Indazole-based macrocycles

Abstract

The present disclosure relates to indazole macrocycles, pharmaceutical compositions containing the macrocycles, and methods of using the macrocycles to treat diseases 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 is incorporated herein by reference. Technical Field

[0002] This disclosure relates to indazole macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of treating diseases such as cancer using macrocyclic compounds. Background Technology

[0003] Protein kinases are tightly regulated signaling proteins that coordinate the activation of signal transduction cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning, G et al., The protein kinase complement of the human genome, Science, 2002, 298:1912-34). Dysregulation of kinase activity is associated with many diseases, including cancer and cardiovascular diseases, degenerative diseases, immune diseases, infectious diseases, inflammatory diseases, and metabolic diseases (Levitzki, A., Protein kinase inhibitors as a therapeutic modality, Acc. Chem. Res., 2003, 36:462-469). The molecular basis for various diseases includes gain-of-function and loss-of-function mutations of kinases, gene amplification and deletion, splicing changes and translocations (Wilson, LJ et al., New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome., Cancer Res., 2018, 78:15-29). The crucial role of kinases in cancer and other diseases makes them attractive targets for drug development. Sixty-two small molecule kinase inhibitors have been approved, 55 of which are used for targeted cancer therapy (Roskoski R. Jr., Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2021 Update, Pharmacol Res 2021, 165:105463). Despite the significant success of kinase inhibitors in targeted cancer therapy, the development of treatment resistance remains a challenge for small molecule kinase inhibitors.Acquired secondary mutations within the kinase domain during treatment often lead to treatment resistance to kinase inhibitors (Pottier, C et al., Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy, Cancer (Basel), 2020, 12:731). Treatment resistance can also arise from tolerant / persistent cell subpopulations that survive in the presence of treatment. Different processes contribute to the emergence of resistant and persistent cells, including pathway rebound through the unwinding of negative feedback loops, transcriptional rewiring mediated by chromatin remodeling, and autocrine / paracrine communication between tumor cells and within the tumor microenvironment (Swayden, M et al., Tolerant / Persister Cancer Cells and the Path to Resistance to Targeted Therapy, Cells, 2020, 9, 2601). Therefore, there is a need to invent kinase inhibitors that can not only target kinase-induced oncogenic drivers and overcome the most common drug resistance mutations, but also resist resistant and persistent cancer cells to overcome drug resistance, thereby achieving better efficacy and longer-lasting disease control.

[0004] Non-small cell lung cancer (NSCLC) is a leading cause of cancer death worldwide (World Health Organization, Cancer Fact Sheet 2017). Activating EGFR mutations have been reported to occur in approximately 10% to 15% of adenocarcinoma cases in Caucasian patients, compared to 50% 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 common EGFR alterations found in NSCLC tumors are short-frame deletions in exon 19 (del19) of the EGFR gene and a single missense mutation L858R in exon 21 (Konduri, K et al., EGFR fusions as Novel Therapeutic Targets in Lung Cancer, Cancer Discovery 2016, 6:601-11).

[0005] Anaplastic lymphoma kinase (ALK) is a member of the insulin-like tyrosine kinase receptor family involved in tumorigenesis in several tumor types. Approximately 5% of non-small cell lung cancer (NSCLC) patients carry rearrangements in the ALK gene (Soda, M. et al., Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer, Nature, 2007, 448, 561-566). ALK inhibitors have been approved by the FDA as standard first-line and second-line treatment for ALK-rearranged NSCLC patients. However, because complete response to ALK inhibitors is rare, almost all ALK-rearranged NSCLC patients inevitably acquire resistance to ALK inhibitors, leading to tumor recurrence. Resistance mechanisms include both ALK-independent and ALK-dependent processes. ALK-independent resistance mechanisms include activation of alternative pathways (e.g., EGFR, c-MET, KRAS, and AXL) or transformation into small cell lung cancer (Gainor, JF et al., Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer, *Cancer Discovery*, 2016, 6, 1118-1133). Although five ALK inhibitors have been approved, their clinical ability to overcome ALK-independent resistance mechanisms is limited. Therefore, it is necessary to develop next-generation multi-targeted ALK inhibitors that can target not only primary ALK fusion genes and secondary ALK resistance mutations, but also mechanisms associated with resistant, persistent cancer cells, to achieve better efficacy and longer duration of response.

[0006] The proviral integration of Moloney murine leukemia virus (PIM) kinase is an oncogenic serine / threonine kinase whose phosphorylation regulates multiple substrates of several cancer features, including tumor metabolism, survival, metastasis, immune evasion, and inflammation (Toth RK, Warfel NA, Targeting PIM Kinases to Overcome Therapeutic Resistance in Cancer. Molecular Cancer Ther. 2021, 20(1):3-10). PIM kinase interacts with many major oncogens, including p53 stabilization, synergistic effects with c-Myc, and significant parallel signaling with PI3K / Akt. Abnormal PIM kinase activity plays an important role in the mechanisms of resistance to chemotherapy, radiotherapy, anti-angiogenic therapy and targeted therapy, which provides a theoretical basis for combination targeted therapy strategies to achieve more durable patient responses (Malone, T et al., Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer. Pharmacol Ther, 2020 Mar;207).

[0007] Cdc-like kinases (CLKs) are evolutionarily conserved bispecific kinases capable of phosphorylating serine, threonine, and tyrosine residues. CLKs catalyze the phosphorylation of SR proteins and the serine- and arginine-rich splicing factor 1-12 (SRSF1-12), which regulate the spliceosome molecular machinery (Martín 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 hallmark of cancer. High-frequency mutations in 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., *New England Journal of Medicine*, 2016, 374:2209-2221). Furthermore, mutations in splicing-related genes have been found in various solid cancers, including lung cancer, breast cancer, and pancreatic cancer (Dvinge, H. et al., RNA splicing factors as oncoproteins and tumor suppressors., *Nature Reviews Cancer*, 2016, 16: 413-430). Modulating pre-mRNA splicing by inhibiting CLK kinase is an attractive anti-tumor strategy, especially for cancers that exhibit aberrant pre-mRNA splicing.

[0008] Therefore, it is necessary to develop a new generation of multi-target ALK inhibitors. These inhibitors should have potent inhibitory effects on oncogenic driver ALK fusion genes and point mutations, other emerging and known ALK resistance mutations, as well as emerging resistance targets in drug-resistant / persistent cancer cells (such as PIM kinase and CLK kinase). Summary of the Invention

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

[0010]

[0011] Where R 1 R 2a R 2b R 3 R 4 R 5 R 7 R 8 A, B, L, m, n, p, and q are as described in this article.

[0012] In one aspect, this disclosure provides a compound of formula II or a pharmaceutically acceptable salt thereof.

[0013]

[0014] Where R 1 R 2a R 2b R 3 R 4 R 5 R 7 R 8 A, B, L, m, n, p, q and each " As described in this article.

[0015] In one aspect, this disclosure provides a compound of formula III or a pharmaceutically acceptable salt thereof.

[0016]

[0017] Where R 2a R 2b R 3 R 4 R 5 R 7 R 8 A, B, L, X 1 X 2 X 3 p, q and each " As described in this article.

[0018] In one aspect, this disclosure provides a compound of formula IV or a pharmaceutically acceptable salt thereof.

[0019]

[0020] Where R 2a R 3 R 4 R 5 R 7 R 8 X1 X 2 X 3 Y 1 Y 2 A, B, L, p, q and each " As described in this article.

[0021] In another aspect, this disclosure relates to a pharmaceutical composition comprising at least one compound of formula (I)-(IV) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to this disclosure may further comprise a pharmaceutically acceptable excipient.

[0022] In another aspect, this disclosure relates to a compound of formula (I)-(IV) used as a medicament or a pharmaceutically acceptable salt thereof.

[0023] In another aspect, this disclosure relates to a method of treating a disease such as cancer, comprising administering to a subject requiring such treatment an effective amount of at least one compound of formula (I)-(IV) or a pharmaceutically acceptable salt thereof.

[0024] In another aspect, this disclosure relates to the use of a compound of formula (I)-(IV) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases such as cancer, and the use of such compounds and salts for treating such diseases.

[0025] In another aspect, this disclosure relates to a method for inhibiting one or more of aberrant ALKs (including oncogenic driver ALK fusion genes (e.g., EML4-ALK) and ALK resistance mutations), aberrant PIM kinases, and / or aberrant CLK kinases), said method comprising contacting cells containing one or more of aberrant ALKs (including one or more oncogenic driver ALK fusion genes 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 this disclosure, said contact being in vitro, ex vivo, or in vivo.

[0026] Additional embodiments, features, and advantages of this disclosure will become apparent from the following detailed description and through practice of this disclosure. The compounds of this disclosure may be described as embodiments of any of the following enumerated terms. It should be understood that any embodiment described herein may be used in conjunction with any other embodiment described herein, provided that such embodiments do not contradict each other.

[0027] 1. A compound of the following formula,

[0028]

[0029] Or its pharmaceutically acceptable salt, wherein

[0030] “ "Optionally, it is a carbon-carbon single bond or a carbon-carbon double bond;

[0031] Ring A is a 5- or 6-membered heteroaryl group or a C6-C ring. 10 Alpha-aryl;

[0032] Ring B is a 5- or 6-membered heteroaryl group;

[0033] Each L is independently -O-, -S-, -S(O)-, -S(O)2-, -N(R) 6 )C(O)-、-C(O)N(R 6 )-、N(R 6 ), N(R 6 )S(O)-、-S(O)N(R 6 )-、-N(R 6 S(O)2-、-S(O)2N(R) 6 - or -C(R) 7 (R) 8 -, the condition is (L) p It does not contain OO, SO, or NN bonds, and (L) p With -NR 3 - Covalent connection points do not form -NN- or -ON- bonds;

[0034] When it exists, each R 1 and R 2b Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a S(O)R a S(O)2R a S(O)NR a R b S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R bNR a C(O)R b NR a C(O)OR b NR a C(O)NR a R b NR a S(O)R b NR a S(O)2R b -NR a S(O)NR a R b NR a S(O)2NR a R b C(O)R a C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b 、P(O)NR a R b -P(O)2NR a R b P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c OC(O)NR c R d OC (=NR) d )NR c R d -OS(O)R c OS(O)2R c OS(O)NR c R d -OS(O)2NR c R d SR c S(O)R c -S(O)2R c -S(O)NR cR d S(O)2NR c R d NR c R d NR c C(O)R d 、N(C(O)R c )(C(O)R d ), NR c C(O)OR d NR c C(O)NR c R d NR c C(=NR d )NR c R d NR c S(O)R d NR c S(O)2R d NR c S(O)NR c R d NR c S(O)2NR c R d C(O)R c C(O)OR c C(O)NR c R d C(=NR) d R d NR c R d PR c R d P(O)R c R d P(O)2R c R d 、P(O)NR c R d P(O)2NR c R d P(O)OR c P(O)2OR c -CN or NO2 substitution;

[0035] R 2a It is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a OC(O)R a -OC(O)NR aR b -OS(O)R a -OS(O)2R a -SR a S(O)R a S(O)2R a S(O)NR a R b S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b NR a C(O)R b NR a C(O)OR b NR a C(O)NR a R b NR a S(O)R b NR a S(O)2R b -NR a S(O)NR a R b NR a S(O)2NR a R b C(O)R a C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b 、P(O)NR a R b -P(O)2NR a R b P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)Rc 、OC(O)NR c R d 、OC(=NR d )NR c R d 、-OS(O)R c 、OS(O)2R c 、OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、S(O)2NR c R d 、NR c R d 、NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、NR c C(O)OR d 、NR c C(O)NR c R d 、NR c C(=NR d )NR c R d 、NR c S(O)R d 、NR c S(O)2R d 、NR c S(O)NR c R d 、NR c S(O)2NR c R d 、C(O)R c 、C(O)OR c 、C(O)NR c R d 、-C(=NR d )NR c R d 、PR c R d 、P(O)R c R d 、P(O)2R c R d 、P(O)NR c Rd P(O)2NR c R d P(O)OR c -P(O)2OR c -CN or NO2 substitution;

[0036] R 3 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1C6 alkyl, C2-C6 alkenyl, C2C6 ynyl, C3-C6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally -OR c -OC(O)R c OC(O)NR c R d OC (=NR) d )NR c R d OS(O)R c OS(O)2R c OS(O)NR c R d -OS(O)2NR c R d -SR c S(O)R c -S(O)2R c -S(O)NR c R d S(O)2NR c R d NR c R d NR c C(O)R d -N(C(O)R c )(C(O)R d ), NR c C(O)OR d NR c C(O)NR c R d NR c C(=NR d )NR c R d NR c S(O)R d NR c S(O)2R d NR cS(O)NR c R d NR c S(O)2NR c R d C(O)R c C(O)OR c C(O)NR c R d -C(=NR) d )NR c R d -PR c R d P(O)R c R d P(O)2R c R d 、P(O)NR c R d P(O)2NR c R d P(O)OR c -P(O)2OR c -CN or -NO2 substitution;

[0037] Each R 4 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6C 10 Aryl, 5- to 10-membered heteroaryl, -OR a OC(O)R a -OC(O)NR a R b -OS(O)R a OS(O)2R a SR a S(O)R a S(O)2R a S(O)NR a R b S(O)2NR a R b -OS(O)NR a R b OS(O)2NR a R b -NR a R b NR a C(O)R b NR a C(O)OR b -NR a C(O)NR a Rb -NR a S(O)R b NR a S(O)2R b -NR a S(O)NR a R b NR a S(O)2NR a R b -C(O)R a C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b 、P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or OR. e OC(O)R e OC(O)NR e R f -OS(O)R e OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e S(O)R e -S(O)2R e S(O)NR e R f S(O)2NR e R f NR e R f -NR e C(O)R f -NR e C(O)OR f NRe C(O)NR e R f NR e S(O)R f -NR e S(O)2R f NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e C(O)OR e C(O)NR e R f -PR e R f -P(O)R e R f P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f P(O)OR e P(O)2OR e -CN or NO2 substitution;

[0038] R 5 It is H, deuterium, C(O)R c C(O)OR c C(O)NR c R d P(O)2R c R d P(O)2NR c R d P(O)2OR c or -S(O)2OR c ;

[0039] When it exists, each R 6 Independently, it is H, deuterium, C1C6 alkyl, C2-C6 alkenyl, C2C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein C1C6 alkyl, C2-C6 alkenyl, C2C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally -OR c -OC(O)R c OC(O)NRc R d 、OC(=NR d )NR c R d 、OS(O)R c 、OS(O)2R c 、OS(O)NR c R d 、-OS(O)2NR c R d 、SR c 、S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、S(O)2NR c R d 、NR c R d 、NR c C(O)R d 、N(C(O)R c )(C(O)R d )、NR c C(O)OR d 、NR c C(O)NR c R d 、NR c C(=NR d )NR c R d 、NR c S(O)R d 、NR c S(O)2R d 、NR c S(O)NR c R d 、NR c S(O)2NR c R d 、C(O)R c 、C(O)OR c 、C(O)NR c R d 、C(=NR d )NR c R d 、PR c R d 、P(O)R c R d 、P(O)2R c R d 、P(O)NR c R d 、P(O)2NRc R d P(O)OR c P(O)2OR c -CN or NO2 substitution;

[0040] Each R 7 and R 8 Independently, it is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6C 10 Aryl, 5- to 10-membered heteroaryl, -OR a OC(O)R a -OC(O)NR a R b -OS(O)R a OS(O)2R a SR a S(O)R a S(O)2R a S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b OS(O)2NR a R b -NR a R b NR a C(O)R b NR a C(O)OR b NR a C(O)NR a R b NR a S(O)R b NR a S(O)2R b -NR a S(O)NR a R b NR a S(O)2NR a R b -C(O)R a C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2Ra R b 、P(O)NR a R b -P(O)2NR a R b P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or OR. e OC(O)R e OC(O)NR e R f -OS(O)R e OS(O)2R e -OS(O)NR e R f OS(O)2NR e R f -SR e S(O)R e -S(O)2R e S(O)NR e R f S(O)2NR e R f NR e R f -NR e C(O)R f NR e C(O)OR f NR e C(O)NR e R f NR e S(O)R f -NR e S(O)2R f NR e S(O)NR e R f -NR e S(O)2NR e R f C(O)R e C(O)OR e C(O)NR e R f -PR e R f -P(O)Re R f P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f P(O)OR e P(O)2OR e -CN or NO2 substitution; or R 7 and R 8 The two carbons in R, together with one or more carbons to which they are attached, may optionally combine to form C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein when R 7 and R 8 When two of them combine to form a C3-C6 cycloalkyl or a 3- to 7-membered heterocycloalkyl group, each hydrogen atom in the resulting C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl group is independently and optionally ORed. e OC(O)R e OC(O)NR e R f -OS(O)R e OS(O)2R e OS(O)NR e R f OS(O)2NR e R f -SR e S(O)R e -S(O)2R e S(O)NR e R f S(O)2NR e R f NR e R f NR e C(O)R f NR e C(O)OR f NR e C(O)NR e R f NR e S(O)R f -NR e S(O)2R f NR e S(O)NR e R f NR e S(O)2NR e R f C(O)R e C(O)OR eC(O)NR e R f -PR e R f -P(O)R e R f P(O)2R e R f 、P(O)NR e R f -P(O)2NR e R f P(O)OR e -P(O)2OR e -CN or NO2 substitution;

