42 mmol, \eq) and 5-(bromomethyl)-4-iodo-l,3-dimethyl-lH-pyrazole (671 mg, 2.13 mmol, 1.5 eq) in DMF (7 mL) was added K2CO3 (589 mg, 4.26 mmol, 3 eq). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=2:l to 1:1) to give (2S)-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)oxy)-N-((4-iodo-l,3-dimethyl-lH-pyrazol-5-yl)methyl)-N-methylpropan-l- amine (590 mg, 0.819 mmol, 57% yield, 96% purity) as a yellow solid. LCMS: (M+l= 692.2).

[0340] Step 5. A mixture of (2S)-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)oxy)-N-((4-iodo-l,3-dimethyl-lH-pyrazol-5-yl)methyl)-N-methylpropan-l-amine (550 mg, 0.795 mmol, 1 eq), Pd(OAc)2 (17.8 mg, 0.0795 mmol, 0.1 eq), TBAC (221 mg, 0.795 mmol, 1 eq) and NaHCO3 (167 mg, 1.99 mmol, 2.5 eq) in DMF (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 130 °C for 2 hr under N2 atmosphere. On completion, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:1 to 1:1) to give (105,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2-(oxan-2-yl)-2,10,ll,12,13,14-hexahydro-877-3,5-ethenotripyrazolo[3,4- / :3’,4,-j:4",3”- nJ [ 1,4Joxazacyclopentadecine (220 mg, 0.316 mmol, 39% yield, 81% purity) as a brown solid. LCMS: (M+l= 564.2).

[0341] Step 6. To a solution of (105,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2-(oxan-2-yl)-2,10,l l,12,13,14-hexahydro-8 / 7-3,5-ethenotripyrazolo[3,4- / :3',4’-j:4",3"-n][l,4]oxazacyclopentadecine (180 mg, 0.319 mmol, 1 eq) in MeOH (2 mL) was added cone. HC1 (12 M, 0.4 mL, 15 eq). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was quenched with saturated solution of NaHCO3 (5 mL) and extracted with ethyl acetate (5 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue purified by preparative HPLC to give (105,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,ll,12,13,14-hexahydro-8 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"- / 7][l,4]oxazacyclopentadecine (86.74 mg, 0.161 mmol, 50.48% yield, 97.67% purity, Formic acid salt) as a white solid (Ex. 19). The analytical data for Ex. 19 can be found in the table below.

[0342] Preparation of (10>5’,17E')-20-fluoro-6,8,10,12,14,16-hexamethyl-2,10,ll,12,13,14-hexahydro-8Z / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine (Ex. 20) 1-4-10                                      Ex. 20

[0343] Step 1. To a solution of 5-bromo-7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH- indazole (2.30 g, 7.07 mmol, 1 eq, 1-3-4) and commercially available 1,3-dimethyl- 1H-pyrazol-5-ol (912 mg, 8.13 mmol, 1.15 eq) in 2-MeTHF (30 mL) was added K2CO3 (1.96 g, 14.2 mmol, 2 eq). The mixture was vacuum degassed and backfilled with N2 three times and stirred at 20 °C for 15 min. Then t-BuBrettphos Pd G3 (604 mg, 0.707 mmol, 0.1 eq) was added to the mixture, and the mixture was vacuum degassed and backfilled with N2 three times and stirred at 70° C for 2 h. On completion, the mixture was filtered, and the filter cake was washed with EA (50 mL), then the mixed solution was extracted with ethyl acetate (50 mL x 2) and water (100 mL). The combined organic phase was washed with brine (50 mL x 2). The aqueous phase was adjusted to pH 3~5 with citric acid and extracted with DCM (20 mL x3). The two combined organic phase were washed with brine (20 mL x2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-ol (2.60 g, 4.67 mmol, 66% yield, 64% purity) as a yellow solid without further purification. LCMS: (M+l: 357.2).

[0344] Ex. 20 was prepared using the above intermediate 1-4-10, following Steps 2-6 from the preparation of Ex. 19. The analytical data for Ex. 20 can be found in the table below.

[0345] Preparation of (2lS,)-l-{(10>5’,17E)-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (Ex. 21).

[0346] Step 1. To a solution of (2S)-N-ethyl-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)oxy)propan-l-amine, which was prepared following the method described in Ex. 19 (1.90 g, 4.03 mmol, 1 eq) and (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-lH-pyrazole (2.27 g, 4.03 mmol, 1 eq) in DMF (19 mL) was added K2CO3 (1.67 g, 12.1 mmol, 3 eq). The mixture was stirred at 80 °C for 4 h. On completion, the reaction mixture was diluted with addition H2O (100 mL) at 25 °C and extracted with EA (50 mL x 3). The combined organic layers were washed with H2O (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (0-100% THF in PE) to give (2S)-N-((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-lH-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)oxy)propan-l-amine (3.30 g, 3.63 mmol, 90% yield) as a brown oil. LCMS: (M+l :908.5).

[0347] Step 2. A mixture of (2S)-N-((l-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-lH-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)oxy)propan-l-amine (1.50 g, 1.65 mmol, 1 eq), Pd(OAc)2 (74.2 mg, 0.330 mmol, 0.2 eq), TBAC (459 mg, 1.65 mmol, 1 eq) and NaHCOs (346.96 mg, 4.13 mmol, 2.5 eq) in DMF (15 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 130 °C for 1 h under N2 atmosphere. On completion, the reaction mixture was diluted with H2O (80 mL) and extracted with EA (40 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product (IOS, 17£)-14- [(25)-2- {[ter / -butyl(dimethyl)silyl]oxy Jpropyl]-12-ethyL20-fluoro-6-(methoxymethyl)-8,10-dimethyl-2-(oxan-2-yl)-16- [(propan-2-yl)oxy ] -2,10,11,12,13,14-hexahydro-8 / 7-3,5-ethenotripyrazolo[3,4: / :3',4'-j:4”,3"-n][l,4]oxazacyclopentadecine (1.20 g, 1.54 mmol, 93% yield) as a brown oil without further purification. LCMS: (M+l :780.6).