[0041] Each R a R b R c R d R e and R f Independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl and C1C6 alkylene-5- to 10-membered heteroaryl, or R a and R b Or R c and R d Or R e and R f Together with the carbon atom it is attached to, it forms 3 to 7-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3 to 7-membered heterocyclic alkyl, and C6-C 10 Aryl, C1-C6 alkylene-C6C 10Each hydrogen atom in an aryl, 5- to 10-membered heteroaryl, or C1C6 alkylene group is independently and optionally replaced by a deuterium, halogen, C1-C6 alkyl, C1C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O) (H or C1-C6 alkyl), -OC(O)N (H or C1-C6 alkyl)2, -OC(O)N (C2-C6 alkylene), OS(O)- (H or C1C6 alkyl), OS(O)2- (H or C1-C6 alkyl), OS(O)N (H or C1-C6 alkyl)2, OS(O)N (C2-C6 alkylene), OS(O)2N (H or C1-C6 alkyl)2, OS( O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), S(O)(H or C1C6 alkyl), S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, S(O)N(C2-C6 alkylene), S(O)2N(H or C1C6 alkyl)2, S(O)2N(C2C6 alkylene), N(H or C1C6 alkyl)2, N(C2C6 alkylene), N(H or C1C6 alkyl)C(O)-(H or C1-C6 alkyl), N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), N(H or C1C6 alkyl)C(O)N( H or C1-C6 alkyl)2, N(H or C1C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1C6 alkyl)S(O)-(H or C1C6 alkyl), -N(H or C1C6 alkyl)S(O)2(H or C1C6 alkyl), N(H or C1C6 alkyl)S(O)N(H or C1C6 alkyl)2, N(H or C1C6 alkyl)S(O)N(C2C6 alkylene), N(H or C1C6 alkyl)S(O)2N(H or C1C6 alkyl)2, N(H or C1C6 alkyl)S(O)2N(C2C6 alkylene), -C(O)-(H or C1C6 alkyl), -C(O)O (H or C1C6 alkyl), C(O)N(C2C6 alkylene), -P(H or C1C6 alkyl)2, -P(C2C6 alkylene), -P(O)(H or C1C6 alkyl)2, -P(O)(C2C6 alkylene), P(O)2(H or C1C6 alkyl)2, P(O)2(C2C6 alkylene), P(O)N(H or C1C6 alkyl)2, P(O)N(C2C6 alkylene), -P(O)2N(H or C1C6 alkyl)2, -P(O)2N(C2C6 alkylene), P(O)O(H or C1C6 alkyl), -P(O)2O(H or C1C6 alkyl), -CN or -NO2 substitution;

[0042] m is 0, 1, 2, or 3;

[0043] n is 0, 1, or 2;

[0044] p is 3, 4, 5, 6, or 7; and

[0045] q is 0, 1, or 2;

[0046] The compound described does not have the following formula

[0047] , , , , , , , , , or .

[0048] 2. A compound of clause 1 or a pharmaceutically acceptable salt thereof having formula II

[0049]

[0050] Each of these " "Independently and optionally, it is a carbon-carbon single bond or a carbon-carbon double bond, and ring A is a 5-membered heteroaryl group."

[0051] 3. A compound of clause 1 or 2 or a pharmaceutically acceptable salt thereof having formula III

[0052]

[0053] in

[0054] Cyclone B is a 5-membered heteroaryl group;

[0055] X 1 X 2 and X 3 Each is independently -O-, -S-, =C(H)-, =C(R)-. 1 -, -N(H)-, -N(R) 1 )- or = N- and ring A is a 5-membered heteroaryl group, provided that X 1 X 2 and X 3 At least one of them is not =C(H)- or =C(R) 1 )-;and

[0056] Each " "Independently and optionally, it is a carbon-carbon single bond or a carbon-carbon double bond."

[0057] 4. A compound of clause 1 or 2 or a pharmaceutically acceptable salt thereof having formula III

[0058]

[0059] in

[0060] Y 1 and Y 2 Each is independently -O-, -S-, =C(H)-, =C(R)-. 2b -, -N(H)-, -N(R) 2b )- or = N- and ring B is a 5-membered heteroaryl group, provided that Y 1 and Y 2 At least one of them is not =C(H)- or =C(R) ab )-;and

[0061] In ring A, " "Optionally, it is a carbon-carbon single bond or a carbon-carbon double bond, one of the bonds in ring B." "It is a carbon-carbon single bond, and one of the bonds in ring B." It is a carbon-carbon double bond.

[0062] 5. The compound of any one of the preceding clauses or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0063] , , , , , , , , , , , , , , , , , , , , , , , , and ,

[0064] Each of these " " " indicates a covalent connection point.

[0065] 6. The compound of any one of the preceding clauses or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0066] , , , , , , , , , , , , , , , and ,

[0067] Each of these " " " indicates a covalent connection point.

[0068] 7. The compound of any of the preceding clauses or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0069] , , , , , , and ,

[0070] Each of these " " " indicates a covalent connection point.

[0071] 8. The compound of clause 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is phenylene and m is 0, 1 or 2.

[0072] 9. A compound or a pharmaceutically acceptable salt thereof from any of the provisions of clauses 1, 2 or 8, wherein ring A is phenylene and m is 0 or 1.

[0073] 10. A compound or a pharmaceutically acceptable salt thereof from any of the clauses 1, 2, 8 or 9, wherein ring A is phenylene, m is 1, and R 1 It is methyl, ethyl, hydroxyethyl, F, Cl, or Br.

[0074] 11. A compound or a pharmaceutically acceptable salt thereof of any of Clauses 1, 2, or 8 to 10, wherein ring A is

[0075] or

[0076] Each of these " " " indicates a covalent connection point.

[0077] 12. The compound of any of the preceding clauses or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroaryl group.

[0078] 13. The compound of any one of the preceding clauses or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroaryl group selected from the group consisting of:

[0079] , , , , , , and ,

[0080] Each of these " " " indicates a covalent connection point.

[0081] 14. The compound of any of the preceding clauses or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroaryl group of the following formula.

[0082] , , , , , or ,

[0083] Each of these " " " indicates a covalent connection point.

[0084] 15. The compound or a pharmaceutically acceptable salt thereof of any of the preceding clauses, wherein R 3 It is H, methyl, ethyl, isopropyl, or cyclopropyl.

[0085] 16. The compound or a pharmaceutically acceptable salt thereof of any of the preceding clauses, wherein R 4 It is H, fluorine, chlorine or methyl.

[0086] 17. The compound or a pharmaceutically acceptable salt thereof of any of the preceding clauses, wherein R 5 It is H.

[0087] 18. The compound of any of the preceding clauses or a pharmaceutically acceptable salt thereof, wherein each L is independently -O-, -C(R) 7 (R) 8 )- or N(R 6 -, the condition is (L) p It does not contain -OO-, -NO-, or -NN- bonds, and (L) p With -NR 3- Connection points do not form -ON- or -NN- bonds.

[0088] 19. The compound or a pharmaceutically acceptable salt thereof of any of the preceding clauses, wherein (L) p It is -O(C(R) 7 (R) 8 ))2-or-O(C(R) 7 (R) 8 ))3-.

[0089] 20. The compound of any of the preceding clauses or a pharmaceutically acceptable salt thereof, wherein, when present, R 6 It is H, methyl, or ethyl.

[0090] 21. The compound or a pharmaceutically acceptable salt thereof of any of the preceding clauses, wherein each R 7 and R 8 It is either H or methyl on its own.

[0091] 22. The compound or a pharmaceutically acceptable salt thereof of any of the preceding clauses, wherein (L) p It is -OC((H)(CH3))-CH2-.

[0092] 23. The compound of any of the preceding clauses is selected from the group consisting of: (2S)-1-{(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0093] (2S)-2-{(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-1-ol;

[0094] (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0095] (2S)-1-[(10S,17E)-16-ethoxy-6-(methoxymethyl)-8,10-dimethyl-12-(prop-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0096] (2S)-1-{(10S,17E)-6-(methoxymethyl)-8,10,12-trimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0097] (2S)-1-[(10S,17E)-12-cyclopropyl-16-ethoxy-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0098] (2S)-1-{(10S,17E)-6-[difluoro(methoxy)methyl]-12-ethyl-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0099] (2S)-1-{(10S,17E)-6-[(difluoromethoxy)methyl]-12-ethyl-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0100] (2S)-1-{(10S,17E)-6-(ethoxymethyl)-12-ethyl-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0101] (2S)-1-{(10S,17E)-6-[(cyclopropoxymethyl]-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0102] (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-6-{[(prop-2-yl)oxy]methyl}-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecane-14-yl]prop-2-ol;

[0103] (2S)-1-{(10S,17E)-6-[(difluoromethoxy)methyl]-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0104] (2S)-1-[(10S,17E)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0105] (2S)-1-{(10S,17E)-6-(ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0106] (2S)-1-{(10S,17E)-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0107] (2S)-1-{(10S,17E)-6-(ethoxymethyl)-12-ethyl-19-fluoro-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0108] (2S)-1-[(10S,17E)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0109] (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0110] (10S,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine heterocyclic pentadecene;

[0111] (10S,17E)-20-fluoro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine heterocyclic pentadecene;

[0112] (2S)-1-{(10S,17E)-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0113] (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0114] (10S,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine heterocyclic pentadecene;

[0115] (10S,17E)-20-chloro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine-heterocyclic pentadecene;

[0116] (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-1-ol; and

[0117] (2S)-2-[(10S,17E)-16-ethoxy-20-fluoro-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-vinylbridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-1-ol;

[0118] Or its pharmaceutically acceptable salt.

[0119] 24. A pharmaceutical composition comprising a compound of any of the preceding clauses and optionally one or more excipients.

[0120] 25. A method of treating a subject's disease, comprising administering a therapeutically effective amount of a compound of any one of clauses 1 to 23 or a pharmaceutical composition of clause 24.

[0121] 26. The compound of any one of the clauses 1 to 23, in a method of treating a disease in a subject.

[0122] 27. Use of a compound of any one of the provisions 1 to 23 in the preparation of a medicament for treating a disease of a subject. Detailed Implementation

[0123] Before further describing this disclosure, it should be understood that this disclosure is not limited to the specific embodiments described, as these embodiments can certainly vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of this disclosure will be limited only by the appended claims.

[0124] For the sake of brevity, the disclosures of publications (including patents) cited in this specification are incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents, applications, published applications, and other publications mentioned herein are incorporated herein by reference in their entirety. If a definition set forth in this section contradicts or otherwise conflicts with a definition set forth in a patent, application, or other publication incorporated herein by reference, the definition set forth in this section shall prevail over the definition incorporated herein by reference.

[0125] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural indicators unless the context clearly specifies otherwise. It should also be noted that claims may be drafted to exclude any optional elements. Therefore, this statement is intended to provide a precondition for the use of exclusive terms such as “unique,” ​​“solely,” or negative limitations in the formulation of claims.

[0126] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-restrictive sense.

[0127] To provide a more concise description, some quantitative expressions given herein are not limited by the term "about". It should be understood that, whether or not the term "about" is explicitly used, each quantity given herein refers to an actual given value and also to an approximation of that given value based on what a person of ordinary skill in the art would reasonably infer, including equivalents and approximations due to the experimental and / or measurement conditions of that given value. Whenever yield is expressed as a percentage, the yield refers to the actual mass of the entity obtained relative to the maximum amount of the entity obtainable under specific stoichiometric conditions. Unless otherwise stated, concentrations given as percentages refer to mass ratios.

[0128] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. While any methods and materials similar to or equivalent to those described and materials herein may also be used in the practice or testing of this disclosure, preferred methods and materials are described hereafter. All publications referenced herein are incorporated by way of citation to disclose and describe methods and / or materials relating to the cited publications.

[0129] Unless otherwise stated, the methods and techniques described in the embodiments herein are generally performed according to conventional methods well known in the art and described in various general and more specific references cited and discussed throughout this specification. See, for example, Loudon, Organic Chemistry, 4th ed., New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., Wiley-Interscience, 2001.

[0130] The chemical nomenclature of the compounds described in this article is typically generated using commercially available ACD / Labs 2022.2.3 (Advanced Chemistry Development, Inc.) or ChemDraw Professional 22.2.0.3300 (PerkinElmer Informatics, Inc.).

[0131] The chemical structures used herein and described in conjunction with the various embodiments described herein, "", "and" Each represents a covalently bonded point of a chemical group or chemical structure, where the identifier is shown as being connected to an adjacent chemical group or chemical structure. For example, in the hypothetical chemical structure AB, where A and B are connected by a covalent bond, in some embodiments, the portion of AB defined by group or chemical structure A may be... , or It indicates that "- "- "and" Each of the symbols represents a bond connection point with A and a covalent bond connection point with B. Alternatively, in some embodiments, the portion of AB defined by the group or chemical structure B can be represented by… , or It means that among them, " "- "and" Each of the symbols represents a bond connection point with B and a covalent bond connection point with A.

[0132] It should be understood that, for clarity, certain features of this disclosure described in the context of individual embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of this disclosure described in the context of individual embodiments may also be provided individually or in any suitable sub-combination. All combinations of embodiments relating to chemical groups represented by variables are specifically covered by this disclosure and disclosed herein, just as each and every combination is individually and explicitly disclosed herein, provided that such combinations contain stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). Furthermore, all sub-combinations of chemical groups listed in embodiments describing such variables are also specifically covered by this disclosure and disclosed herein, just as each and every such sub-combination of chemical groups is individually and explicitly disclosed herein.

[0133] Chemical definition

[0134] The term "alkyl" refers to a straight-chain or branched monovalent hydrocarbon group. The term "alkylene" refers to a straight-chain or branched divalent hydrocarbon group. In some embodiments, it may be advantageous to limit the number of atoms in "alkyl" or "alkylene" to a specific atomic range, such as C1-C. 20 Alkyl or C1-C 20 Alkylene, C1-C 12 Alkyl or C1-C 12Alkylene or C1-C6 alkylene or C1-C6 alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that, in accordance with those skilled in the art and the teachings provided herein, would be considered equivalent to any of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n-propylene ((-CH2-)3), isopropylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), etc. It should be understood that alkyl or alkylene groups may be unsubstituted or substituted as described herein. Alkyl or alkylene groups may be substituted by any substituents in the various examples described herein, including one or more of such substituents.

[0135] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having one or more double bonds. The term "alkenylene" refers to a straight-chain or branched divalent hydrocarbon group having one or more double bonds. In some embodiments, it may be advantageous to limit the number of atoms in "alkenyl" or "alkenylene" to a specific atomic range, such as C2-C. 20 alkenyl or C2-C 20 alkenyl, C2-C 12 alkenyl or C2-C 12 Alkenyl or C2-C6 alkenyl or C2-C6 alkenyl. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Examples of alkenyl groups include ethenylene (or vinylene) (-CH=CH-), n-propenyl (-CH=CHCH2-), isopropenyl (-CH=CH(CH3)-), etc. The term includes cis and trans isomers and mixtures thereof. It should be understood that alkenyl or alkenyl groups can be unsubstituted or substituted as described herein. Alkenyl or alkenyl groups can be substituted by any substituents in the various embodiments described herein, including one or more of such substituents.

[0136] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having one or more triple bonds. The term "ynynyl" refers to a straight-chain or branched divalent hydrocarbon group having one or more triple bonds. In some embodiments, it may be advantageous to limit the number of atoms in "alkynyl" or "ynynyl" to a specific atomic range, such as C2-C. 20 Alkyne group or C2-C 20 alkyne group, C2-C 12 Alkyne group or C2-C 12The alkynyl or C2-C6 alkynyl or C2-C6 alkynyl group. Examples of alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), etc. It should be understood that the alkynyl or alkynyl group can be unsubstituted or substituted as described herein. The alkynyl or alkynyl group can be substituted by any substituent in the various embodiments described herein, including one or more of such substituents.

[0137] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic monovalent carbon ring. The term "cycloalkylene" refers to a saturated or partially saturated monocyclic or polycyclic divalent carbon ring. In some embodiments, it may be advantageous to limit the number of atoms in "cycloalkyl" or "cycloalkylene" to a specific atomic range, for example, having 3 to 12 ring atoms. Polycyclic carbon rings include fused, bridged, and spirocyclic polycyclic systems. Illustrative examples of cycloalkyl include monovalent groups of the following entities, while cycloalkylene includes divalent groups of the following entities in the form of suitable moiety:

[0138] , , , , , , , , , ,

[0139] , , , ,

[0140] , , , , and .

[0141] In particular, the cyclopropyl moiety can be derived from the structural formula Description. Specifically, the cyclopropyl moiety can be derived from the structural formula... Description. It should be understood that cycloalkyl or cycloalkylene groups may be unsubstituted or substituted as described herein. Cycloalkyl or cycloalkylene groups may be substituted by any substituents in the various embodiments described herein, including one or more of such substituents.

[0142] The term "halogen" or "halogenated" refers to chlorine, fluorine, bromine, or iodine.

[0143] The term "haloalkyl" refers to an alkyl group having one or more halosubstituents. Examples of haloalkyl groups include -CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F. The term "haloalkylene" refers to an alkyl group having one or more halosubstituents. Examples of haloalkyl groups include -CF2-, -C(H)(F)-, -C(H)(Br)-, -CH2CF2-, and -CH2C(H)(F)-.

[0144] The term "aryl" refers to a monovalent, all-carbon monocyclic or fused-ring polycyclic group having a fully conjugated π-electron system. The term "arylene" refers to a divalent, all-carbon monocyclic or fused-ring polycyclic group having a fully conjugated π-electron system. In some embodiments, it may be advantageous to limit the number of atoms in "aryl" or "arylene" to a specific atomic range, such as monovalent, all-carbon monocyclic or fused-ring polycyclic groups with 6 to 14 carbon atoms (C6-C4). 14 Aryl groups, monovalent all-carbon monocyclic or fused-ring polycyclic groups with 6 to 10 carbon atoms (C6-C50, C ... 10 Aryl groups, divalent all-carbon monocyclic or fused-ring polycyclic groups with 6 to 14 carbon atoms (C6-C50, C ... 14 arylene groups, divalent all-carbon monocyclic or fused-ring polycyclic groups with 6 to 10 carbon atoms (C6-C50, C ... 10 Aryl groups (including, but not limited to, phenyl, naphthyl, and anthracene). Examples of aryl groups (including, but not limited to, phenylene, naphthylene, and anthracene). It should be understood that aryl or aryl groups can be unsubstituted or substituted as described herein. Aryl or aryl groups can be substituted by any substituents in the various embodiments described herein, including one or more of such substituents.

[0145] The term "heterocyclic alkyl" refers to a saturated or partially saturated monovalent monocyclic or polycyclic structure having one or more non-carbon ring atoms. The term "heterocyclic alkylene" refers to a saturated or partially saturated divalent monocyclic or polycyclic structure having one or more non-carbon ring atoms. In some embodiments, it may be advantageous to limit the number of atoms in a "heterocyclic alkyl" or "heterocyclic alkylene" to a specific range of ring atoms, such as 3 to 12 ring atoms (3 to 12-membered), or 3 to 7 ring atoms (3 to 7-membered), or 3 to 6 ring atoms (3 to 6-membered), or 4 to 6 ring atoms (4 to 6-membered), 5 to 7 ring atoms (5 to 7-membered), or 4 to 10 ring atoms (4 to 10-membered). In some embodiments, it may be advantageous to limit the number and type of cyclic heteroatoms in a "heterocyclic alkyl" or "heterocyclic alkylene" to a specific range or type of heteroatoms, such as 1 to 5 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Polycyclic systems include fused, bridged, and spirocyclic systems. The ring structure may optionally contain an oxo group or an imino group on the carbocyclic member, or up to two oxo groups on the thiocyclic member. Illustrative examples of heterocyclic alkyl groups include monovalent groups of the following entities, while heterocyclic alkylene groups include divalent groups of the following entities in the form of suitable bonded groups:

[0146] , , , , , , , , , , , ,

[0147] , , , , , , , , , ,

[0148] , , , , , , , ,

[0149] , , , , and .

[0150] A three-membered heterocyclic ring may contain at least one heteroatom ring atom, wherein the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of three-membered heterocyclic groups include monovalent and divalent groups of ethylene oxide, aziridine, and cyclothioethane. A four-membered heterocyclic ring may contain at least one heteroatom ring atom, wherein the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocyclic groups include monovalent and divalent groups of aziridine, oxobutane, and thiobutane. A five-membered heterocyclic ring may contain at most four heteroatom ring atoms, wherein (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 at most four ring atoms are nitrogen. Non-limiting examples of five-membered heterocyclic groups include monovalent and divalent groups of pyrrolidine, tetrahydrofuran, 2,5-dihydro-1H-pyrrole, pyrazolidine, thiazolylidine, 4,5-dihydro-1H-imidazolium, dihydrothiophene-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolyl-2-one, pyrrolidine-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolane-2-one, and oxazolidine-2-one. A six-membered heterocycle may contain up to four heteroatomic ring atoms, wherein (a) at least one ring atom is oxygen and sulfur, and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur, and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocyclic groups include monovalent or divalent groups of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxacyclohexane-2-one, piperazine-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A "heterobicyclic" is a fused bicyclic system comprising a heterocycle fused to a cycloalkyl group or another heterocycle.

[0151] It should be understood that heterocyclic alkyl or heterocyclic alkyl groups may be unsubstituted or substituted as described herein. Heterocyclic alkyl or heterocyclic alkyl groups may be substituted by any substituents in the various embodiments described herein, including one or more of such substituents.

[0152] The term "heteroaryl" refers to a fully unsaturated monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (having a ring structure with ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having 3 to 12 ring atoms per heterocycle. The term "hybrid aryl" refers to a dicyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (having a ring structure with ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having 3 to 12 ring atoms per heterocycle. In some embodiments, it may be advantageous to limit the number of ring atoms in a "heteroaryl" or "hybrid aryl" to a specific range of atomic members, such as 5- to 10-membered heteroaryls or 5- to 10-membered hybrid aryls. In some cases, a 5- to 10-membered heteroaryl may be a monocyclic or fused bicyclic ring having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, such as N, O, or S. In some cases, 5- to 10-membered heteroaryl groups can be monocyclic or fused bicyclic with 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 the carbocyclic member, or at most two oxo groups on the sulfide ring member. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent groups of the following entities, while examples of 5- to 10-membered heteroaryl groups include divalent groups of the following entities in the form of suitable bonding groups:

[0153] , , , , , , , , , ,

[0154] , , , , , , , ,

[0155] , , , , , ,

[0156] , , , and .

[0157] In some embodiments, the "monocyclic" heteroaryl group may be a five- or six-membered aromatic heterocycle. A five-membered heteroaryl or heteroalkylene group may contain up to four heteroatomic ring atoms, wherein (a) at least one ring atom is oxygen and sulfur, and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur, and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include monovalent groups of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetraazole. Non-limiting examples of five-membered heteroalkylene groups include divalent groups of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetraazole. A six-membered heteroaryl or heteroaryl group may contain up to four heteroatom ring atoms, wherein (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 groups of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of six-membered heteroaryl groups include divalent groups of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” or “bicyclic heteroaryl” is a fused bicyclic system comprising a heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent groups of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthidine, 1,8-naphthidine, isoquinoline-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzi[d]imidazolium, benzo[d]oxazole, and benzo[d]thiazole. Non-limiting examples of bicyclic heteroaryl groups include divalent groups of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthidine, 1,8-naphthidine, isoquinoline-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzi[d]imidazolium, benzo[d]oxazole, and benzo[d]thiazole.

[0158] In particular, the pyrazole moiety can be derived from the structural formula Description. In particular, an example of the pyrazolyl group can be derived from the structural formula. describe.

[0159] It should be understood that heteroaryl or heteroalkylene groups may be unsubstituted or substituted as described herein. Heteroaryl or heteroalkylene groups may be substituted by any substituent in the various embodiments described herein, including one or more of such substituents.

[0160] The term "oxo" refers to the carbonyl oxygen. For example, a cyclopentyl group substituted with an oxo group is cyclopentanone.

[0161] The term "substituted" means that the specified group or portion contains one or more substituents. The term "unsubstituted" means that the specified group does not contain any substituents. When the term "substituted" is used to describe a structural system, substitution means that substitution occurs at any position on the system where valence is permissible. In some embodiments, "substituted" means that the specified group or portion contains one, two, or three substituents. In other embodiments, "substituted" means that the specified group or portion contains one or two substituents. In still other embodiments, "substituted" means that the specified group or portion contains one substituent.

[0162] Any formula described herein is intended to represent a compound of that structure, as well as certain variations or forms. For example, the formulas given herein are intended to include racemic forms, or one or more enantiomers, diastereomers, or geometric isomers, or mixtures thereof. Additionally, any formulas given herein are also intended to refer to hydrates, solvates, or polymorphs of such compounds, or mixtures thereof.

[0163] Any formulas given herein are intended to represent both the unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are substituted with atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, […]. 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds labeled with this type of isotope can be used for metabolic studies (preferably using...) 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) Detection or imaging techniques [e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT)], including drug or substrate tissue distribution determination, or for use in patient radiotherapy. Additionally, heavier isotopes such as deuterium (i.e., 2H) Substitution can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents by performing the schemes or examples and preparations disclosed below. For example, certain chemical entities of formulas (I)-(III) can be isotopically labeled such that they comprise one or two deuterium isotopes. Exemplary isotope-labeled (e.g., deuterated) groups include

[0164] , and

[0165] Each of these " " " indicates a covalent connection point.

[0166] Some chemical entities of formulas (I)-(IV) can be described in two or more tautomer forms. Any and all alternative tautomers are included within the scope of these formulas, and it should not be inferred whether a chemical entity exists in its described tautomer form. It should be understood that some chemical entities described herein can exist in different tautomer forms. Those skilled in the art will readily understand that tautomers can generally be considered the same compound due to rapid interconversion. Examples of tautomers include, but are not limited to, enol-keto tautomers, amine-imine tautomers, etc.

[0167]

[0168] When applied to a class of substituents in this paper, where j>i is named "(atom)". i -(atom) j "This refers to embodiments of the present disclosure in which each and every one of the number of atomic members from i to j (inclusive) is implemented independently. For example, the terms C1-C3 independently refer to embodiments having one carbon member (C1), embodiments having two carbon members (C2), and embodiments having three carbon members (C3).

[0169] When more than one such possibility is permitted, any disubstituent mentioned herein is intended to cover a variety of connection possibilities. For example, reference to disubstituent -JK- (where J≠K) herein refers to such a disubstituent in which J is connected to a first substituent member and K is connected to a second substituent member, and it also refers to such a disubstituent in which J is connected to a second substituent member and K is connected to a first substituent member.

[0170] It should be understood that some compounds described herein include one or more positions that can exist as stereoisomers. For example, some compounds described herein include one or more carbon atoms that can exist in one or more stereoisomeric arrangements. It should be understood that carbon atoms that can exist in stereoisomeric arrangements, without showing any stereoisomeric arrangements, include every possible stereoisomeric arrangement as disclosed. For example, when a carbon atom has four groups that can be prioritized according to the Cahn-Ingold Prelog rule known to those skilled in the art, it will be understood herein as: not describing a specific stereochemical definition (as shown in the structure on the left), but also describing two possible enantiomers (S) and (R) as follows:

[0171]

[0172] According to the Cahn-Ingold Prelog rule, R a >R b >R c >R d .

[0173] This disclosure also includes pharmaceutically acceptable salts of compounds represented by formulas (I)-(IV), preferably those compounds and specific compounds illustrated herein, pharmaceutical compositions comprising such salts, and methods of using such salts.

[0174] "Pharmaceutically acceptable salt" is intended to mean a salt of the free acid or base of the compounds described herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See also SM Berge et al., "Pharmaceutical Salts," *J. Pharm. Sci.*, 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a subject without excessive toxicity, irritation, or anaphylactic reactions. The compounds described herein may have sufficiently acidic groups, sufficiently basic groups, both types of functional groups, or more than one group of each type, and thus react with many inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts.

[0175] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, hexanoates, heptarates, propionates, oxalates, malonates, succinates, octanoates, sebacic acid, fumarates, maleates, and butynediene-1. ,4-Diosyl salt, hexyn-1,6-diosyl salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985.

[0176] For compounds of formulas (I)-(IV) containing basic nitrogen, pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, by treating the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, nitric acid, boric acid, phosphoric acid, etc.; or organic acids such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, hydroxyethanesulfonic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauryl acid, etc. Acids, pyranoside (e.g., glucuronic acid or galacturonic acid), α-hydroxy acids (e.g., mandelic acid, citric acid or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid, 2-acetoxybenzoic acid, naphtholic acid or cinnamic acid), sulfonic acids (e.g., laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid); or any compatible mixture of acids, such as those given by way of example herein, and any other acids and mixtures thereof considered equivalents or acceptable substitutes according to the ordinary level of skill in the art.

[0177] This disclosure also relates to pharmaceutically acceptable prodrugs of compounds of formulas (I)-(IV), and treatment methods using such pharmaceutically acceptable prodrugs. The term "prodrug" refers to a precursor of a specified compound that, upon administration to a subject, produces the compound in vivo through a chemical or physiological process (e.g., solvent degradation or enzymatic cleavage) or under physiological conditions (e.g., the prodrug is converted to a compound of formulas (I)-(IV) upon reaching physiological pH). A "pharmaceuticalally acceptable prodrug" is a non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. Illustrative procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs," H. Bundgaard, Elsevier, 1985.

[0178] This disclosure also relates to pharmaceutically active metabolites of compounds of formulas (I)-(IV), and the use of such metabolites in the methods of this disclosure. "Pharmaceutically active metabolite" refers to the pharmacologically active product of a compound of formulas (I)-(IV) or its salts metabolized in vivo. The prodrugs and active metabolites of the compounds can be determined using conventional techniques known or available in the art. See, for example, Bertolini et al., *Journal of Medicinal Chemistry*, 1997, 40, 2011-2016; Shan et al., *Journal of Pharmacy*, 1997, 86(7), 765-767; Bagshawe, *Drug Dev. Res.*, 1995, 34, 220-230; Bodor, *Advances in Drug Research*, 1984, 13, 255-331; Bundgaard, *Design of Prodrugs* (Elsevier Press, 1985); and Larsen, *Design and Application of Prodrugs*. "of Prodrugs, Drug Design and Development" (edited by Krogsgaard-Larsen et al., Harwood Academic Publishers, 1991).

[0179] Representative Examples

[0180] In some embodiments, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0181]

[0182] Where R 1 R 2a R 2b R 3 R 4 R 5 R 7 R 8 A, B, L, m, n, p, and q are as described in this article.

[0183] In some embodiments, this disclosure provides a compound of formula II or a pharmaceutically acceptable salt thereof.

[0184]

[0185] Where R 1 R 2a R 2b R 3 R 4 R 5 R 7 R 8 A, B, L, m, n, p, q and each " As described in this article.

[0186] In some embodiments, this disclosure provides a compound of formula III or a pharmaceutically acceptable salt thereof.

[0187]

[0188] Where R 2a R 2b R 3 R 4 R 5 R 7 R 8 A, B, L, X 1 X 2 X 3 p, q and each " As described in this article.

[0189] In some embodiments, this disclosure provides a compound of formula IV or a pharmaceutically acceptable salt thereof.

[0190]

[0191] Where R 2a R 3 R 4R 5 R 7 R 8 X 1 X 2 X 3 Y 1 Y 2 A, B, L, p, q and each " As described in this article.

[0192] In some embodiments, one, two, or more hydrogen atoms in each compound contained in the structures of formulas (I)-(IV) are replaced by deuterium atoms.

[0193] In some embodiments, ring A is a 5- to 10-membered heteroaryl group. In some embodiments, ring A is a 5- or 6-membered heteroaryl group. In some embodiments, ring A is a 5-membered heteroaryl group. In some embodiments, ring A is a 6-membered heteroaryl group.

[0194] In some embodiments, ring A is a 5- or 6-membered heteroaryl, such as a monocyclic 5- or 6-membered heteroaryl, wherein each hydrogen atom in the 5- or 6-membered heteroaryl as described herein is independently and optionally R 1 Replace, R 1 It is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NRa C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NRc R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0195] In some embodiments, ring A is a pyridine group, an isoxazolyl group, an isothiazolyl group, an pyridinezolate group, or an imidazolate group, wherein each hydrogen atom in the pyridine group, isoxazolyl group, isothiazolyl group, pyridinezolate group, and imidazolate group is independently and optionally R 1 Replace, R 1 It is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -ORa -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c Rd -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0196] In some embodiments, ring A is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl, wherein each hydrogen atom in pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl is independently and optionally R 1 Replace, R 1 It is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a Rb -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR cC(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0197] In some embodiments, ring A is a 5- or 6-membered heteroaryl, such as a monocyclic 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl as described herein is optionally surrounded by 1, 2, or 3 R groups. 1 (m R) 1 The substitutions are each independently selected from the group consisting of: deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2Ra -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN and -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c Rd 、-OS(O)R c 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=NR d )NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=NR d )NR c R d 、-PR c R d 、-P(O)R c R d 、-P(O)2R c R d 、-P(O)NR c R d 、-P(O)2NR c R d 、-P(O)ORc -P(O)2OR c Replaced with -CN or -NO2.

[0198] In some embodiments, ring A is a pyridine group, an isoxazolyl group, an isothiazolyl group, an pyridine group, or an imidazolyl group, wherein each is optionally surrounded by 1, 2, or 3 R groups. 1 (m R) 1 The substitutions are each independently selected from the group consisting of: deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b-P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d-NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN and -NO2 substitution.

[0199] In some embodiments, ring A has the following formula

[0200]

[0201] in" "Optionally, it is a carbon-carbon single bond or a carbon-carbon double bond, each..." " represents a covalent connection point, and R 1 And m as described herein. In some embodiments, ring A has the following formula

[0202]

[0203] in" "Optionally, it is a carbon-carbon single bond or a carbon-carbon double bond, each..." "" indicates a covalent connection point, ring A is a 5-membered hypoheteroaryl group, and R 1 And m as described in this article.

[0204] In some embodiments, ring A has the following formula

[0205]

[0206] in" "Optionally, it is a carbon-carbon single bond or a carbon-carbon double bond, each..." " indicates a covalent connection point, X" 1 X 2and X 3 Each is independently -O-, -S-, =C(H)-, =C(R)-. 1 -, -N(H)-, -N(R) 1 )- or =N-, provided that X 1 X 2 and X 3 At least one of them is not =C(H)- or =C(R) 1 )-, ring A is a 5-membered heteroaryl group, and R 1 And m as described in this article.