[0348] Step 3. To a solution of (10S,17E)-14-[(2S)-2-{ [ter / -butyl(dimethyl)silyl]oxy}propyl]-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-2-(oxan-2-yl)-16-[(propan-2-yl)oxy]-2,10,1 l,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4: / :3',4’-j:4”,3”-n][l,4]oxazacyclopentadecine (1.10 g, 1.41 mmol, 1 eq) in MeOH (10 mL) was added cone. HC1 (12 M, 2 mL, 17.0 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched by addition sat. NaHCOs solution at 0 °C to adjust to pH = 7 and extracted with MeOH / DCM (1 / 15) (30 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give (2S)-l-{(10S,17£)-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo|3,4; / :3',4'- / :4",3”- / ?|| 1,4|oxazacyclopentadecin-14-yl]propan-2-ol (268.88 mg, 0.433 mmol, 30.71% yield, 93.69% purity) as a white solid (Ex. 21). The analytical data for Ex. 21 can be found in the table below.

[0349] Ex. 22 was prepared following the method described for the preparation of Ex. 21, using intermediate 1-2-9 in Step 1. The analytical data for Ex. 22 can be found in the table below.

[0350] Preparation of (10l5',17£,)-20-chloro-6,8,10,12,14,16-hexamethyl-2,10,ll,12,13,14-hexahydro-8 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l ,4]oxazacyclopentadecine (Ex. 23). OH tBuBrettPhosPdG3 K2CO3, 2-MeTHF Step 1 DBAD, PPh3 THF Step 2 N OH TFA 1-3-1 1-5-10

[0351] Step 1. A solution of 5-bromo-7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (700 mg, 2.05 mmol, 1 eq), commercially available l,3-dimethyl-lH-pyrazol-5-ol (264 mg, 2.36 mmol, 1.15 eq), K2CO3 (566 mg, 4.10 mmol, 2 eq), and tBuBrettPhos Pd G3 (175 mg, 0.205 mmol, 0.1 eq) in 2-MeTHF (7 mL) was degassed and purged with Nz3 times, and then the mixture was stirred at 80 °C for 1 h under N2 atmosphere. On completion, the mixture was filtered and concentrated to give a residue, quenched with water (15 mL), extracted with DCM / MeOH (10:1) (15 mLx3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 15:1) to give4-(7-chloro-l-(tetrahydro-2H- pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-ol (300 mg, 0.805 mmol, 39% yield) as a brown solid. LCMS: (M+l:373.0).

[0352] Step 2. To a solution of 4-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-ol (230 mg, 0.617 mmol, 1 eq), (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N-methylacetamide (171 mg, 0.925 mmol, 1.5 eq, T-3-1), PPh3 (243 mg, 0.925 mmol, 1.5 eq) in THF (3 mL) was degassed and purged with N2 for 3 times, and then DBAD (284 mg, 1.23 mmol, 2 eq) in THF (3 mL) was added at 0 °C. The mixture was stirred at 25 °C for 1 h under N2 atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:1 to 2:1) to give N-((2S)-2-((4-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-yl)oxy)propyl)-2,2,2-trifluoro-N-methylacetamide (520 mg, 0.231 mmol, 37% yield, 24% purity) as a white solid. LCMS: (M+l :540.3)

[0353] Step 3. To a solutionofN-((2S)-2-((4-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-yl)oxy)propyl)-2,2,2-trifluoro-N- methylacetamide (520 mg, 0.963 mmol, 1 eq) in THF (5 mL) and H2O (1 mL) was added lithium hydroxide hydrate (242 mg, 5.78 mmol, 6 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was quenched with water (5 mL) and extracted with 2-MeTHF (5 mLx3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=l:0 to 10:1) to give (2S)-2-((4-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-yl)oxy)-N-methylpropan-l-amine (130 mg, 0.293 mmol, 30% yield) as a yellow oil. LCMS: (M+l :444.2)

[0354] Step 4. A mixture of (2S)-2-((4-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-yl)oxy)-N-methylpropan-l-amine (130 mg, 0.293 mmol, 1 eq), 5-(bromomethyl)-4-iodo-l,3-dimethyl-lH-pyrazole (138 mg, 0.439 mmol, 1.5 eq), and K2CO3 (121 mg, 0.878 mmol, 3 eq) in DMF (2 mL) was stirred at 80 °C for 1 h. The mixture was quenched with water (10 mL) and extracted with EA (10 mLx3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF=l:0 to 2:1) to give (2S)-2-((4-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-yl)oxy)-N-((4-iodo-l,3-dimethyl-lH-pyrazol-5-yl)methyl)-N-methylpropan-1 -amine (180 mg, 0.265 mmol, 91% yield) as a yellow oil. LCMS: (M+l :678.3)

[0355] Step 5. To a solution of (2S)-2-((4-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-yl)oxy)-N-((4-iodo-l,3-dimethyl-lH-pyrazol-5-yl)methyl)-N-methylpropan-l-amine (180 mg, 0.265 mmol, 1 eq) in DMF (2 mL) was added NaHCOs (1.66 mg, 0.664 mmol, 2.5 eq), TBAC (73.8 mg, 0.265 mmol, 1 eq) and Pd(0Ac)2 (11.9 mg, 0.053 mmol, 0.2 eq). The mixture was degassed and purged with N2 3 times, and then stirred at 130 °C for 1 h under N2 atmosphere. On completion, the mixture was quenched with water (8 mL) and extracted with ethyl acetate (5 mLx3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF= 1:0 to 1:2) to give (105,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2-(oxan-2-yl)-2,10,ll,12,13,14-hexahydro-8 / 7-3,5-ethenotripyrazolo[3,4; / :3',4'-j:4”,3"-n][l,4]oxazacyclopentadecine (110 mg, 0.200 mmol, 75% yield) as a brown oil. LCMS: (M+l:550.2).

[0356] Step 6. A solution of (8S,17E(10S,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2-(oxan-2-yl)-2,10,ll,12,13,14-hexahydro-87 / -3,5-ethenotripyrazolo[3,4- / :3',4,-j:4",3"-n][l,4]oxazacyclopentadecine (90.0 mg, 0.164 mmol, 1 eq) in cone. HC1 (12 M, 0.9 mL, 32.5 eq) and MeOH (2.7 mL) was stirred at 25 °C for 30 min. On completion, the mixture was concentrated to give a residue. The residue was purified by preparative HPLC to give (105',17£)-20-chloro-6,8,10,12,14,16-hexamethyl-2,10,ll,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4: / :3',4'-j:4”,3"- / i][l,4]oxazacyclopentadecine (29.28 mg, 0.0628 mmol, 38.41% yield, FA salt) as a white solid (Ex. 23). The analytical data for Ex. 23 can be found in the table below.

[0357] Preparation of (105,17E,)-20-chloro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,1 l,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4: / :3',4'-j:4",3"- n][l,4]oxazacyclopentadecine (Ex. 24). 1-6-10                                         Ex. 24

[0358] Step 1. A mixture of 5-bromo-7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (700 mg, 2.05 mmol, 1 eq), commercially available 3-(methoxymethyl)-l-methyl-lH-pyrazol-5-ol (335 mg, 2.36 mmol, 1.15 eq), K2CO3 (566 mg, 4.10 mmol, 2 eq), tBuBrettPhosPdG3 (175 mg, 0.205 mmol, 0.1 eq) in 2-MeTHF (7 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 h under N2 atmosphere. On completion, the mixture was filtered and concentrated to give a residue, quenched with water (15 mL), and extracted with DCM / MeOH (10:1) (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 15:1) to give 4-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-3-(methoxymethyl)-l-methyl-lH-pyrazol-5-ol (450 mg, 1.12 mmol, 55% yield) as abrown solid. LCMS: (M+l :403.0).

[0359] Ex. 24 was prepared using the above intermediate 1-6-10, following the method described in Steps 2-6 from the preparation of Ex. 23. The analytical data for Ex. 24 can be found in the table below.

[0360] Preparation of (25)-2-[(105,17£)-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl- 2,8,10,ll,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4”,3"- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (Ex. 25). DBAD, PPh3, THF Step 1 Step 3

[0361] Step 1. To 4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-ol (100 mg, 0.281 mmol), which was synthesized following the method described in Step 1 for the preparation of Ex. 19, (R)-N-ethyl-2,2,2-trifluoro-N-(2- hydroxypropyl)acetamide (67.06 mg, 0.337 mmol), and PPhs (110 mg, 0.421 mmol) in dry THF (1 mL) at 0 °C was added DBAD (96.91 mg, 0.421 mmol). The mixture was stirred for 18 h at 22 °C. The mixture was concentrated under reduced pressure. Flash column chromatography (20-100% EA in Hexanes) provided N-ethyl-2,2,2-trifluoro-N-((2S)-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l ,3-dimethyLlH-pyrazol-5-yl)oxy)propyl)acetamide (125 mg, 0.233 mmol, 82.87% yield). LCMS: m / z 538.32 (M+l)

[0362] Step 2. To N-ethyl-2,2,2-trifluoro-N-((2S)-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-yl)oxy)propyl)acetamide (125 mg, 0.233 mmol) in THF (1 mL) was added Li OH (2 M, 1 mL) in water. The mixture was stirred at 22 °C for 2 h, cooled to -20 °C, diluted with DCM (2 mL), and 2M HC1 (aq. 1 mL) was added with vigorous stirring. The reaction was diluted with DCM and water (5 mL each) and the layers were separated. The aqueous layer was extracted again with DCM (2x5 mL). The combined organic layer was washed with brine and dried over sodium sulfate. The volatiles were evaporated to give (2S)-N-ethyl-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-yl)oxy)propan-l-amine, which was taken forward without further purification assuming quantitative yield. LCMS: m / z 442.37 (M+l).

[0363] Step 3. To (2S)-N-ethyl-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-yl)oxy)propan-l-amine (102.6 mg, 0.232 mmol) in DMF (1.5 mL) was added K2CO3 (96 mg, 0.697 mmol), followed by (S)-l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-lH-pyrazole (210 mg, 0.382 mmol). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was cooled and diluted with DCM (10 mL), then filtered. The filtrate was diluted with DCM and water (10 mL each). After separation of layers, the aqueous layer was extracted with DCM again (2x 10 mL). The combined organic layer was washed with brine and then dried over sodium sulfate. Flash column chromatography (20-50% EA in Hexanes) provided (2S)-N-((l-((S)-l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-L3-dimethyl-lH-pyrazol-5-yl)oxy)propan-l-amine (115 mg, 0.133 mmol, 57.29% yield) . LCMS: m / z 864.50 (M+l)

[0364] Step 4. To (2S)-N-((l-((S)-l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3-dimethyl-lH-pyrazol-5-yl)oxy)propan-l-amine (115 mg, 0.133 mmol) in DMF (1 mL) was added NaHCOs (33.55 mg, 0.399 mmol) and TBAC (44 mg, 0.16 mmol). Argon was bubbled through, followed by addition of Pd(OAc)2 (3 mg, 0.013 mmol). The vessel was sealed, and the mixture was stirred at 140 °C for 1 hr. The reaction was cooled, diluted with DCM and water (10 mL each), and the layers were separated. The aqueous layer was extracted again with DCM (2x10 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (0-10% Methanol in DCM) provided (10S,17E)-14-[(2S)-l-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]-16-ethoxy-12-ethy]-20-fluoro-6,8,10-trimethy]-2-(oxan-2-yl)-2,10,l 1,12,l3,l4-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3',4'-j:4",3"-n][l,4]oxazacyclopentadecine (54.49 mg, 0.074 mmol, 56% yield). LCMS: m / z, 736.59 (M+l)

[0365] Step 5. To a solution of (10S,17E)-14-[(2S)-l-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2-(oxan-2-yl)-2,10,ll,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4-f:3',4'-j:4",3"-n][l,4]oxazacyclopentadecine (54.49 mg, 0.074 mmol) in DCM (1 mL) was added TFA (745.00 mg, 6.53 mmol, 0.5 mL). The mixture was stirred at 22 °C for 18 h. The volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC to afford (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2,8,10,ll,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4-f:3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (21.04 mg, 0.0389 mmol, 52.56% yield, 99.43% purity) as a white solid (Ex. 25). The analytical data for Ex. 25 can be found in the table below.