[0207] In some embodiments, ring A is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl, wherein each is optionally surrounded by 1, 2, 3, 4, or 5 R groups. 1 (m R) 1 The substitutions are each independently selected from the group consisting of: deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b-NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NRc R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0208] 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.

[0209] In some embodiments, ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0210] , , , , , , , , , , , , , , , , , , , , , , , , and ,

[0211] Each of these " " represents a covalently coupled point, and each R 1 Independently as described in this article.

[0212] In some embodiments, ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0213] , , , , , , , , , , , , , , , and ,

[0214] Each of these " " represents a covalently coupled point, and each R 1 Independently as described in this article.

[0215] In some embodiments, ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0216] , , and ,

[0217] Each of these " " represents a covalently coupled point, and each R 1 Independently as described in this article.

[0218] In some embodiments, ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0219] , , , , , , and ,

[0220] Each of these " " represents a covalently coupled point, and each R 1 Independently as described in this article.

[0221] In some embodiments, ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0222] , , , , , , and ,

[0223] Each of these " " represents a covalently coupled point, and each R 1 Independently as described in this article.

[0224] In some embodiments, ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0225] , , , , , and ,

[0226] Each of these " " represents a covalent connection point, and R 1 As described in this article.

[0227] In some embodiments, ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0228] , , , , , , , , , , , , and ,

[0229] Each of these " " represents a covalently coupled point, and each R 1 Independently as described in this article.

[0230] In some embodiments, each R 1 Independently, it is deuterium, halogen, or C1-C6 alkyl, wherein each hydrogen atom in the C1-C6 alkyl group is independently a optionally substituted deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)Rc -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2. In some embodiments, R 1 It is each R 1 Independently, it is methyl, ethyl, F, Cl, Br, or ,in" " " indicates a covalent connection point.

[0231] In some embodiments, ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0232] , , , , , , , , , , , , , and ,

[0233] Each of these " " " indicates a covalent connection point.

[0234] In some embodiments, ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0235] , , , , , , and ,

[0236] Each of these " " " indicates a covalent connection point.

[0237] In some embodiments, ring A is a 5-membered heteroaryl group selected from the group consisting of:

[0238] , , , , and ,

[0239] Each of these " " " indicates a covalent connection point.

[0240] In some embodiments, ring A is C6-C 10 The aryl group is m, which is 0, 1, or 2.

[0241] In some embodiments, ring A is C6-C 10 Aromatic compounds, including C6-C as described herein. 10 Alpha-aryl groups are optionally enclosed by 1 or 2 R groups. 1 (m R) 1 The substitutions are each independently selected from the group consisting of: deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR aR b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN and -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NRc C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0242] In some embodiments, ring A is phenylene or naphthylene, wherein each is optionally surrounded by 1, 2, 3, or 4 R groups. 1 (m R) 1 The substitutions are each independently selected from the group consisting of: deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a Rb -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR.c 、-OC(O)R c 、-OC(O)NR c R d 、-OC(=NR d )NR c R d 、-OS(O)R c 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=NR d )NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=NR d )NR c R d 、-PR c R d 、-P(O)R c R d 、-P(O)2Rc R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0243] In some embodiments, ring A is C6-C 10 arylene, and m as defined herein. In some embodiments, ring A is phenylene, and m as defined herein.

[0244] In some embodiments, ring A is a phenylene, wherein the phenylene is optionally surrounded by one or two R atoms as described herein. 1 (m R) 1 The substitutions are each independently selected from the group consisting of: deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NRa R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN and -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d-NR c C(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0245] In some embodiments, ring A is phenylene, m is 1, and R 1 It can be, for example, a halogenated (e.g., F, Cl, or Br) or optionally substituted (e.g., hydroxyl-substituted to form a hydroxyethyl) C1-C6 alkyl group (e.g., methyl or ethyl). In some embodiments, ring A is phenylene and m is 0, 1, or 2. In some embodiments, ring A is phenylene, m is 1, and R 1 It is methyl, ethyl, hydroxyethyl, F, Cl, or Br.

[0246] In some embodiments, ring A is

[0247] or

[0248] Each of these " " " indicates a covalent connection point.

[0249] In some embodiments, ring B is a 5- to 10-membered heteroaryl group or a C6-C group. 10 Aromatic. In some embodiments, ring B is a monocyclic or bicyclic C6-C 10 A 5- to 10-membered heteroaryl group, which may be monocyclic or bicyclic.

[0250] In some embodiments, ring B is a 5- or 6-membered heteroaryl group. In some embodiments, ring B is a 5- or 6-membered heteroaryl group. In some embodiments, ring B is a 5-membered heteroaryl group. In some embodiments, ring B is a 6-membered heteroaryl group.

[0251] In some embodiments, ring B is a 5- or 6-membered heteroaryl, such as a monocyclic 5- or 6-membered heteroaryl, wherein each hydrogen atom in the 5- or 6-membered heteroaryl as described herein is independently and optionally R 2b Replace, R 2b It is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NRa S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR cR d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0252] In some embodiments, ring B is an isoxazolyl, isothiazolyl, or pyrazolyl group, wherein each hydrogen atom in the isoxazolyl, isothiazolyl, or pyrazolyl group and the imidazolyl group is independently and optionally R 2b Replace, R 2b It is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a Rb -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=NR d )NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=NR d )NR c R d 、-PR c R d 、-P(O)R c R d 、-P(O)2R c R d 、-P(O)NR c R d 、-P(O)2NR c R d 、-P(O)OR c 、-P(O)2OR cReplaced with -CN or -NO2.

[0253] In some embodiments, ring B is an isoxazolyl, isothiazolyl, or pyrazolyl group, wherein each hydrogen atom in the isoxazolyl, isothiazolyl, or pyrazolyl group is independently and optionally R 2b Replace, R 2b It is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2Ra R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c Rd -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0254] In some embodiments, ring B is a 5- or 6-membered heteroaryl group, such as a monocyclic 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group as described herein is optionally surrounded by one or two R groups. 2b (n R) 2b The substitutions are each independently selected from the group consisting of: deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)Rb -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c Rd -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0255] In some embodiments, ring B is an isoxazolyl, isothiazolyl, or pyrazolyl group, wherein each is optionally surrounded by one or two R groups. 2b (n R) 2b The substitutions are each independently selected from the group consisting of: deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C10 Aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)2NR a R b , -P(O)OR a , -P(O)2OR a-CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d-C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0256] In some embodiments, ring B has the following formula:

[0257]

[0258] Where Y 1 and Y 2 Each is independently -O-, -S-, =C(H)-, =C(R)-. 2b -, -N(H)-, -N(R) 2b )- or =N-, a " in ring B "It is a carbon-carbon single bond, and one of the bonds in ring B." It is a carbon-carbon double bond.

[0259] 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.

[0260] In some embodiments, ring B is a 5-membered heteroaryl group selected from the group consisting of:

[0261] , , , , , , and ,

[0262] Each of these " " represents a covalently coupled point, and each R 2a and R 2b Independently as described in this article.

[0263] In some embodiments, R 2aIt is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2ORa -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c Rd -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c Replaced with -CN or -NO2.

[0264] In some embodiments, R 2a It is a halogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 ynyl group, C3-C6 cycloalkyl group, 3- to 7-membered heterocyclic alkyl group, or C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NRc R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2 are substituted. In some embodiments, R 2a It is methyl, ethyl, methylmethoxy, methylethoxy, methylisopropoxy, methylcyclopropoxy, methyl-difluoromethoxy, or difluoromethylmethoxy.

[0265] In some embodiments, R 2b It is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NRa R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)Rc 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=NR d )NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=NR d )NR c R d 、-PR c R d 、-P(O)R c R d 、-P(O)2R c R d 、-P(O)NR c R d 、-P(O)2NR c R d 、-P(O)OR c 、-P(O)2ORc -CN or -NO2 are substituted. In some embodiments, R 2b It is methyl or ethyl.

[0266] In some embodiments, ring B is a 5-membered heteroaryl group selected from the group consisting of:

[0267] , , , , , or ,

[0268] Each of these " " " indicates a covalent connection point.

[0269] In some embodiments, ring B is a 5-membered heteroaryl group selected from the group consisting of:

[0270] , , , , or ,

[0271] Each of these " " " indicates a covalent connection point.

[0272] In some embodiments, R 3 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) d )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2Rc -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR d )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) d )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2 are substituted. In some embodiments, R 3 It is H or C1-C6 alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally -OR c、-OC(O)R c 、-OC(O)NR c R d 、-OC(=NR d )NR c R d 、-OS(O)R c 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=NR d )NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=NR d )NR c R d 、-PR c R d 、-P(O)R c R d 、-P(O)2R c Rd -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2 are substituted. In some embodiments, R 3 It is H or a C1-C6 alkyl group. In some embodiments, R 3 It is H or methyl. In some embodiments, R 3 It is H, methyl, ethyl, isopropyl, or cyclopropyl.

[0273] 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.

[0274] In the embodiments, the compound comprises a portion of the following formula.

[0275] , or ,

[0276] Where R 4 and R 5 As defined in this article, and each " " " indicates a covalent connection point.

[0277] In some embodiments, each R 4 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a Rb -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f-S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2 are substituted. In some embodiments, each R 4 Independently, it is deuterium, halogen, or C1-C6 alkyl. In some embodiments, each R 4 It is H, fluorine, chlorine or methyl.

[0278] In some embodiments, R 5 It is H, deuterium, -C(O)R c -C(O)OR c -C(O)NR c R d -P(O)2R c R d -P(O)2NR c R d -P(O)2OR c or -S(O)2OR c In some embodiments, R 5It is H or deuterium. In some embodiments, R 5 It is H. In some embodiments, R 5 It is -C(O)R c -C(O)OR c -C(O)NR c R d -P(O)2R c R d -P(O)2NR c R d -P(O)2OR c or -S(O)2OR c .

[0279] In the embodiments, the compound comprises a portion of the following formula.

[0280] , , , or ,

[0281] Each of these " " " indicates a covalent connection point.

[0282] In some embodiments, each L is independently -O-, -S-, -S(O)-, -S(O)2-, -N(R)-. 6 )C(O)-、-C(O)N(R 6 )-、-N(R 6 )-、-N(R 6 )S(O)-、-S(O)N(R 6 )-、-N(R 6 S(O)2-、-S(O)2N(R) 6 - or -C(R) 7 (R) 8 -, the condition is (L) p It does not contain OO, SO, or NN keys. In some embodiments, each L is independently -C(R) 7 (R) 8 -, -C(O)-, -O- or -N(R)- 6 -, the condition is (L) p Does not contain -OO- or -ON(R) 6 )-key, and (L) p With -NR 3 - Covalent linkage points do not form -NN- or -ON- bonds. In some embodiments, each L is independently -O-, -C(R) 7 (R) 8 - or -N(R) 6-, the condition is (L) p It does not contain -OO-, -NO-, or -NN- bonds, and (L) p and -NR 3 - Connection points do not form -ON- or -NN- bonds.

[0283] In some embodiments, p is 3, 4, 5, 6, or 7. 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.

[0284] In some embodiments, -(L) p -Includes-(CR) 7 R 8 )C(O)N(R 6 )-(CR 7 R 8 )2-、-(CR 7 R 8 )N(R 6 )C(O)-(CR 7 R 8 )2-、-N(R 6 )-C(O)(CR 7 R 8 )2O(CR 7 R 8 )2-、-CR 7 R 8 O(CR 7 R 8 )2O-(CR 7 R 8 )2、-O(CR 7 R 8 )2O(CR 7 R 8 )2-、-CR 7 R 8 O-CR 7 R 8 -C(O)N(R 6 )-(CR 7 R 8 )2-、-(CR 7 R 8 )3O(CR 7 R 8 )2-、-(CR 7 R 8 )2O(CR 7 R 8 )3-、-CR7 R 8 -N(R 6 )-(CR 7 R 8 )2-, -CR 7 R 8 -N(R 6 )-(CR 7 R 8 )3-, -O(CR 7 R 8 )2O(CR 7 R 8 )3-, -(CR 7 R 8 )2-N(R 6 )-(CR 7 R 8 )3-, -(CR 7 R 8 )2-N(R 6 )-(CR 7 R 8 )2-, -O-(CR 7 R 8 )2-, -O-(CR 7 R 8 )3- or -O-(CR 7 R 8 )4-.

[0285] In some embodiments, -(L) p - is -(CR 7 R 8 )C(O)N(R 6 )-(CR 7 R 8 )2-, -(CR 7 R 8 )N(R 6 )C(O)-(CR 7 R 8 )2-, -N(R 6 )-C(O)(CR 7 R 8 )2O(CR 7 R 8 )2-, -CR 7 R 8 O(CR 7 R 8 )2O-(CR 7 R 8 )2, -O(CR 7 R 8 )2O(CR 7 R 8)2-、-CR 7 R 8 O-CR 7 R 8 -C(O)N(R 6 )-(CR 7 R 8 )2-、-(CR 7 R 8 )3O(CR 7 R 8 )2-、-(CR 7 R 8 )2O(CR 7 R 8 )3-、-CR 7 R 8 -N(R 6 )-(CR 7 R 8 )2-、-CR 7 R 8 -N(R 6 )-(CR 7 R 8 )3-、-O(CR 7 R 8 )2O(CR 7 R 8 )3-、-(CR 7 R 8 )2-N(R 6 )-(CR 7 R 8 )3-、-(CR 7 R 8 )2-N(R 6 )-(CR 7 R 8 )2-、-O-(CR 7 R 8 )2-、-O-(CR 7 R 8 )3- or -O- (CR 7 R 8 )4-.

[0286] In some embodiments, when present, each R 6 Independently, it is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally -ORc 、-OC(O)R c 、-OC(O)NR c R d 、-OC(=NR d )NR c R d 、-OS(O)R c 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=NR d )NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=NR d )NR c R d 、-PR c R d 、-P(O)R c R d 、-P(O)2Rc R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2 are substituted. In some embodiments, R, when present, 6 It is H or C1-C6 alkyl. In some embodiments, R, when present, 6 It is H, methyl, or ethyl.

[0287] In some embodiments, each R 7 and R 8 Independently, it is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b -NR a C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a Rb -C(O)R a -C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e Rf -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2 substitution; or R 7 and R 8 The two carbons in R, together with one or more carbons to which they are attached, may optionally combine to form C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein when R 7 and R 8 When two of them combine to form a C3-C6 cycloalkyl or a 3- to 7-membered heterocycloalkyl group, each hydrogen atom in the resulting C3- to C6 cycloalkyl or heterocycloalkyl group is independently and optionally -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR eS(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2 are substituted. In some embodiments, R, when present, 7 It is H, C1-C6 alkyl, OH, or -OCH3. In some embodiments, R, when present, 7 It is H, methyl, -OH, or -OCH3. In some embodiments, R, when present, 8 It is H, C1-C6 alkyl, -OH, or -OCH3. In some embodiments, R, when present, 8 It is H, methyl, -OH, or -OCH3. In some embodiments, when present, each R 7 and R 8 It is H. In some embodiments, each R 7 and R 8 It is either H or methyl on its own.

[0288] In some embodiments, each R a R b R c R d R e and R f Independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl and C1-C6 alkylene-5- to 10-membered heteroaryl, or Ra and R b or R c and R d or R e and R f Together with the carbon atom it is attached to, it forms 3 to 7-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3 to 7-membered heterocyclic alkyl, and C6-C 10 Aryl, C1-C6 alkylene-C6-C 10Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, or C1-C6 alkylene-5- to 10-membered heteroaryl groups is independently and optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C -2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C -6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C Substitutions include 1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2, -P(O)(C2-C6 alkylene), -P(O)2(H or C1-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6 alkyl), -CN or -NO2.

[0289] In some embodiments, R 6 It is H or C1-C6 alkyl. In some embodiments, R, when present, 6 It is H, methyl, or ethyl. In some embodiments, R, when present, 7 It is H, C1-C6 alkyl, OH, or -OCH3. In some embodiments, R, when present, 7 It is H, methyl, -OH, or -OCH3. In some embodiments, R, when present, 8 It is H, C1-C6 alkyl, -OH, or -OCH3. In some embodiments, R, when present, 8 It is H, methyl, -OH, or -OCH3. In some embodiments, when present, each R 7 and R 8 It is H. In some embodiments, each R 7 and R 8 It is either H or methyl on its own.

[0290] In some embodiments, -(L) p -Yes-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)-, -(CH 2)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)-.

[0291] In some embodiments, -(L) p -Yes-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)-, -(C H2)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)-.

[0292] In some embodiments, -(L) p -Including -CH2N(H)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4- and -O(CH2)2O(CH2)2-.

[0293] In some embodiments, -(L) p - are -CH2N(H)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4- and -O(CH2)2O(CH2)2-.

[0294] In some embodiments, (L) p It is -O(C(R) 7 (R) 8 ))2-or-O(C(R) 7 (R) 8 ))3-. In some embodiments, (L) p It is -OC((H)(CH3))-CH2-.