[0366] Ex. 26 was prepared following Steps 1-5 as described in the preparation of Ex. 25, using 1-3-1 in Step 1. The analytical data for Ex. 26 can be found in the table below. Table 1 Ex# Structure MS m / z |M+H|+ ‘HNMR 5 ppm 1 J / \       OH N" \ oZ "   r-( A— N  * \       At Jn Wy HN-N          | 564.2 (400 MHz, DMSO-cfc) 8 = 12.80 (s, 1H), 8.49 (s, 1H), 7.98 - 7.88 (m, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.50 (d,7=8.8 Hz, 1H), 7.11 (d, 7= 16.8 Hz, 1H), 4.91 (quin, J= 6.0 Hz, 1H), 4.85 (d, 7 = 4.4 Hz, 1H), 4.64 - 4.55 (m, 1H), 4.38 (s, 2H), 3.98 - 3.82 (m, 5H), 3.70 (s, 3H), 3.34 (s, 3H), 2.92 -2.86 (m, 2H), 2.47 - 2.43 (m, 1H), 1.40 (t, 7 =6.4 Hz, 6H), 1.13 - 1.06 (m, 3H), 0.96 (d, 7 = 6.4 Hz, 3H), 0.88 (t, 7 = 7.2 Hz, 3H). Ex# Structure MS m / z [M+H]+ ‘HNMR 5 ppm 18 \ o / = / z^z z / jY'-I   Z—     '   > z         O"-< —z __ / ° XZ'Z> z^o T 568.4 (400 MHz, METHANOL-d4 ) 5 = 8.33 (d, J = 7.2 Hz, 1H), 8.06 (brd, J = 16.8 Hz, 1H), 7.24 (d, J = 11.2 Hz, 1H), 7.15 (d, J = 16.8 Hz, 1H), 4.97 - 4.88 (m, 1H), 4.62 -4.57 (m, 1H), 4.50 - 4.44 (m, 1H), 4.38-4.29 (m, 2H),4.13 - 4.04 (m, 2H), 4.03 - 3.94 (m, 3H), 3.76 (s, 3H), 3.21 (s, 3H), 2.95 - 2.82 (m, 2H), 2.53 -2.41 (m, 2H), 1.48 (t, J = 7.2 Hz, 3H), 1.20 (d,J = 6.4 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H), 0.84 (t, J = 7.2 Hz, 3H) 19 / V . n-n .2-HN-N 480.1 (400 MHz, METHANOL-d4 ) 8 = 8.25 - 8.13 (m, 2H), 7.63 (brd, J = 12.8 Hz, 1H), 6.94 (brd, J = 17.2 Hz, 1H), 4.834.76 (m, 1H), 4.47 - 4.32 (m, 2H), 3.87 (brs, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 3.49 - 3.40 (m, 3H), 2.93 - 2.78 (m, 2H), 2.47 (s, 3H), 2.27 (s, 3H), 1.02 (br d, J = 6.4 Hz, 3H) 20 / \ , N-N / i rN' A.        / / zn kXj\ / / HN-N 450.1 (400 MHz, DMSO-d6 ) 6 = 13.42 (brs, 1H), 8.18 (s, 1H), 8.08 (d, J = 17.2 Hz, 1H), 7.35 (d, J = 12.8 Hz, 1H), 6.88 (d, J = 17.2 Hz, 1H), 4.65 (br t, J = 6.4 Hz, 1H), 3.94 - 3.78 (m, 2H), 3.74 (s, 3H), 3.61 (s, 3H), 2.97 - 2.84 (m, 1H), 2.74 (dd, J = 8.0, 14.4 Hz, 1H), 2.36 (d, J = 16.0 Hz, 6H), 2.20 (s, 3H), 0.95 (d, J = 6.4 Hz, 3H) 21 n- / vX / °H 7 7 HN-N          \ 582.3 (400 MHz, DMSO-d6 ) 8 = 13.34 (brs, 1H), 8.30 (s, 1H), 7.93 (d, J = 17.0 Hz, 1H), 7.58 (brd, J= 13.6 Hz, 1H), 7.11 (d, J = 17.2 Hz, 1H), 4.90 (Id, J = 6.0, 12.4 Hz, 1H), 4.85 (d, J = 4.4 Hz, 1H), 4.61 (br d, J = 4.0 Hz, 1H), 4.39 (s, 2H), 4.01 - 3.82 (m, 5H), 3.69 (s, 3H), 3.34 (s, 3H), 2.89 (brd, J = 3.2 Hz, 2H), 2.49-2.41 (m, 1H), 1.39 (t, J = 6.4 Hz, 6H), 1.09 (d, J = 5.6 Hz, 3H), 0.97 (br d, J = 6.4 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H) 22 \ O \=\   / = Z "■CKA I 7— ' * C Xz'Z^L z^o T 568.2 (400 MHz, METHANOL-d4 ) 8 = 8.26 (s, 1H), 8.03 (brd, J = 17.2 Hz, 1H), 7.57 (br d, J = 13.2 Hz, 1H), 7.19 (d, J = 17.2 Hz, 1H), 4.62 (br s, 1H), 4.40 (s, 2H), 4.37 - 4.30 (m, 2H), 4.15-4.08 (m, 1H), 4.02 -3.90 (m, 4H), 3.71 (s, 3H), 3.45 (s, 3H), 2.99 - 2.82 (m, 2H), 2.57-2.47 (m, 2H), 1.50 (t, J = 7.2 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 0.99 (br d, J = 6.4 Hz, 3H), 0.88 (br t,J = 7.2 Hz, 3H) 23 — \ \=\   / = Z KnX I 7—    '   > Z^ / V / —z XX x 466.1 (400 MHz, METHANOL-d4 ) 8 = 8.27 (brs, 1H), 8.12 (br d, J= 17.2 Hz, 1H), 7.52 (s, 1H), 6.91 (br d, J = 17.6 Hz, 1H), 4.67 (br d, J = 5.4 Hz, 1H), 3.83 (br s, 2H), 3.78 (s, 3H), 3.65 (s, 3H), 2.90 - 2.72 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 2.22 (br s, 3H), 0.97 (br d, J = 6.4 Hz, 3H) 24 n-\ 7 - HN-N 496.1 (400 MHz, METHANOL-d4 ) 8 = 8.28 (br d, J = 7.2 Hz, 1H), 8.18-8.06 (m, 1H), 7.87 -7.79 (m, 1H), 6.92 (br d, J = 17.2 Hz, 1H), 4.70 (br s, 1H), 4.39 - 4.27 (m, 2H), 3.83 (br s,2H), 3.78 (s, 3H), 3.71 (s, 3H), 3.46 (s, 3H), 2.93 - 2.72 (m, 2H), 2.47 (s, 3H), 2.23 (br s, 3H), 0.99 (br d, J = 5.6 Hz, 3H) 25 o X "O     / ^z /      / —K I z= /  v—\ 538.4 (499 MHz, METHAN0L-d4 ) 5 ppm 8.31 (s, 1 H), 8.05 (d, 1=16.97 Hz, 1 H), 7.32 (d, 1=12.32 Hz, 1 H), 7.22 (d, 1=16.97 Hz, 1 H), 4.68 (brs, 1H), 4.49 (brdd, 1=12.46, 7.26 Hz, 1 H), 4.31 -4.40 (m, 2 H), 4.00 (br d, J=4.65 Hz, 2 H), 3.82 (dd, 1=11.23, 8.21 Hz, 1H), 3.69-3.71 (m, 3 H), 3.67 (br d, 1=4.65 Hz, 1 H), 2.93 - 3.01 (m, 1 H), 2.85 -2.91 (m, 1 H), 2.54 - 2.63 (m, 2H), 2.43 (s, 3H), 1.48 (t, 1=7.12 Hz, 3 H), 1.41 (d, J=6.57 Hz, 3H), 1.02 (d, 1=6.30 Hz, 3 H), 0.94 (t, J=7.12Hz, 3H) 26 / = Z 1    / —    1 zy \_ / —z zr 524.3 (499 MHz, METHAN0L-d4 ) 5 ppm 8.24 (s, 1 H), 8.11 (d, 1=16.97 Hz, 1 H), 7.33 (d, 1=12.87 Hz, 1 H), 7.22 (d, 1=16.70 Hz, 1 H), 4.77-4.83 (m, 1 H), 4.44 - 4.52 (m, 1 H), 4.36 (quind, J=7.02, 7.02, 7.02,7.02, 3.15 Hz, 2 H), 3.90 - 3.97 (m, 1 H), 3.86 (d, 1=13.96 Hz, 1 H), 3.80 - 3.84 (m, 1 H), 3.65 - 3.73 (m, 4 H), 2.90-2.96 (m, 1 H), 2.81 (dd, 1=14.51,7.94 Hz, 1 H), 2.42 (s, 3H), 2.37 (s, 3H), 1.48 (t, J=6.98 Hz, 3H), 1.40 (d, J=6.57 Hz, 3H), 1.04 (d, J=6.30 Hz, 3 H)

[0367] Screen assays

[0368] Biochemical Assay

[0369] CLK and PIM kinase activity evaluation at Reaction Biology Corporation

[0370] The inhibition activities against enzymatic kinases were evaluated at Reaction Biology Corporation (See, www.reactionbiology.com) using HotSpot assay platform, a radiometric assay based on conventional filter-binding assays, that directly measures kinase catalytic activity toward a specific substrate (Anastassiadis T, et al. Comprehensive Assay of Kinase Catalytic Activity Reveals Features of Kinase Inhibitor Selectivity. Nat Biotechnol. 2011, 29:1039-45). Briefly, specific kinase / substrate pairs along with required cofactors were prepared in reaction buffer; 20 mM HEPES pH 7.5, 10 mM MgCh, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM NasV04, 2 mM DTT, 1% DMSO. Compounds are delivered into the reaction, followed ~ 20 minutes later by addition of a mixture of ATP (Sigma, St. Louis MO) and 33P ATP (Perkin Elmer, Waltham MA) to a final concentration of 10 pM. Reactions were carried out at room temperature for 120 min, followed by spotting of the reactions onto P81 ion exchange filter paper (Whatman Inc., Piscataway, NJ). Unbound phosphate was removed by extensive washing of filters in 0.75% phosphoric acid. After subtraction of background derived from control reactions containing inactive enzyme, kinase activity data was expressed as the percent remaining kinase activity in test samples compared to vehicle (dimethyl sulfoxide) reactions. ICso values and curve fits were obtained using Prism (GraphPad Software) and shown in Table 1.