[0295] In some embodiments, this disclosure provides a compound selected from the group consisting of (2S)-1-{(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0296] (2S)-2-{(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-1-ol;

[0297] (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0298] (2S)-1-[(10S,17E)-16-ethoxy-6-(methoxymethyl)-8,10-dimethyl-12-(prop-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0299] (2S)-1-{(10S,17E)-6-(methoxymethyl)-8,10,12-trimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0300] (2S)-1-[(10S,17E)-12-cyclopropyl-16-ethoxy-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0301] (2S)-1-{(10S,17E)-6-[difluoro(methoxy)methyl]-12-ethyl-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0302] (2S)-1-{(10S,17E)-6-[(difluoromethoxy)methyl]-12-ethyl-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0303] (2S)-1-{(10S,17E)-6-(ethoxymethyl)-12-ethyl-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0304] (2S)-1-{(10S,17E)-6-[(cyclopropoxymethyl]-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0305] (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-6-{[(prop-2-yl)oxy]methyl}-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecane-14-yl]prop-2-ol;

[0306] (2S)-1-{(10S,17E)-6-[(difluoromethoxy)methyl]-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0307] (2S)-1-[(10S,17E)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0308] (2S)-1-{(10S,17E)-6-(ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0309] (2S)-1-{(10S,17E)-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0310] (2S)-1-{(10S,17E)-6-(ethoxymethyl)-12-ethyl-19-fluoro-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0311] (2S)-1-[(10S,17E)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0312] (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0313] (10S,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine heterocyclic pentadecene;

[0314] (10S,17E)-20-fluoro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine heterocyclic pentadecene;

[0315] (2S)-1-{(10S,17E)-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol;

[0316] (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol;

[0317] (10S,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine heterocyclic pentadecene;

[0318] (10S,17E)-20-chloro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine-heterocyclic pentadecene;

[0319] (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-1-ol; and

[0320] (2S)-2-[(10S,17E)-16-ethoxy-20-fluoro-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-vinylbridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-1-ol;

[0321] Or its pharmaceutically acceptable salt.

[0322] In some embodiments, the compound does not have the following formula

[0323] , , , , , , , , , or .

[0324] The following are illustrative examples of compounds represented by formula (I):

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333] And its pharmaceutically acceptable salts.

[0334] Those skilled in the art will recognize that the species listed or described herein are not exhaustive, and other species within the scope of these defined terms may also be selected.

[0335] Pharmaceutical Composition

[0336] For therapeutic purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are substances that are non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate the administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, fillers, emulsifiers, or flavor modifiers. In a preferred embodiment, the pharmaceutical composition according to this disclosure is a sterile composition. The pharmaceutical composition may be prepared using compounding techniques known or available to those skilled in the art.

[0337] This disclosure also considers sterile compositions, including those that comply with national and local regulations governing such compositions.

[0338] According to conventional methods known in the art for preparing various dosage forms, the pharmaceutical compositions and compounds described herein can be formulated into solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or formulated with a solid carrier into pills, tablets, lozenges, suppositories, sachets, sugar-coated pills, granules, powders, powders for reconstitution, or capsules. The pharmaceutical compositions of this disclosure can be administered via suitable routes of delivery (e.g., oral, parenteral, rectal, nasal, topical, or ocular) or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0339] For oral administration, the compounds of this disclosure may be provided in solid form (e.g., tablets or capsules) or as a solution, emulsion, or suspension. To prepare oral compositions, the compounds of this disclosure may be formulated to produce doses, for example, about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 mg to 250 mg per day, or about 250 mg to 1 g per day. Oral tablets may include one or more active ingredients mixed with compatible pharmaceutically acceptable excipients (e.g., diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, and preservatives). Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Exemplary liquid oral excipients include ethanol, glycerin, water, etc. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginate are exemplary disintegrants. Binders may include starch and gelatin. The lubricant (if present) may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with enteric coating.

[0340] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules. To prepare hard gelatin capsules, one or more active ingredients can be mixed with solid, semi-solid, or liquid diluents. Soft gelatin capsules can be prepared by mixing the active ingredient with water, oil (e.g., peanut oil or olive oil), liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0341] Liquids intended for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or provided as a dried product for reconstitution with water or other suitable media prior to use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous mediators, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethanol, or water; preservatives (e.g., methylparaben or propylparaben or sorbic acid); wetting agents, such as lecithin; and flavoring or coloring agents as desired.

[0342] For parenteral administration, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the pharmaceutical preparations disclosed herein may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity, or in parenteral acceptable oils. Suitable aqueous media include Ringer's solution and isotonic sodium chloride. Such forms may be available in single-dose forms (e.g., ampoules or disposable injection devices), in multi-dose forms (e.g., vials from which appropriate doses can be dispensed), or in solid forms or pre-concentrated forms suitable for preparing injectable formulations. Exemplary infusion doses range from about 1 to 1000 μg / kg / min of a pharmaceutical preparation mixed with a drug carrier, lasting from several minutes to several days.

[0343] For nasal, inhalation, or oral administration, the pharmaceutical compositions of the present invention can be administered, for example, using a spray formulation that also contains a suitable carrier. The compositions of the present invention can be formulated as suppositories for rectal administration.

[0344] For topical application, the compounds of this disclosure are preferably formulated as creams or ointments or similar mediators suitable for topical application. For topical application, the compounds of the present invention can be mixed with a drug carrier at a concentration of about 0.1% to about 10% of the drug to the mediator. Another mode of administration of the agents of this disclosure can utilize patch formulations for transdermal delivery.

[0345] As used herein, the term "treat" or "treatment" encompasses both "preventive" and "curative" treatment. "Preventive" treatment refers to delaying the progression of a disease, its symptoms, or a medical condition; suppressing potential symptoms; or reducing the risk of disease or symptom development or recurrence. "Cure" treatment includes reducing the severity of an existing disease, its symptoms, or condition, or suppressing its worsening. Therefore, treatment includes improving or preventing the worsening of existing disease symptoms, preventing the occurrence of other symptoms, improving or preventing the underlying systemic causes of symptoms, suppressing a condition or disease (e.g., stopping its progression), alleviating a condition or disease, causing a condition or disease to subside, relieving the condition caused by a condition or disease, or stopping the symptoms of a condition or disease.

[0346] The term "subject" refers to a mammalian patient, such as a human, who requires this type of treatment.

[0347] Exemplary diseases include cancer, pain, neurological disorders, 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, childhood renal cell carcinoma, breast cancer, and ER. +Breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid angioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, Spitz-like tumor, sarcoma, astrocytoma, low-grade glioma of the brain, secretory breast cancer, mammary analogue carcinoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CML), acute myeloid leukemia (AML), congenital mesodermal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, melanoma of the skin, squamous cell carcinoma of the head and neck, pediatric glioma, prostate cancer, squamous cell carcinoma of the lung, serous cystadenocarcinoma of the ovary, melanoma of the skin, castration-resistant prostate cancer, Hodgkin's lymphoma, and serous and clear cell endometrial carcinoma. In some embodiments, cancers include lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophageal-gastric cancer, glioblastoma, head and neck cancer, inflammatory myofibroblastic tumor, and anaplastic large cell lymphoma.

[0348] In one aspect, the compounds and pharmaceutical compositions disclosed herein specifically target ALK. Therefore, these compounds and pharmaceutical compositions can be used to prevent, reverse, mitigate, or inhibit diseases, such as cancers driven by ALK activity. In some embodiments, the compounds described herein can target ALK in oncogenic driver fusion genes, such as EML4-ALK. In some embodiments, the compounds described herein can target ALK fusion genes having one or more drug-resistant mutations.

[0349] In one aspect, the compounds and pharmaceutical compositions disclosed herein specifically target PIM kinase. In some embodiments, the compounds described herein can target PIM kinase activity to overcome resistance mechanisms to chemotherapy, radiotherapy, anti-angiogenic therapy, and targeted therapy. In some embodiments, methods for treating targeted cancers such as AML are described.

[0350] In one aspect, the compounds and pharmaceutical compositions disclosed herein specifically target CLK kinase. In some embodiments, the compounds described herein can target CLK kinase activity to regulate pre-mRNA splicing by inhibiting CLK kinase activity, thereby treating diseases such as cancer. In some embodiments, methods for treating target cancers such as myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, AML, lung cancer, breast cancer, and pancreatic cancer are described.

[0351] In the inhibition methods disclosed herein, "effective amount" refers to an amount sufficient to inhibit the target protein. This target regulation can be measured using conventional analytical methods, such as those described below. This regulation can be used in various settings, including in vitro assays. In such methods, the cells are preferably cancer cells exhibiting aberrant signaling due to the ALK, PIM, and / or CLK mutations described herein.

[0352] In the treatment methods according to this disclosure, "effective amount" means an amount or dose that is generally sufficient to provide the desired therapeutic benefit in a subject requiring such treatment, such as a subject described herein suffering from a disease like cancer, including those associated with aberrant ALK, including oncogenic driver fusion genes (such as EML4-ALK) and ALK resistance mutations, aberrant PIM kinases, and / or aberrant CLK kinases. The effective amount or dose of the compounds of this disclosure may be determined using conventional methods (e.g., modeling, dose escalation, or clinical trials) taking into account conventional factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject's health status, condition and weight, and the judgment of the treating physician. Exemplary doses range from about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. The total dose may be administered as a single dose or in divided dose units (e.g., BID, TID, QID).

[0353] Once a patient's condition improves, the dosage can be adjusted for preventative or maintenance therapy. For example, the dosage or frequency of administration, or both, can be reduced to a level that maintains the desired therapeutic or preventative effect, depending on the symptoms. Of course, treatment can be discontinued if symptoms have subsided to an appropriate level. However, patients may require long-term intermittent treatment in case of any symptom recurrence. Patients may also require long-term chronic treatment.

[0354] Drug combination

[0355] The compounds of the present invention described herein can be combined with one or more additional active ingredients in pharmaceutical compositions or methods for treating the diseases and conditions described herein. The additional active ingredients include other therapeutic agents or pharmaceuticals that reduce the side effects of therapies targeting the intended disease target. Such combinations can be used to increase efficacy, improve other disease symptoms, reduce one or more side effects, or reduce the required dosage of the compounds of the present invention. The additional active ingredients can be administered in a pharmaceutical composition separate from the compounds of the present disclosure, or can be included together with the compounds of the present disclosure in a single pharmaceutical composition. The additional active ingredients can be administered simultaneously with, before, or after the administration of the compounds of the present disclosure.

[0356] Combination agents that include additional active ingredients are those known or found to be effective in treating the diseases and conditions described herein, including those active against another target associated with the disease. For example, the compositions and formulations disclosed herein, as well as the treatment methods, may further comprise other drugs or agents, such as other active agents that can be used to treat or alleviate the target disease or related symptoms or conditions. For cancer indications, additional such agents include, but are not limited to, kinase inhibitors (e.g., ALK inhibitors (e.g., crizotinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib)), standard chemotherapeutic agents (e.g., alkylating agents), antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum-based drugs, mitotic inhibitors, antibodies, hormone therapy, or corticosteroids.

[0357] Chemical synthesis methods

[0358] The following examples are provided to illustrate, but do not limit, this disclosure. Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified by selecting suitable starting materials and reagents to obtain other compounds of formulas (I)-(IV).

[0359] Abbreviations: The examples and materials used herein include, but are not limited to, materials described by the following abbreviations known to those skilled in the art:

[0360]

[0361]

[0362]

[0363]

[0364] Preparation of intermediates

[0365] Preparation of (1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl methanesulfonate (I-1-1).

[0366]

[0367] To a solution of commercially available N-[(2R)-2-hydroxypropyl]carbamate tert-butyl ester (10.0 g, 57.0 mmol, 1 equivalent) in DCM (20 mL), methanesulfonyl methanesulfonate (14.9 g, 85.6 mmol, 1.5 equivalent) and TEA (171 mmol, 23.8 mL, 3 equivalent) were added. The mixture was stirred at 0 °C for 1 hour. After stirring, the reaction mixture was quenched by adding H₂O (30 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with a saturated solution of NaCl (50 mL), filtered, and concentrated under reduced pressure to give [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate (12.0 g, 47.3 mmol, 83% yield) as a white solid. I-1-1 was used without further purification.

[0368] Preparation of (R)-N-ethyl-2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (I-2-1).

[0369]

[0370] Step 1. Ethylamine (2 M, 258 mL, 3 equivalents) was added to a solution of commercially available (R)-2-methylethylene oxide (10 g, 172.18 mmol, 1 equivalent) in MeOH (100 mL). The mixture was stirred at 25 °C for 12 hours. After completion, the mixture was concentrated to give (R)-1-(ethylamino)prop-2-ol (8.13 g, 78.8 mmol, 46% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ = 3.84 - 3.70 (m, 1H), 2.74 - 2.55 (m, 3H), 2.45 -2.34 (m, 2H), 1.16 - 1.05 (m, 6H).

[0371] Step 2. To a solution of (2R)-1-(ethylamino)prop-2-ol (8.13 g, 78.8 mmol, 1 equivalent) in DCM (80 mL), add (2,2,2-trifluoroacetyl)-2,2,2-trifluoroacetate (24.8 g, 118 mmol, 16.4 mL, 1.5 equivalents) and TEA (39.9 g, 394 mmol, 5 equivalents), and then stir the mixture at 0 °C for 1 hour. Afterward, the reaction mixture is partitioned between DCM (100 mL × 3) and water (100 mL), and the combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the 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+1: 200.1).

[0372] Preparation of (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N-methylacetamide (I-3-1).

[0373]

[0374] Following the method for preparing I-2-1, methylamine was used instead of ethylamine in step 1 to prepare I-3-1. 1 H NMR(400 MHz, CDCl3) δ = 4.05 - 3.96 (m, 1H), 3.38 (d, J = 3.6 Hz, 1H), 3.34 -3.24 (m, 2H), 3.16 (d, J =1.6 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H).

[0375] Preparation of 5-bromo-1-tetrahydropyran-2-yl-3-vinyl-indazole (I-1-4)

[0376]

[0377]

[0378] Step 1. At 0 °C, t-BuOK (5.70 g, 50.7 mmol, 2 equivalents) was added to a solution of commercially available 5-bromo-1H-indazole (5.00 g, 25.3 mmol, 1 equivalent) in THF (50 mL), followed by the addition of I2 (7.08 g, 27.9 mmol, 1.1 equivalents) in THF (50 mL). The reaction mixture was stirred at 25 °C for 12 hours. After completion, the residue was diluted with water and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 5-bromo-3-iodo-1H-indazole (8.10 g, 98.8% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ = 13.69 (s,1H), 7.60 (d, J = 1.2 Hz, 1H), 7.55 - 7.53 (m, 2H). LCMS: (M+1: 324.4).

[0379] Step 2. DHP (5.27 g, 62.7 mmol, 2.5 equivalents) was added to a mixture of 5-bromo-3-iodo-1H-indazole (8.10 g, 25.0 mmol, 1 equivalent) and TosOH (863 mg, 5.02 mmol, 0.2 equivalents) in toluene (200 mL). The reaction mixture was stirred at 90 °C for 12 hours. After completion, the residue was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. 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 a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.75 - 7.70 (m, 1H), 7.62 - 7.58 (m, 2H), 5.83 (dd, J = 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+1: 408.7).

[0380] Step 3. Pd(dppf)Cl2 (1.49 g, 2.04 mmol, 1 equivalent) and Na2CO3 (6.48 g, 61.1 mmol, 3 equivalent) were added to a mixture of 5-bromo-3-iodo-1-tetrahydropyran-2-yl-indazole (8.30 g, 20.3 mmol, 1 equivalent) and potassium trifluoro(vinyl)borate (2.73 g, 20.3 mmol, 1 equivalent) in dioxane (80 mL) and H2O (12 mL). The reaction mixture was stirred at 80 °C under N2 for 12 hours. After completion, the residue was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give 5-bromo-1-tetrahydropyran-2-yl-3-vinyl-indazole as a white solid (6.00 g, 19.5 mmol, 95.7% yield). 1 H NMR(400 MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.57 (d, J =8.8 Hz, 1H), 7.01 (dd, J = 11.6, 17.6 Hz, 1H), 6.14 (d, J = 18.0 Hz, 1H), 5.85 (d, J = 9.6 Hz, 1H), 5.53 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 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).

[0381] Preparation of 5-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole (I-2-4)

[0382]

[0383] Following the method described in steps 1-3 for preparing I-1-4, I-2-4 is prepared from commercially available 5-bromo-6-fluoro-1H-indazole in step 1 using NaOH as a base and DMF as a solvent. 1H NMR (400 MHz, CDCl3) δ = 8.09 (d,J = 6.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 11.2, 18.0 Hz, 1H), 6.05 (dd, J = 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).

[0384] Preparation of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole (I-3-4).

[0385]

[0386] I-3-4 was prepared from commercially available 5-bromo-7-fluoro-1H-indazole, using DMF as a solvent in step 1, dioxane as a solvent in step 2, and Cs2CO3 as a base in step 3, according to the method described in steps 1-3 for preparing I-1-4. 1 H NMR (400 MHz, DMSO-d6) δ = 8.11 (s, 1H), 7.59 (d, J = 11.2 Hz, 1H), 7.01 (dd, J = 11.2, 17.9 Hz, 1H), 6.17 (d, J = 18.0Hz, 1H), 5.83 - 5.73(m, 1H), 5.57 (d, J = 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, J = 10.4 Hz, 2H), 1.78 - 1.68 (m, 1H), 1.55 (d,J = 3.2 Hz, 2H). LCMS: (M+1:325.0).