[0371] Table 1. Inhibition of kinase activities of CLK and PIM Ex# CLK1 IC50 (nM) CLK2 IC50 (nM) CLK3 IC50 (nM) CLK4 IC50 (nM) PIM1 IC50 (nM) PIM2 IC50 (nM) PIM3 IC50 (nM) 1 4.0 0.32 22 2.4 0.29 155 3.8 39 1294 11

[0372] Inhibition of cell proliferation assays

[0373] Ba / F3 cells were purchased from DSMZ. The EML4-ALK gene was synthesized at GenScript and cloned into pCDH-CMV-MCS-EFl-Puro plasmid (System Biosciences, Inc.). Ba / F3 EML4-ALK cell line was generated by infecting Ba / F3 cells with lentivirus containing EML4-ALK genes. Stable cell lines were selected by puromycin treatment, followed by IL-3 withdrawal.

[0374] 2000 Ba / F3 EML4-ALK or Ba / F3 +IL3 (Ipg / mL) cells per well were seeded in 384-well white plate and then treated with indicated compounds for 72 hours. Cell proliferation was measured using CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) following the manufacturer’s protocol. IC50 values were determined using Prism software (GraphPad Software, San Diego, CA) and shown in Table 2. Table 2 Ex.# Ba / F3 EML4-ALK IC50 (nM) Ba / F3 +IL3 ICso (nM) 1 <1 2843 18 320 4050 19 39 106 20 894 2692 21 <1 3145 22 <1 847 Ex.# Ba / F3 EML4-ALK ICso (nM) Ba / F3 +IL3 ICso (nM) 23 1353 6461 24 2114 7324 25 46 26 97

Claims

1. A compound of the formulaR7Ior a pharmaceutically acceptable salt thereof, wherein“------” is optionally a carbon-carbon single bond or a carbon-carbon double bond;ring A is a 5- or 6-membered heteroarylene or Ce-Cio arylene;ring B is a 5- or 6-membered heteroarylene;each L is independently -0-, -S-, -S(O)-, -S(O)2-, -N(R6)C(0)-, -C(0)N(R6)-, -N(R6)-, -N(R6)S(O)-, -S(0)N(R6)-, -N(R6)S(O)2-, -S(O)2N(R6)-, or -C(R7)(RS)-, provided that (L)P does not comprise an O-O, S-0, or N-N bond, and the point of covalent attachment of (L)p to -NR3- does not form a -N-N- or a -O-N- bond;each R1 and R2b, when present, is independently deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -0C(0)Ra, -0C(0)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(0)2NRaRb, -0S(0)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)0Rb, -NRaC(0)NRaRb, -NRaS(0)Rb, -NRaS(O)2Rb, -NRaS(0)NRaRb, -NRaS(0)2NRaRb, -C(0)Ra, -C(0)0Ra, -C(0)NRaRb, -PRaRb, -P(0)RaRb, -P(0)2RaRb, -P(0)NRaRb, -P(0)2NRaRh, -P(0)0Ra, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORC, -0C(0)Rc, -0C(0)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -0S(0)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(0)NRcRd, -S(0)2NRcRd, -NRcRd, -NRcC(0)Rd,-N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRd) RdNRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORc, -CN, or -NO2;R2a is deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -0C(0)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(0)NRaRb, -S(0)2NRaRb, -0S(0)NRaRb, -0S(0)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)0Rh, -NRaC(0)NRaRb, -NRaS(0)Rb, -NRaS(0)2Rb, -NRaS(0)NRaRb, -NRaS(0)2NRaRb, -C(0)Ra, -C(O)ORa, -C(0)NRaRb, -PRaRb, -P(0)RaRb, -P(0)2RaRb, -P(0)NRaRb, -P(0)2NRaRb, -P(O)ORa, -P(0)20Ra, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6haloalkyl, -ORC, -0C(0)Rc, -0C(0)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(0)NRcRd, -S(0)2NRcRd, -NRcRd, -NRcC(0)Rd, -N(C(0)Rc)(C(0)Rd), -NRcC(0)0Rd, -NRcC(0)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(0)Rd, -NRcS(0)2Rd, -NRcS(0)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(0)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(0)RcRd, -P(O)2RcRd, -P(0)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2;R3 is H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -ORC, -0C(0)Rc, -0C(0)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(0)NRcRd, -S(0)2NRcRd, -NRcRd, -NRcC(0)Rd, -N(C(0)Rc)(C(0)Rd), -NRcC(0)0Rd, -NRcC(0)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(0)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(0)0Rc, -C(0)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(0)RcRd, -P(O)2RcRd, -P(0)NRcRd, -P(0)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2;each R4 is independently deuterium, halogen, C1 -Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -0C(0)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(0)NRaRb, -S(0)2NRaRb, -0S(0)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)0Rb, -NRaC(0)NRaRb, -NRaS(0)Rb, -NRaS(0)2Rb, -NRaS(0)NRaRb, -NRaS(0)2NRaRb, -C(0)Ra, -C(O)ORa, -C(0)NRaRb, -PRaRb, -P(0)RaRb, -P(O)2RaRb,-P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-C& alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORe, -0C(0)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(0)NReRf, -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(0)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(0)Re, -C(0)0Re, -C(0)NReRf, -PReRf, -P(0)ReRf, -P(0)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(0)20Re, -CN, or -NO2;R5 is H, deuterium, -C(O)RC, -C(O)ORC, -C(0)NRcRd, -P(0)2RcRd, -P(O)2NRcRd, -P(O)2ORc, or -S(O)2ORc;each R6, when present, is independently H, deuterium, C1-C6 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10membered heteroaryl is independently optionally substituted by -ORC, -0C(0)Rc, -0C(0)NRcRd, -0C(=NRd)NRcRd, -OS(O)RC, -OS(O)2RC, -0S(0)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(0)NRcRd, -S(0)2NRcRd, -NRcRd, -NRcC(0)Rd, -N(C(0)Rc)(C(0)Rd), -NRcC(0)0Rd, -NRcC(0)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(0)Rd, -NRcS(0)2Rd, -NRcS(0)NRcRd, -NRcS(0)2NRcRd, -C(O)RC, -C(0)0Rc, -C(0)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(0)RcRd, -P(0)2RcRd, -P(0)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2;each R7 and R8, is independently H, deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10membered heteroaryl, -ORa, -0C(0)Ra, -0C(0)NRaRh, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(0)NRaRb, -S(0)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)0Rb, -NRaC(0)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(0)NRaRb, -NRaS(0)2NRaRb, -C(0)Ra, -C(O)ORa, -C(0)NRaRb, -PRaRb, -P(0)RaRb, -P(O)2RaRb, -P(0)NRaRb, -P(0)2NRaRb, -P(0)0Ra, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cwaryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORe, -0C(0)Re, -0C(0)NReRf, -OS(O)Re, -OS(O)2Re, -0S(0)NReRf, -0S(0)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(0)NReRf, -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(0)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(0)Re, -C(0)0Re,-C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or two of R7 and R8, taken together with the carbon or carbons to which they are attached, optionally combine to form a C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl formed when two of R7 and R8 are taken together is independently optionally substituted by -ORe, -0C(0)Re, -0C(0)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -0S(0)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(0)NReRf, -S(0)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(0)Rf, -NReS(0)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(0)Re, -C(0)0Re, -C(0)NReRf, -PReRf, -P(0)ReRf, -P(0)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(0)0Re, -P(0)20Re, -CN, or -NO2;each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, Ci-Ce alkylene-Ce-Go aryl, 5- to 10-membered heteroaryl, and Ci-Ce alkylene-5- to 10-membered heteroaryl, or Ra and Rb or Rc and Rd or Re and Rf, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, G-Goaryl, Ci-Cealkylene-Ce-Cioaryl, 5- to 10-membered heteroaryl, or Ci-Ce alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OCi-Ce alkyl, -0C(0)-(H or Ci-C6 alkyl), -0C(0)N(H or Ci-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or Ci-C6 alkyl), -OS(O)2-(H or Ci-C6 alkyl), -OS(O)N(H or Ci-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or Ci-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or Ci-C6 alkyl), -S(O)(H or Ci-C6 alkyl), -S(O)2(H or Ci-C6 alkyl), -S(O)N(H or Ci-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(0)2N(H or Ci-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or Ci-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or Ci-C6 alkyl)C(O)-(H or Ci-C6 alkyl), -N(H or Ci-C6 alkyl)C(O)O(H or Ci-C6 alkyl), -N(H or Ci-C6 alkyl)C(O)N(H or Ci-C6 alkyl)2, -N(H or Ci-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or Ci-C6 alkyl)S(O)-(H or G-G, alkyl), -N(H or G-C6 alkyl)S(O)2(H or Ci-C6 alkyl), -N(H or Ci-C6 alkyl)S(O)N(H or Ci-C6 alkyl)2, -N(H or Ci-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or Ci-C6 alkyl)S(O)2N(H or Ci-C6 alkyl)2, -N(H or Ci-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(0)-(H or Ci-C6 alkyl), -C(0)0(H or Ci-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or Ci-C6 alkyl)2, -P(C2-C6 alkylene), -P(0)(H or Ci-C6 alkyl)2, -P(O)(C2-C6 alkylene), -P(O)2(H or Ci-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(0)N(H or G-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(0)2N(H or Ci-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(0)0(H or Ci-C6 alkyl), -P(0)20(H or Ci-C6 alkyl), -CN, or -NO2;m is 0, 1,2, or 3;n is 0, 1, or 2;p is 3, 4, 5, 6, or 7; andq is 0, 1, or 2;wherein the compound is not of the formula2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula IIII wherein each “------” is independently optionally a carbon-carbon single bond or a carboncarbon double bond, and ring A is a 5-membered heteroarylene.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the formula IIIIIIwhereinring B is a 5-membered heteroarylene;X1, X2, and X3 are each independently -0-, -S-, =C(H)-, =C(R])-, -N(H)-, -N(R’)-, or =N- and ring A is a 5-membered heteroarylene, provided that at least one of X1, X2, and X3 is not =C(H)-, or =C(R’)-; andeach “------” is independently optionally a carbon-carbon single bond or a carboncarbon double bond.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the formula IIIR7IVwhereinY1 and Y2 are each independently -0-, -S-, =C(H)-, =C(R2h)-, -N(H)-, -N(R2b)-, or =N- and ring B is a 5-membered heteroarylene, provided that at least one of Y1 and Y2 is not =C(H)-, or =C(Rab)-; and“------” in ring A is optionally a carbon-carbon single bond or a carbon-carbondouble bond, one “------” in ring B is a carbon-carbon single bond, and one “------” inring B is a carbon-carbon double bond.

5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroarylene selected from the group consisting ofwherein each “ represents a point of covalent attachment.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroarylene selected from the group consisting ofwherein each “*s\sxsxs'” represents a point of covalent attachment.

7. The compound of any one of the preceding claims, or a pharmaceutically acceptable saltthereof, wherein ring A is a 5-membered heteroarylene selected from the group consisting ofwherein each “ vaaat" represents a point of covalent attachment.

8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenylene, and m is 0, 1, or 2.

9. The compound of any one of claims 1, 2, or 8, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenylene, and m is 0 or 1.

10. The compound of any one of claims 1,2, 8, or 9, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenylene, m is 1, and R1 is methyl, ethyl, hydroxy ethyl, F, Cl, or Br.

11. The compound of any one of claims 1, 2, or 8 to 10, or a pharmaceutically acceptable saltthereof, wherein ring A iswherein each          represents a point of covalent attachment.

12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroarylene.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroarylene selected from the group consisting ofwherein each “ v / wv'” represents a point of covalent attachment.

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable saltthereof, wherein ring B is a 5-membered heteroarylene of the formulawherein each “« / vw*” represents a point of covalent attachment.

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is H, methyl, ethyl, isopropyl, or cyclopropyl.

16. The compound of any one of the preceding claims, or a pharmaceutically acceptable saltthereof, wherein R4 is H, fluoro, chloro, or methyl.