[0387] Preparation of 5-bromo-7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole (I-4-4).

[0388]

[0389] Following the methods described in steps 1-3 for the preparation of I-1-4, I-4-4 was prepared in step 2 using PPTS as a catalyst and DCM as a solvent from commercially available 5-bromo-7-chloro-1H-indazole. LCMS: (M+23: 364.8)

[0390] Preparation of 3-isopropoxy-1H-pyrazole-5-carboxylate (I-1-5)

[0391]

[0392] To a solution of commercially available ethyl 3-hydroxy-1H-pyrazole-5-carboxylate (10.0 g, 64.0 mmol, 1 equivalent) in DMF (100 mL), K₂CO₃ (26.5 g, 192 mmol, 3 equivalents) and 2-iodopropane (21.8 g, 128 mmol, 2 equivalents) were added. The mixture was stirred at 12 °C for 12 hours. After completion, the reaction mixture was partitioned between ethyl acetate (300 mL × 3) and water (300 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10:1 to 10:1) to give ethyl 3-isopropoxy-1H-pyrazole-5-carboxylate (6.00 g, 30.3 mmol, 47% yield) as a white solid. LCMS: (M+1: 199.1).

[0393] Preparation of tert-butyl-dimethyl-[(1S)-2-[5-(bromomethyl)-4-iodo-3-isopropoxy-pyrazol-1-yl]-1-methyl-ethoxy]silane (I-1-9)

[0394]

[0395]

[0396] Step 1: To a solution of commercially available (2S)-2-[tert-butyl(dimethyl)silyl]oxyprop-1-ol (4.49 g, 23.6 mmol, 2 equivalents) and ethyl 3-isopropoxy-1H-pyrazole-5-carboxylate (I-1-5, 2.34 g, 11.81 mmol, 1 equivalent) in 2-Me THF (4 mL), PPh3 (6.81 g, 25.9 mmol, 2.2 equivalents) and DIAD (5.25 g, 25.9 mmol, 2.2 equivalents) were added. The mixture was stirred at 25 °C for 12 hours. After completion, the mixture was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, 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 (I-1-6, 4.43 g, crude) as a white solid. LCMS: (M+1: 371.1). The product (I-1-6) was used in the next step without further purification.

[0397] Step 2: LiAlH4 (2.5 M, 6.95 mL, 1.5 equivalents) was added to a solution of ethyl 2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-isopropoxy-pyrazole-3-carboxylate (I-1-6, 4.29 g, 11.6 mmol, 1 equivalent) in THF (40 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours. After stirring, water (0.6 mL), 15% NaOH (0.6 mL), and water (2.0 mL) were added sequentially. The mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE:THF = 6:1 to 6:1) to give a brown solid [2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-isopropoxy-pyrazole-3-yl]methanol (I-1-7, 2.26 g, 6.88 mmol, 59% yield). LCMS: (M+1: 329.1). The product (I-1-7) was used in the next step without further purification.

[0398] Step 3: NIS (2.12 g, 9.41 mmol, 1.5 equivalents) was added to a solution of [2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-isopropoxy-pyrazole-3-yl]methanol (I-1-7, 2.06 g, 6.27 mmol, 1 equivalent) in ACN (20 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours. After completion, the reaction mixture was partitioned between ethyl acetate (25 mL × 3) and water (25 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE:THF = 6:1 to 6:1) to give a purple oil, [2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-4-iodo-5-isopropoxy-pyrazol-3-yl]methanol (I-1-8, 2.79 g, 6.13 mmol, 98% yield). LCMS: (M+1: 455.4). The product (I-1-8) was used in the next step without further purification.

[0399] Step 4: Under a nitrogen atmosphere at 0°C, PPh3 (692 mg, 2.64 mmol, 1.2 equivalents) was added to a solution of [2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-4-iodo-5-isopropoxy-pyrazole-3-yl]methanol (I-1-8, 1.00 g, 2.20 mmol, 1 equivalent) in DCM (10 mL), followed by CBr4 (876 mg, 2.64 mmol, 1.2 equivalents). The mixture was stirred at 25°C for 1 hour. After completion, the mixture was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE:THF = 6:1 to 6:1) to give a brown oily substance, [(1S)-2-[5-(bromomethyl)-4-iodo-3-isopropoxy-pyrazol-1-yl]-1-methyl-ethoxy]-tert-butyl-dimethyl-silane (I-1-9, 1.06 g, 2.05 mmol, 93% yield). LCMS: (M+1: 519.0).

[0400] Preparation of (S)-5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-1H-pyrazole (I-2-9)

[0401]

[0402] Step 1. PPh3 (3.67 g, 14.0 mmol, 2.2 equivalents) was added to a solution of commercially available ethyl 3-ethoxy-1H-pyrazole-5-carboxylate (I-2-5, 1.17 g, 6.35 mmol, 1 equivalent) and commercially available (S)-2-((tert-butyldimethylsilyl)oxy)prop-1-ol (1.81 g, 9.53 mmol, 1.5 equivalents) in 2-MeTHF (20 mL). The mixture was stirred at 25 °C for 0.5 h, and then DIAD (2.83 g, 14.0 mmol, 2.2 equivalents) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was then concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 10:1) to obtain (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-1H-pyrazole-5-carboxylic acid ethyl ester (I-2-6, 1.96 g, crude product), which was a yellow oil. LCMS: (M+1:357.2).

[0403] Step 2. LAH (2.5 M, 2.96 mL, 1.5 equivalents) was added to a solution of (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-1H-pyrazole-5-carboxylic acid ethyl ester (I-2-6, 1.76 g, 4.94 mmol, 1 equivalent) in THF (18 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. After stirring, the mixture was quenched sequentially with water (0.3 mL), 15% NaOH (0.3 mL), and water (0.9 mL). The combined organic phases were dried over Na₂SO₄, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE:THF = 4:1) to obtain a yellow oily substance (S)-(1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-1H-pyrazol-5-yl)methanol (I-2-7, 1.46 g, crude). LCMS: (M+1:315.3).

[0404] Step 3. NIS (992 mg, 4.41 mmol, 1.1 equivalents) was added to a solution of (S)-(1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-1H-pyrazol-5-yl)methanol (I-2-7, 1.26 g, 4.01 mmol, 1 equivalent) in ACN (13 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. After stirring, the mixture was quenched with saturated Na₂SO₃ (20 mL) at 0 °C and extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE:THF = 10:1) to obtain a yellow oily substance (S)-(1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methanol (I-2-8, 2.05 g, crude). LCMS: (M+1:441.1).

[0405] Step 4. Under N2, NIS (15.3 g, 68.1 mmol, 2 equivalents) and PPh3 (13.4 g, 51.1 mmol, 1.5 equivalents) were added to a solution of (S)-(1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methanol (I-2-8, 15.0 g, 34.1 mmol, 1 equivalent) in DCM (150 mL), and the mixture was stirred at 0 °C for 2 hours. After completion, the mixture was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA = 1:0 to 10:1) to give (S)-5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-1H-pyrazole (I-2-9, 15.0 g, 27.3 mmol, 80% yield) as a yellow solid. LCMS: (M+1:551.0).

[0406] Preparation of 5-(bromomethyl)-4-iodo-1,3-dimethyl-1H-pyrazole (I-3-9).

[0407]

[0408] Step 1. NIS (14.7 g, 65.4 mmol, 1.1 equivalent) was added to a solution of ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate (10.0 g, 59.5 mmol, 1.0 equivalent) in ACN (100 mL). The mixture was stirred at 60 °C for 16 hours. After stirring, the mixture was quenched with saturated Na₂SO₃ (500 mL) and extracted with ethyl acetate (250 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 4-iodo-1,3-dimethyl-1H-pyrazole-5-carboxylate (17 g, crude) as a colorless oil. LCMS: (M+1:295.2).

[0409] Step 2. LiBH4 (14.8 g, 680 mmol, 25 equivalents) was added to a solution of ethyl 4-iodo-1,3-dimethyl-1H-pyrazole-5-carboxylate (8.00 g, 27.2 mmol, 1.0 equivalent) in MeOH (150 mL) at 0 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was then quenched with water (200 mL) and concentrated under vacuum to obtain a residue. Water (100 mL) was added to the residue and extracted with ethyl acetate (60 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The crude product was milled with PE / EA (10:1) at 25 °C for 10 minutes to give (4-iodo-1,3-dimethyl-1H-pyrazole-5-yl)methanol (6.30 g, 22.5 mmol, 83% yield) as a white solid. LCMS: (M+1:252.9).

[0410] Step 3. PBr3 (4.73 g, 17.5 mmol, 1.1 equivalent) was added to a solution of (4-iodo-1,3-dimethyl-1H-pyrazole-5-yl)methanol (4 g, 15.9 mmol, 1.0 equivalent) in DCM (40 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours. After stirring, the mixture was adjusted to pH 7–8 with NaHCO3. Then, water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give 5-(bromomethyl)-4-iodo-1,3-dimethyl-1H-pyrazole (2.70 g, 8.57 mmol, 54% yield) as a white solid. 1H NMR (400 MHz, CDCl3-d) δ = 4.46 (s, 2H), 3.91 (s, 3H), 2.23 (s, 3H); LCMS: (M+1:316.8).

[0411] Preparation of (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-1H-pyrazole (I-4-9).

[0412]

[0413] A mixture of (S)-(1-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazol-5-yl)methanol (13.0 g, 28.6 mmol, 1 equivalent, I-1-8) and PPh3 (11.3 g, 42.9 mmol, 1.5 equivalent) in DCM (130 mL) was degassed and purged three times with N2. NIS (12.9 g, 57.2 mmol, 2 equivalents) was then added to the mixture. The mixture was stirred at 0 °C under N2 atmosphere for 2 hours. After this, the reaction mixture was quenched at 0 °C by adding saturated NaHCO3 solution (100 mL), diluted with H2O (400 mL), and extracted with EA (300 mL, 100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1) to give (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-1H-pyrazole (12.0 g, 21.3 mmol, 74% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 4.80 (td, J = 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+1: 565.1).

[0414] Preparation of (S)-1-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-1H-pyrazole (I-5-9).

[0415]

[0416] Step 1. At 0°C and N2, (R)-1-((tert-butyldimethylsilyl)oxy)prop-2-ol (1.58 kg, 8.29 mol, 1.25 equivalent), PPh3 (2.61 kg, 9.94 mol, 1.5 equivalent), and DIAD (2.01 kg, 9.94 mol, 1.93 L, 1.5 equivalent) were added to a solution of ethyl 3-ethoxy-1H-pyrazole-5-carboxylate (1.65 kg, 6.63 mol, 1.93 L, 1.5 equivalent) in THF (16.5 L). The mixture was stirred at 25°C for 1 hour. After stirring, the reaction mixture was concentrated under vacuum and milled five times with MTBE (5 L) to remove triphenylphosphine oxide. The mixture was filtered and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 20:1) to give (S)-1-(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-3-ethoxy-1H-pyrazole-5-carboxylic acid ethyl ester (7.16 kg, 10.0 mol, 76% yield, 50% purity) as a yellow oil. 1 H NMR (400 MHz, CDCl3-d) δ 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+1:357.6).

[0417] Step 2. Add LAH (2.5 M, 2.01 L, 1 equivalent) to a solution of (S)-1-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-3-ethoxy-1H-pyrazole-5-carboxylic acid ethyl ester (1.79 kg, 5.02 mol, 1 equivalent) in THF (8 L) at 0 °C. Stir the mixture at 0 °C for 0.5 h. After completion, slowly quench the reaction mixture with 190 mL (0 °C) of water, then add 15% sodium hydroxide (190 mL) and water (190 mL × 3). Then filter the mixture. The combined organic layers were washed with brine (1500 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give (S)-(1-(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-3-ethoxy-1H-pyrazol-5-yl)methanol (1.35 kg, 4.29 mol, 85.5% yield), a yellow oil. LCMS: (M+1: 315.4).

[0418] Step 3. NIS (1.03 kg, 4.59 mol, 1.07 equivalent) was added to a solution of (S)-(1-(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-3-ethoxy-1H-pyrazol-5-yl)methanol (1.35 kg, 4.29 mol, 1 equivalent) in ACN (9.5 L) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched dropwise with an aqueous sodium sulfite solution (9.5 L), then concentrated and extracted with EA (2000 mL × 3). The combined organic layers were washed with brine (2000 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA = 25:1–5:1) to give (S)-(1-(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methanol (700 g, 1.59 mol, 37% yield) as a white solid. LCMS: (M+1:441.4).

[0419] Step 4. Degas the solution of (S)-(1-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methanol (1.00 kg, 2.27 mol, 1 equivalent) and NIS (1.02 kg, 4.54 mol, 2 equivalent) in DCM (7 L) and purge three times with N2. Dissolve PPh3 (893 g, 3.41 mol, 1.5 equivalent) in DCM (800 mL) and slowly add it to the reaction solution at 0 °C. Stir the mixture at 25 °C under N2 for 1 hour. After completion, pour the mixture into a saturated sodium sulfite (7000 mL) aqueous solution and extract the aqueous phase with DCM (2000 mL × 3). Wash the combined organic phases with brine (2000 mL × 2), dry to anhydrous Na2SO4, filter, and concentrate under vacuum. The residue was purified by silica gel chromatography (0-90% petroleum ether / ethyl acetate) to give a yellow oil (S)-1-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-1H-pyrazole (905 g, 1.55 mol, 95% yield, 94% purity). LCMS: (M+1:551.1)

[0420] Preparation of the final macrocyclic compound

[0421] Preparation of (2S)-1-{(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol (Example 1)

[0422]

[0423]

[0424]

[0425] Step 1: A mixture of commercially available 5-(methoxymethyl)-2-methylpyrazole-3-ol (1.16 g, 8.14 mmol, 1 equivalent), 5-bromo-1-tetrahydropyran-2-yl-3-vinyl-indazole (3.00 g, 9.77 mmol, 1.2 equivalent), tBubrettPhosPd G3 (I-1-4, 695 mg, 813 μmol, 0.1 equivalent), and K2CO3 (3.37 g, 24.4 mmol, 3 equivalent) in dioxane (10 mL) was degassed and purged three times with N2. The mixture was then stirred at 130 °C under N2 atmosphere for 0.5 h. After completion, the reaction mixture was quenched by adding H2O (20 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with a saturated NaCl solution (30 mL), filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 10:1) to give 5-(methoxymethyl)-2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-indazole-5-yl)pyrazol-3-ol (I-1-10, 500 mg, 1.33 mmol, 16% yield) as a white solid. 1 HNMR (400 MHz, CDCl3) δ = 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+1: 369.0).

[0426] Step 2. K₂CO₃ (337 mg, 2.44 mmol, 3 equivalents) was added to a solution of 5-(methoxymethyl)-2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-indazole-5-yl)pyrazol-3-ol (I-1-10, 300 mg, 814 μmol, 1 equivalent) and [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate (I-1-1, 412 mg, 1.63 mmol, 2 equivalents) in DMF (5 mL). The mixture was stirred at 80 °C for 2 hours. After completion, the reaction mixture was quenched by adding H₂O (15 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with a saturated solution of NaCl (20 mL), filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:1) to give N-[(2S)-2-[5-(methoxymethyl)-2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)pyrazol-3-yl]oxypropyl] tert-butyl carbamate (I-1-11, 180 mg, 342 μmol, 42% yield) as a white solid. LCMS: (M+1: 526.3).

[0427] Step 3. Add NaH (38.8 mg, 970 μmol, 60% purity, 3 equivalents) to a solution of N-[(2S)-2-[5-(methoxymethyl)-2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-indazole-5-yl)pyrazol-3-yl]oxypropyl]carbamate (I-1-11, 170 mg, 323 μmol, 1 equivalent) in DMF (3 mL). Stir the mixture at 0 °C for 0.5 h. Then add tert-butyl-dimethyl-[(1S)-2-[5-(bromomethyl)-4-iodo-3-isopropoxy-pyrazol-1-yl]-1-methyl-ethoxy]silane (I-1-9, 167 mg, 323 μmol, 1 equivalent) to the above mixture. Stir the mixture at 25 °C for 1 h. After completion, the reaction mixture was quenched by adding H2O (10 mL) and extracted with EA (5 mL × 3). The combined organic layers were washed with NaCl (10 mL), filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3:1) to give 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-yl]oxypropyl]tert-butyl carbamate as a white solid (I-1-12, 130 mg, 135 μmol, 41% yield). LCMS: (M+1: 962.5).

[0428] Step 4. Place 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-yl]oxypropyl] tert-butyl carbamate (I-1-12, 110 mg, 114 μmol, 1 equivalent), Pd(OAc)2 (5.13 mg, 22.8 μmol, 0.2 equivalent), TBAC (31.7 mg, 114 μmol, 1 equivalent) and NaHCO3 (24.0 mg, 285 μmol, 2.5 equivalent) in DMF (3 The mixture was degassed and purged three times with N2, then stirred at 90°C under N2 atmosphere for 2 hours. After completion, the reaction mixture was quenched by adding H2O (5 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with a saturated NaCl solution (10 mL), filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:1) to give (10S,17E)-14-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}propyl]-6-(methoxymethyl)-8,10-dimethyl-2-(oxecyclohexane-2-yl)-16-[(prop-2-yl)oxy]-2,8,10,11,13,14-hexahydro-12H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecane-12-carboxylic acid tert-butyl ester (I-1-13, 40.0 mg, 47.9 μmol, 41% yield). LCMS: (M+1: 834.7).

[0429] Step 5: Add HCl / dioxane (0.5 mL, 1 equivalent) to a solution of (10S,17E)-14-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}propyl]-6-(methoxymethyl)-8,10-dimethyl-2-(oxacyclohexane-2-yl)-16-[(prop-2-yl)oxy]-2,8,10,11,13,14-hexahydro-12H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecane-12-carboxylic acid tert-butyl ester (I-1-13, 40.0 mg, 47.9 μmol, 1 equivalent) in DCM (2 mL). Stir the mixture at 25°C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure to give (2S)-1-{(10S,17E)-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol (I-1-14, 20.0 mg, 37.3 μmol, 77% yield) as a white solid. LCMS: (M+1:536.3).

[0430] Step 6. To a solution of (2S)-1-{(10S,17E)-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-vinylbridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol (I-1-14, 20.0 mg, 37.3 μmol, 1 equivalent) in MeOH (2 mL), add AcOH (2.24 mg, 37.3 μmol, 1 equivalent), acetaldehyde (1.64 mg, 37.3 μmol, 1 equivalent), and NaBH(OAc)3 (7.91 mg, 37.3 μmol, 1 equivalent). Stir the mixture at 25 °C for 2 hours. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product was analyzed by reversed-phase column chromatography (CD02-Waters Xbidge BEH C18150). 25 10 μm; Mobile phase: [water (NH3H2O)-ACN]; Gradient: 34%-64% B) purification over 10 min to give (2S)-1-{(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol as a white solid (Example 1, 2.69 mg, 4.77 μmol, 12.78% yield). Analytical data for Example 1 are provided in Table 1.

[0431] Preparation of (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol (Example 18):

[0432]

[0433] Step 1. Potassium carbonate (4.25 g, 30.8 mmol, 2 equivalents) was added to a solution of 5-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole (5.00 g, 15.4 mmol, 1 equivalent) and commercially available 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-ol (2.51 g, 17.9 mmol, 1.15 equivalents) in 2-MeTHF (70 mL), and the mixture was stirred at 20 °C for 15 min. The resulting mixture was degassed under vacuum and backfilled with N2 three times; then t-BuBrettphos Pd G3 (1.31 g, 1.54 mmol, 0.1 equivalents) was added to the mixture, and the mixture was degassed under vacuum and backfilled with N2 three times and stirred at 70 °C for 16 h. After completion, the mixture was filtered, the filter cake was washed with EA (50 mL), and the mixture was extracted with ethyl acetate (50 mL × 2) and water (100 mL). The combined organic phases were washed with brine (50 mL × 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 × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-ol (8.00 g, 12.4 mmol, 40% yield, 60% purity) as a brown gel. LCMS: (M+1: 387.2).

[0434] Step 2. A mixture of 4-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-ol (7.33 g, 11.4 mmol, 1 equivalent), (R)-N-ethyl-2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (I-2-1, 3.40 g, 17.1 mmol, 1.5 equivalent) and PPh3 (4.48 g, 17.1 mmol, 1.5 equivalent) in dioxane (70 mL) was degassed and purged three times with N2. DBAD (5.24 g, 22.8 mmol, 2 equivalent) was then added to the mixture at 0 °C under N2 atmosphere. The mixture was then stirred at 20 °C under N2 atmosphere for 2 hours. After completion, the mixture was concentrated under vacuum to obtain the 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-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)acetamide (5.00 g, 8.81 mmol, 77% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 8.00 (d, J = 6.8Hz, 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, J = 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), 2.09 - 1.90 (m, 2H), 1.82 - 1.67(m, 1H), 1.59 (d, J = 3.6 Hz, 2H), 1.14 - 1.04 (m, 3H), 1.02 - 0.95 (m, 3H).

[0435] Step 3. To a solution of N-ethyl-2,2,2-trifluoro-N-((2S)-2-((4-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)acetamide (4.50 g, 7.93 mmol, 1 equivalent) in THF (40 mL) and H2O (8 mL), LiOH·H2O (1.66 g, 39.6 mmol, 5 equivalents) was added. The mixture was stirred at 20 °C for 3 hours. After completion, the reaction mixture was filtered, the filtrate was separated, and the aqueous phase was partitioned between ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1:0 to 0:1) to give (2S)-N-ethyl-2-((4-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl-1-amine (6.33 g, 11.8 mmol, 74% yield, 88% purity), as a brown oil. LCMS: (M+1: 472.4).

[0436] Step 4. Add K₂CO₃ (1.76 g, 12.7 mmol, 3 equivalents) to a solution of (2S)-N-ethyl-2-((4-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl-1-amine (2.00 g, 4.24 mmol, 1 equivalent) and (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-5-(iodomethyl)-1H-pyrazole (1.40 g, 2.54 mmol, 0.6 equivalents) in DMF (20 mL). Stir the mixture at 60 °C for 2 hours. After completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2:1 to 1:1) to give (2S)-N-((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl-1-amine (1.40 g, 1.57 mmol, 36% yield). LCMS: (M+1:894.5).

[0437] Step 5. Dissolve (2S)-N-((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl-1-amine (1.25 g, 1.40 mmol, 1 equivalent), TBAC (388 mg, 1.40 mmol, 1 equivalent), Pd(OAc)2 (31.3 mg, 0.140 mmol, 0.1 equivalent) and NaHCO3 (293 mg, 3.50 mmol, 2.5 equivalent) in DMF (13 The mixture was degassed and purged three times with N2, and then stirred at 130°C under N2 atmosphere for 2 hours. After completion, the mixture was diluted with water (35 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2:1 to 1:1) to give (10S,17E)-14-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}propyl]-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-2-(oxecyclohexane-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinyl pentadecene (1.00 g, 1.31 mmol, 93% yield) as a yellow solid. LCMS: (M+1: 766.6).

[0438] Step 6. Add concentrated HCl (12 M, 20.7 mmol, 2 mL, 16.6 equivalents) to a solution of (10S,17E)-14-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}propyl]-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-2-(oxacyclohexane-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinyl pentadecene (950 mg, 1.24 mmol, 1 equivalent) in MeOH (10 mL). Stir the mixture at 25 °C for 2 hours. After completion, filter and concentrate the mixture to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 10:1 to 1:1) to give (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-vinylbridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol (274.93 mg, 0.455 mmol, 36.71% yield, 94% purity) as a white solid (Example 18). Analytical data for Example 18 are shown in the table below.

[0439] Preparation of (10S,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinyl pentadecanene (Example 19).

[0440]

[0441]

[0442] Step 1. A mixture of commercially available 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-ol (2.99 g, 21.0 mmol, 1.2 equivalents), 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole (5.70 g, 17.5 mmol, 1 equivalent), K₂CO₃ (7.27 g, 52.6 mmol, 3 equivalents), and tBuBrettPhosPdG₃ (899 mg, 1.05 mmol, 0.06 equivalents) in dioxane (57 mL) was degassed and purged three times with N₂. The mixture was then stirred at 130 °C under N₂ atmosphere for 1 hour. After completion, the mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid column chromatography (0-10% MeOH / DCM) to give 4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-ol (6.20 g, 16.0 mmol, 92% yield) as a brown solid. LCMS: (M+1:387.2).

[0443] Step 2. A mixture of 4-(7-fluoro-1-tetrahydropyran-2-yl-3-vinyl-indazole-5-yl)-5-(methoxymethyl)-2-methylpyrazol-3-ol (1.00 g, 2.59 mmol, 1 equivalent), (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N-methylacetamide (718 mg, 3.88 mmol, 1.5 equivalent), and PPh3 (1.36 g, 5.18 mmol, 2 equivalent) in dioxane (20 mL) was degassed and purged three times with N2. DBAD (1.19 g, 5.18 mmol, 2 equivalent) was added to the mixture at 0 °C, and the mixture was then stirred at 25 °C under N2 atmosphere for 2 hours. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 2:1 to 1:1) to give 2,2,2-trifluoro-N-((2S)-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-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).

[0444] Step 3. To a solution of 2,2,2-trifluoro-N-((2S)-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)-N-methylacetamide (2.30 g, 4.16 mmol, 1 equivalent) in THF (20 mL) and H2O (4 mL), LiOH·H2O (871 mg, 20.7 mmol, 5 equivalents) was added. The mixture was stirred at 25 °C for 2 hours. After completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 4:1 to 1:1) to give (2S)-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)-N-methylpropyl-1-amine (750 mg, 1.56 mmol, 37% yield, 95% purity) as a yellow solid. LCMS: (M+1 = 458.3).

[0445] Step 4. K₂CO₃ (589 mg, 4.26 mmol, 3 equivalents) was added to a solution of (2S)-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)-N-methylpropyl-1-amine (650 mg, 1.42 mmol, 1 equivalent) and 5-(bromomethyl)-4-iodo-1,3-dimethyl-1H-pyrazole (671 mg, 2.13 mmol, 1.5 equivalents) in DMF (7 mL). The mixture was stirred at 80 °C for 2 hours. After completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 2:1 to 1:1) to give (2S)-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)-N-((4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)methyl)-N-methylpropyl-1-amine (590 mg, 0.819 mmol, 57% yield, 96% purity). LCMS: (M+1 = 692.2).

[0446] Step 5. Degas the mixture of (2S)-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)-N-((4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)methyl)-N-methylpropyl-1-amine (550 mg, 0.795 mmol, 0.1 equivalent), Pd(OAc)2 (17.8 mg, 0.0795 mmol, 0.1 equivalent), TBAC (221 mg, 0.795 mmol, 1 equivalent) and NaHCO3 (167 mg, 1.99 mmol, 2.5 equivalent) in DMF (6 mL) and purge with N2 three times. Then stir the mixture at 130 °C under N2 atmosphere for 2 hours. After completion, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 1:1 to 1:1) to give (10S,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2-(oxecyclohexane-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadene as a brown solid (220 mg, 0.316 mmol, 39% yield, 81% purity). LCMS: (M+1 = 564.2).

[0447] Step 6. Add concentrated HCl (12 M, 0.4 mL, 15 equivalents) to a solution of (10S,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2-(oxacyclohexane-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadene (180 mg, 0.319 mmol, 1 equivalent) in MeOH (2 mL). Stir the mixture at 25 °C for 2 hours. After completion, quench the mixture with saturated NaHCO3 solution (5 mL) and extract with ethyl acetate (5 mL × 3). Dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate to obtain the residue. The residue was purified by preparative HPLC to give (10S,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadene (86.74 mg, 0.161 mmol, 50.48% yield, 97.67% purity, formate) as a white solid (Example 19). Analytical data for Example 19 are shown in the table below.

[0448] Preparation of (10S,17E)-20-fluoro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinyl pentadecanene (Example 20).

[0449]

[0450] Step 1. K₂CO₃ (1.96 g, 14.2 mmol, 2 equivalents) was added to a solution of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole (2.30 g, 7.07 mmol, 1 equivalent, I-3-4) and commercially available 1,3-dimethyl-1H-pyrazol-5-ol (912 mg, 8.13 mmol, 1.15 equivalents) in 2-MeTHF (30 mL). The mixture was degassed under vacuum and backfilled three times with N₂, and stirred at 20 °C for 15 min. Then, t-BuBrettphos Pd G₃ (604 mg, 0.707 mmol, 0.1 equivalents) was added to the mixture, and the mixture was degassed under vacuum and backfilled three times with N₂, and stirred at 70 °C for 2 h. After completion, the mixture was filtered, the filter cake was washed with EA (50 mL), and the mixture was extracted with ethyl acetate (50 mL × 2) and water (100 mL). The combined organic phases were washed with brine (50 mL × 2). The aqueous phase was adjusted to pH 3–5 with citric acid and extracted with DCM (20 mL × 3). The two combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give 4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazole-5-ol (2.60 g, 4.67 mmol, 66% yield, 64% purity) as a yellow solid without further purification. LCMS: (M+1: 357.2).

[0451] Example 20 was prepared using intermediate I-4-10 as described above, following steps 2-6 of the preparation method from Example 19. Analytical data for Example 20 are shown in the table below.

[0452] Preparation of (2S)-1-{(10S,17E)-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol (Example 21).

[0453]

[0454]

[0455] Step 1. Add K₂CO₃ (1.67 g, 12.1 mmol, 3 equivalents) to a solution of (2S)-N-ethyl-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)prop-1-amine (1.90 g, 4.03 mmol, 1 equivalent) and (S)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-1H-pyrazole (2.27 g, 4.03 mmol, 1 equivalent) in DMF (19 mL). Stir the mixture at 80 °C for 4 hours. After completion, the reaction mixture was diluted with added H2O (100 mL) at 25 °C and extracted with EA (50 mL × 3). The combined organic layers were washed with H2O (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid column chromatography (0-100% THF / PE) to give (2S)-N-((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl-1-amine (3.30 g, 3.63 mmol, 90% yield). LCMS: (M+1:908.5).

[0456] Step 2. Dissolve (2S)-N-((1-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-1H-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl-1-amine (1.50 g, 1.65 mmol, 1 equivalent), Pd(OAc)2 (74.2 mg, 0.330 mmol, 0.2 equivalent), TBAC (459 mg, 1.65 mmol, 1 equivalent) and NaHCO3 (346.96 mg, 4.13 mmol, 2.5 equivalent) in DMF (15 The mixture in mL was degassed and purged three times with N2, and then stirred at 130 °C under N2 atmosphere for 1 hour. After completion, the reaction mixture was diluted with H2O (80 mL) and extracted with EA (40 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product (10S,17E)-14-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}propyl]-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-2-(oxecyclohexane-2-yl)-16-[(prop-2-yl)oxy]-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinyl pentadecene (1.20 g, 1.54 mmol, 93% yield) was an unpurified brown oil. LCMS: (M+1:780.6).

[0457] Step 3. Add concentrated HCl (12 M, 2 mL, 17.0 equivalents) to a solution of (10S,17E)-14-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}propyl]-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-2-(oxacyclohexane-2-yl)-16-[(prop-2-yl)oxy]-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinyl pentadecene (1.10 g, 1.41 mmol, 1 equivalent) in MeOH (10 mL). Stir the mixture at 25 °C for 1 hour. After completion, the mixture was quenched by adding a saturated NaHCO3 solution at 0°C to adjust the pH to 7, and extracted with MeOH / DCM (1 / 15) (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC to give (2S)-1-{(10S,17E)-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol (268.88 mg, 0.433 mmol, 30.71% yield, 93.69% purity) as a white solid (Example 21). Analytical data for Example 21 are shown in the table below.

[0458] Example 22 was prepared using intermediate I-2-9 from step 1, following the method described in Example 21. Analytical data for Example 22 are shown in the table below.

[0459] Preparation of (10S,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadene (Example 23).

[0460]

[0461] Step 1. A solution of 5-bromo-7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole (700 mg, 2.05 mmol, 1 equivalent), commercially available 1,3-dimethyl-1H-pyrazole-5-ol (264 mg, 2.36 mmol, 1.15 equivalent), K₂CO₃ (566 mg, 4.10 mmol, 2 equivalent), and tBuBrettPhos Pd G₃ (175 mg, 0.205 mmol, 0.1 equivalent) in 2-MeTHF (7 mL) was degassed and purged three times with N₂. The mixture was then stirred at 80 °C for 1 hour under N₂ atmosphere. After completion, the mixture was filtered and concentrated to obtain a residue, quenched with water (15 mL), and extracted with DCM / MeOH (10:1) (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 15:1) to give 4-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazole-5-ol (300 mg, 0.805 mmol, 39% yield) as a brown solid. LCMS: (M+1:373.0).

[0462] Step 2. A solution of 4-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazole-5-ol (230 mg, 0.617 mmol, 1 equivalent), (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N-methylacetamide (171 mg, 0.925 mmol, 1.5 equivalent, I-3-1), and PPh3 (243 mg, 0.925 mmol, 1.5 equivalent) in THF (3 mL) was degassed and purged three times with N2. Then, DBAD (284 mg, 1.23 mmol, 2 equivalent) in THF (3 mL) was added at 0 °C. The mixture was stirred at 25 °C under N2 atmosphere for 1 hour. After completion, the mixture was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE:THF = 1:1 to 2:1) to give N-((2S)-2-((4-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-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+1:540.3)

[0463] Step 3. Lithium hydroxide hydrate (242 mg, 5.78 mmol, 6 equivalents) was added to a solution of N-((2S)-2-((4-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl)-2,2,2-trifluoro-N-methylacetamide (520 mg, 0.963 mmol, 1 equivalent) in THF (5 mL) and H2O (1 mL). The mixture was stirred at 25 °C for 16 hours. After completion, the mixture was quenched with water (5 mL) and extracted with 2-MeTHF (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1:0 to 10:1) to give (2S)-2-((4-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)-N-methylpropyl-1-amine (130 mg, 0.293 mmol, 30% yield) as a yellow oil. LCMS: (M+1:444.2)

[0464] Step 4. A mixture of (2S)-2-((4-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)-N-methylpropyl-1-amine (130 mg, 0.293 mmol, 1 equivalent), 5-(bromomethyl)-4-iodo-1,3-dimethyl-1H-pyrazole (138 mg, 0.439 mmol, 1.5 equivalent) and K2CO3 (121 mg, 0.878 mmol, 3 equivalent) in DMF (2 mL) was stirred at 80 °C for 1 hour. The mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / THF = 1:0 to 2:1) to give (2S)-2-((4-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)-N-((4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)methyl)-N-methylpropyl-1-amine (180 mg, 0.265 mmol, 91% yield). LCMS: (M+1:678.3)

[0465] Step 5. To a solution of (2S)-2-((4-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)-N-((4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)methyl)-N-methylpropyl-1-amine (180 mg, 0.265 mmol, 1 equivalent) in DMF (2 mL), add NaHCO3 (1.66 mg, 0.664 mmol, 2.5 equivalent), TBAC (73.8 mg, 0.265 mmol, 1 equivalent), and Pd(OAc)2 (11.9 mg, 0.053 mmol, 0.2 equivalent). Degas the mixture and purge it three times with N2, then stir at 130 °C for 1 hour under N2 atmosphere. After completion, the mixture was quenched with water (8 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / THF = 1:0 to 1:2) to give (10S,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2-(oxacyclohexane-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadene (110 mg, 0.200 mmol, 75% yield). LCMS: (M+1:550.2).