17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Rs is H.

18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each L is independently -0-, -C(R7)(R8)-, or -N(R6)-, provided that (L)p does not contain an -O-O-, -N-0-, or -N-N- bond and the point of attachment of (L)p to -NR3- does not form an -0-N- or -N-N- bond.

19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein (L)p is -O(C(R7)(R8))2- or -O(C(R7)(R8))s-.

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H, methyl, or ethyl.

21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R7 and R8 is independently H or methyl.

22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein (L)p is -0-C((H)(CHs))-CH2-.

23. The compound of claim 1, selected from the group consisting of (2S)-l-{(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol; (2S)-2-{(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(propan-2-yr)oxy]-2,8,10,ll,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl Jpropan-1 -ol;(2S)-l-[(10S,17 / )-16-ethoxy-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-2,8,10,l 1,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3’,4'-j:4",3”-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;(2S)-1 - [(1 OS, 17 / )-16-ethoxy-6-(methoxymethyl)- 8,10-dimethyl- 12-(propan-2-yl)-2,8,10,ll,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;(25)-1 - {(105,17 / 7)-6-(methoxymethyl)-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / 3',4'- / 4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;(25)-1 - [(105,17 / 7)-12-cyclopropyl-16-ethoxy-6-(methoxymethyl)-8,1O-dimethyl-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / 3',4'- / 4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl]propan-2-ol;(25)-1 - {(105,1 IE) - 6 - [difluoro(methoxy )methyl] -12-ethyl- 8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4’- / 4",3”-m] [ 1,4]oxazacyclopentadecin-14-yl }propan-2-ol;(25)-1 - {(105,17E)-6- [(difluoromethoxy)methyl] -12-ethyl- 8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4’- / 4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;(25)-1-{( 105,17 / 7)-6-(ethoxymethyl)-12-ethyl-8,10-dimethyl-16-L(propan-2-yl)oxyJ-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / 3',4'- / 4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;(25)-1 - {(105,1 IE) - 6 - [(cyclopropyloxy)methy 1]-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,ll,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4: / 3',4'- / 4”,3"->7][l,4]oxazacyclopentadecin-14-yl}propan-2-ol;(25)-1 - [(105,17 / 7)-16-ethoxy-12-ethyl-8,10-dimethyl-6- {[(propan-2-yl)oxy ]methyl} -2,8,10,11,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4: / 3',4'- / 4", 3"-n] [ 1,4]oxazacyclopentadecin-14-yl]propan-2-ol;(25)-1 - {(105,17 / 7)-6- [(difluoromethoxy)methyl] -16-ethoxy-12-ethyl- 8,10-dimethy 1-2,8,10,11,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / 3', 4'- / 4", 3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;(25)-1 - [(105,17 / 7)-16-ethoxy-6-(ethoxy methyl)-12-ethyl-20-fluoro- 8,10-dimethyl-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'- / 4”,3"->7][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;(25)-1 - {(105,17£)-6-(ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl-16- [(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4’- / 4",3"-ra][l,4]oxazacyclopentadecin-14-yl}propan-2-ol;(25)-1 - {(105,17 / 7)-12-ethyl-19-fluoro-6-(methoxymethyl)- 8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14Z7-3,5-ethenotripyrazolo[3,4- / 3',4'- / 4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;(25)-1 - {(105,17£')-6-(ethoxymethyl)-12-ethyl-19-fluoro-8,10-dimethyl-16- [(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-147 / -3,5-ethenotripyrazolo[3,4- / :3',4’- / 4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;(25)-l-[( 105,17£)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / : 3',4'- / 4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl]propan-2-ol;(25)-1 - [(105,1 IE)-16-ethoxy-12-ethyl-19-fluoro-6-(methoxy methyl)- 8,10-dimethyl-2,8,10,ll,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4: / 3',4'- / 4”,3"->7][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;(105,17£j-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,ll,12,13,14-hexahydro-877-3,5-ethenotripyrazolo[3,4- / 3',4'- / 4",3"-;7][l,4]oxazacyclopentadecine;(105,17E)-20-fluoro-6,8,10,12,14,16-hexamethyl-2,10,ll,12,13,14-hexahydro-877-3,5-ethenotripyrazoloL3,4- / :3',4'- / 4”,3"-nJ[l,4Joxazacyclopentadecine;(25)-1 - {(105,1 IE) -12-ethyl-20-fluoro-6-(methoxymethyl)- 8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-147 / -3,5-ethenotripyrazolo[3,4- / :3',4'- / 4",3"-n] [ 1,4]oxazacyclopentadecin-14-yl} propan-2-ol;(25)-l-[(105,17E)-16-ethoxy-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / 3',4'- / 4”,3"-n] [ 1,4]oxazacyclopentadecin- 14-yl]propan-2-ol;(105,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2,10,ll,12,13,14-hexahydro-877-3,5-ethenotripyrazolo[3,4; / :3',4’- / 4”,3"-n][l,4]oxazacyclopentadecine;(105,17E)-20-chloro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,ll,12,13,14-hexahydro-8 / / -3,5-ethenotripyrazolo[3,4- / :3',4'- / 4",3"- / 7][l,4]oxazacyclopentadecine;(25)-2-[(105,17£)-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / 3’,4'- / 4”,3”-;?] [l,4]oxazacyclopentadecin-14-yl]propan-l-ol; and(25)-2-1( 105,17E)-16-ethoxy-20-fluoro-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / 3',4'- / 4",3”- / 7][l,4]oxazacyclopentadecin-14-yl]propan-l-ol; or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound of any one of the preceding claims, and optionally one or more excipients.

25. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of claims 1 to 23, or a pharmaceutical compositionof claim 24.

26. A compound according to any one of claims 1 to 23, for use in a method of treating disease in a subject.

27. Use of a compound according to any one of claims 1 to 23, in the manufacture of a medicament for the treatment of disease in a subject.