[0466] Step 6. Dissolve (8S,17E(10S,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2-(oxacyclohexane-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadene (90.0 mg, 0.164 mmol, 1 equivalent) in concentrated HCl (12 M, 0.9 mL, 32.5 equivalents) and MeOH (2.7 mmol / L). The solution in mL was stirred at 25 °C for 30 min. After completion, the mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC to give (10S,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadene (29.28 mg, 0.0628 mmol, 38.41% yield, FA salt) as a white solid (Example 23). The analytical data for Example 23 are shown in the table below.

[0467] Preparation of (10S,17E)-20-chloro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinyl pentadecanene (Example 24).

[0468]

[0469] Step 1. A mixture of 5-bromo-7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazole (700 mg, 2.05 mmol, 1 equivalent), commercially available 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-ol (335 mg, 2.36 mmol, 1.15 equivalent), K₂CO₃ (566 mg, 4.10 mmol, 2 equivalent), and tBuBrettPhosPdG₃ (175 mg, 0.205 mmol, 0.1 equivalent) in 2-MeTHF (7 mL) was degassed and purged three times with N₂. The mixture was then stirred at 80 °C for 1 hour under N₂ atmosphere. After completion, the mixture was filtered and concentrated to obtain a residue, which was quenched with water (15 mL) and extracted with DCM / MeOH (10:1) (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 15:1) to give 4-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-ol (450 mg, 1.12 mmol, 55% yield) as a brown solid. LCMS: (M+1:403.0).

[0470] Example 24 was prepared using intermediate I-6-10 as described in steps 2-6 of the preparation from Example 23. Analytical data for Example 24 are shown in the table below.

[0471] Preparation of (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-1-ol (25).

[0472]

[0473] Step 1. At 0°C, 100 mg (0.281 mmol) of 4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazole-5-ol (synthesized according to the method described in Step 1 for the preparation of Example 19), (R)-N-ethyl-2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (67.06 mg, 0.337 mmol), and PPh3 (110 mg, 0.421 mmol) were added to anhydrous THF (1 mL). The mixture was stirred at 22°C for 18 hours. The mixture was then concentrated under reduced pressure. Rapid column chromatography (20-100% EA / hexane) yielded N-ethyl-2,2,2-trifluoro-N-((2S)-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl)acetamide (125 mg, 0.233 mmol, 82.87% yield). LCMS: m / z 538.32 (M+1)

[0474] Step 2. To N-ethyl-2,2,2-trifluoro-N-((2S)-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl)acetamide (125 mg, 0.233 mmol), add an aqueous solution of LiOH (2 M, 1 mL). Stir the mixture at 22 °C for 2 hours, cool to -20 °C, dilute with DCM (2 mL), and add 2 M HCl (1 mL aqueous solution) with vigorous stirring. Dilute the reaction mixture with DCM and water (5 mL each) and separate the layers. Extract the aqueous layer again with DCM (2 × 5 mL). Wash the combined organic layers with brine and dry with sodium sulfate. The evaporator was evaporated to give (2S)-N-ethyl-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl-1-amine, and the process was continued without further purification, assuming quantitative yield. LCMS: m / z 442.37 (M+1).

[0475] Step 3. Add K₂CO₃ (96 mg, 0.697 mmol) to (2S)-N-ethyl-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl-1-amine (102.6 mg, 0.232 mmol) in DMF (1.5 mL), followed by (S)-1-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-1H-pyrazole (210 mg, 0.382 mmol). Stir the mixture at 60 °C for 1 hour. Cool the reaction mixture and dilute with DCM (10 mL), then filter. Dilute the filtrate with DCM and water (10 mL each). After separation of the layers, the aqueous layer was extracted again with DCM (2 × 10 mL). The combined organic layers were washed with brine and then dried over sodium sulfate. Rapid column chromatography (20-50% EA / hexane) yielded (2S)-N-((1-((S)-1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)prop-1-amine (115 mg, 0.133 mmol, 57.29% yield). LCMS: m / z 864.50 (M+1)

[0476] Step 4. Add NaHCO3 (33.55 mg, 0.399 mmol) and TBAC (44 mg, 0.16 mmol) to (2S)-N-((1-((S)-1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-N-ethyl-2-((4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-indazol-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl-1-amine (115 mg, 0.133 mmol) in DMF (1 mL). Purge with argon gas, then add Pd(OAc)2 (3 mg, 0.013 mmol). Seal the container and stir the mixture at 140 °C for 1 hour. The reactants were cooled, diluted with 10 mL each of DCM and water, and the layers were separated. The aqueous layer was extracted again with DCM (2 × 10 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Rapid column chromatography (0-10% methanol / DCM) yielded (10S,17E)-14-[(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propyl-2-yl]-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2-(oxecyclohexane-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadene (54.49 mg, 0.074 mmol, 56% yield). LCMS: m / z 736.59 (M+1)

[0477] Step 5. Add TFA (745.00 mg, 6.53 mmol, 0.5 mL) to a solution of (10S,17E)-14-[(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propyl-2-yl]-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2-(oxacyclohexane-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinyl decylene (54.49 mg, 0.074 mmol) in DCM (1 mL). Stir the mixture at 22 °C for 18 hours. Volatile substances were removed under reduced pressure, and the residue was purified by preparative HPLC to give (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-1-ol (21.04 mg, 0.0389 mmol, 52.56% yield, 99.43% purity) as a white solid (Example 25). Analytical data for Example 25 are shown in the table below.

[0478] Example 26 was prepared using step I-3-1 from step 1, following steps 1-5 as described in the preparation of Example 25. The analytical data for Example 26 are shown in the table below.

[0479] Table 1

[0480]

[0481]

[0482]

[0483]

[0484] Screening assay

[0485] Biochemical assay

[0486] Evaluation of CLK and PIM kinase activity by Reaction Biology Corporation

[0487] Inhibitory activity against kinases was evaluated using the HotSpot assay platform at Reaction Biology (see www.reactionbiology.com). The HotSpot assay platform is a radioassay based on a conventional filter-binding assay that directly measures the catalytic activity of a kinase against a specific substrate (Anastassiadis T et al., Comprehensive Assay of Kinase Catalytic Activity Reveals Features of Kinase Inhibitor Selectivity., *Nature Biotechnol.*, 2011, 29:1039-45). In brief, specific kinase / substrate pairs and the required cofactors were prepared in the following reaction buffers: 20 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO. The compound was delivered to the reaction vessel, and then ATP (Sigma, St. Louis, MO) was added approximately 20 minutes later. 33 A mixture of P ATP (Perkin Elmer, Waltham, MA) was prepared to a final concentration of 10 μM. The reaction was carried out at room temperature for 120 minutes, and then the reactants were spotted onto P81 ion-exchange filter paper (Whatman Inc., Piscataway, NJ). Unbound phosphate was removed by thoroughly washing the filter with 0.75% phosphoric acid. Kinase activity data are expressed as a percentage of residual kinase activity in the test sample compared to the reaction with the methyl sulfoxide after subtracting the background from the control reaction containing inactive enzymes. IC50 was obtained using Prism (GraphPad software). 50 The values ​​and curve fitting are shown in Table 1.

[0488] Table 1. Inhibition of CLK and PIM kinase activity

[0489]

[0490] Cell proliferation inhibition assay

[0491] Ba / F3 cells were purchased from DSMZ. The EML4-ALK gene was synthesized in GenScript and cloned into the pCDH-CMV-MCS-EF1-Puro plasmid (System Biosciences, Inc.). Ba / F3 EML4-ALK cell lines were generated by infecting Ba / F3 cells with a lentivirus containing the EML4-ALK gene. Stable cell lines were selected by treatment with puromycin followed by IL-3 removal.

[0492] 2000 Ba / F3 EML4-ALK or Ba / F3 + IL3 (1 μg / mL) cells per well were seeded in 384-well white plates and treated with the specified compound for 72 hours. Cell proliferation was measured using a CellTiter-Glo 2.0 luciferase-based ATP assay (Promega, Madison, WI) according to the manufacturer's protocol. IC50 was measured using Prism software (GraphPad Software, San Diego, CA). 50 The values ​​are then displayed in Table 2.

[0493] Table 2

[0494]

Claims

1. A compound of the following formula, Or its pharmaceutically acceptable salt, wherein " "Optionally, it is a carbon-carbon single bond or a carbon-carbon double bond; Ring A is a 5- or 6-membered heteroaryl group or a C6-C ring. 10 Alpha-aryl; Ring B is a 5- or 6-membered heteroaryl group; Each L is independently -O-, -S-, -S(O)-, -S(O)2-, -N(R) 6 )C(O)-、-C(O)N(R 6 )-、N(R 6 ), N(R 6 )S(O)-、-S(O)N(R 6 )-、-N(R 6 S(O)2-、-S(O)2N(R) 6 - or -C(R) 7 (R) 8 -, the condition is (L) p It does not contain OO, SO, or NN bonds, and (L) p With -NR 3 - Covalent connection points do not form -NN- or -ON- bonds; When it exists, each R 1 and R 2b Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a S(O)R a S(O)2R a S(O)NR a R b S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b NR a C(O)R b NR a C(O)OR b NR a C(O)NR a R b NR a S(O)R b NR a S(O)2R b -NR a S(O)NR a R b NR a S(O)2NR a R b C(O)R a C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b 、P(O)NR a R b -P(O)2NR a R b P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c OC(O)NR c R d OC (=NR) d )NR c R d -OS(O)R c OS(O)2R c OS(O)NR c R d -OS(O)2NR c R d SR c S(O)R c -S(O)2R c -S(O)NR c R d S(O)2NR c R d NR c R d NR c C(O)R d 、N(C(O)R c )(C(O)R d ), NR c C(O)OR d NR c C(O)NR c R d NR c C(=NR d )NR c R d NR c S(O)R d NR c S(O)2R d NR c S(O)NR c R d NR c S(O)2NR c R d C(O)R c C(O)OR c C(O)NR c R d C(=NR) d R d NR c R d PR c R d P(O)R c R d P(O)2R c R d 、P(O)NR c R d P(O)2NR c R d P(O)OR c P(O)2OR c -CN or NO2 substitution; R 2a It is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a -SR a S(O)R a S(O)2R a S(O)NR a R b S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b -NR a R b NR a C(O)R b NR a C(O)OR b NR a C(O)NR a R b NR a S(O)R b NR a S(O)2R b -NR a S(O)NR a R b NR a S(O)2NR a R b C(O)R a C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b 、P(O)NR a R b -P(O)2NR a R b P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR. c -OC(O)R c OC(O)NR c R d OC (=NR) d )NR c R d -OS(O)R c OS(O)2R c OS(O)NR c R d -OS(O)2NR c R d -SR c S(O)R c -S(O)2R c -S(O)NR c R d S(O)2NR c R d NR c R d NR c C(O)R d -N(C(O)R c )(C(O)R d ), NR c C(O)OR d NR c C(O)NR c R d NR c C(=NR d )NR c R d NR c S(O)R d NR c S(O)2R d NR c S(O)NR c R d NR c S(O)2NR c R d C(O)R c C(O)OR c C(O)NR c R d -C(=NR) d )NR c R d PR c R d P(O)R c R d P(O)2R c R d 、P(O)NR c R d P(O)2NR c R d P(O)OR c -P(O)2OR c -CN or NO2 substitution; R 3 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein C1C6 alkyl, C2-C6 alkenyl, C2C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally -OR c -OC(O)R c OC(O)NR c R d OC (=NR) d )NR c R d OS(O)R c OS(O)2R c OS(O)NR c R d -OS(O)2NR c R d -SR c S(O)R c -S(O)2R c -S(O)NR c R d S(O)2NR c R d NR c R d NR c C(O)R d -N(C(O)R c )(C(O)R d ), NR c C(O)OR d NR c C(O)NR c R d NR c C(=NR d )NR c R d NR c S(O)R d NR c S(O)2R d NR c S(O)NR c R d NR c S(O)2NR c R d C(O)R c C(O)OR c C(O)NR c R d -C(=NR) d )NR c R d -PR c R d P(O)R c R d P(O)2R c R d 、P(O)NR c R d P(O)2NR c R d P(O)OR c -P(O)2OR c -CN or -NO2 substitution; Each R 4 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6C 10 Aryl, 5- to 10-membered heteroaryl, -OR a OC(O)R a -OC(O)NR a R b -OS(O)R a OS(O)2R a SR a S(O)R a S(O)2R a S(O)NR a R b S(O)2NR a R b -OS(O)NR a R b OS(O)2NR a R b -NR a R b NR a C(O)R b NR a C(O)OR b NR a C(O)NR a R b -NR a S(O)R b NR a S(O)2R b -NR a S(O)NR a R b NR a S(O)2NR a R b C(O)R a C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b 、P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or OR. e OC(O)R e OC(O)NR e R f -OS(O)R e OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e S(O)R e -S(O)2R e S(O)NR e R f S(O)2NR e R f NR e R f -NR e C(O)R f -NR e C(O)OR f NR e C(O)NR e R f NR e S(O)R f -NR e S(O)2R f NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e C(O)OR e C(O)NR e R f -PR e R f -P(O)R e R f P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f P(O)OR e P(O)2OR e -CN or NO2 substitution; R 5 It is H, deuterium, C(O)R c C(O)OR c C(O)NR c R d P(O)2R c R d P(O)2NR c R d P(O)2OR c or -S(O)2OR c ; When it exists, each R 6 Independently, it is H, deuterium, C1C6 alkyl, C2-C6 alkenyl, C2C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein C1C6 alkyl, C2-C6 alkenyl, C2C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl or 5- to 10-membered heteroaryl group is independently and optionally -OR c -OC(O)R c OC(O)NR c R d OC (=NR) d )NR c R d OS(O)R c OS(O)2R c OS(O)NR c R d -OS(O)2NR c R d SR c S(O)R c -S(O)2R c -S(O)NR c R d S(O)2NR c R d NR c R d NR c C(O)R d 、N(C(O)R c )(C(O)R d ), NR c C(O)OR d NR c C(O)NR c R d NR c C(=NR d )NR c R d NR c S(O)R d NR c S(O)2R d NR c S(O)NR c R d NR c S(O)2NR c R d C(O)R c C(O)OR c C(O)NR c R d C(=NR) d )NR c R d PR c R d P(O)R c R d P(O)2R c R d 、P(O)NR c R d P(O)2NR c R d P(O)OR c P(O)2OR c -CN or NO2 substitution; Each R 7 and R 8 Independently, it is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6C 10 Aryl, 5- to 10-membered heteroaryl, -OR a OC(O)R a -OC(O)NR a R b -OS(O)R a OS(O)2R a SR a S(O)R a S(O)2R a S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b OS(O)2NR a R b -NR a R b NR a C(O)R b NR a C(O)OR b NR a C(O)NR a R b NR a S(O)R b NR a S(O)2R b -NR a S(O)NR a R b NR a S(O)2NR a R b C(O)R a C(O)OR a -C(O)NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b 、P(O)NR a R b -P(O)2NR a R b P(O)OR a -P(O)2OR a -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently optionally replaced by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or OR. e OC(O)R e OC(O)NR e R f -OS(O)R e OS(O)2R e -OS(O)NR e R f OS(O)2NR e R f -SR e S(O)R e -S(O)2R e S(O)NR e R f S(O)2NR e R f NR e R f -NR e C(O)R f NR e C(O)OR f NR e C(O)NR e R f NR e S(O)R f -NR e S(O)2R f NR e S(O)NR e R f -NR e S(O)2NR e R f C(O)R e C(O)OR e C(O)NR e R f -PR e R f -P(O)R e R f P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f P(O)OR e P(O)2OR e -CN or NO2 substitution; or R 7 and R 8 The two carbons in R, together with one or more carbons to which they are attached, may optionally combine to form C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein when R 7 and R 8 When two of them combine to form a C3-C6 cycloalkyl or a 3- to 7-membered heterocycloalkyl group, each hydrogen atom in the resulting C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl group is independently and optionally ORed. e OC(O)R e OC(O)NR e R f -OS(O)R e OS(O)2R e OS(O)NR e R f OS(O)2NR e R f -SR e S(O)R e -S(O)2R e S(O)NR e R f S(O)2NR e R f NR e R f NR e C(O)R f NR e C(O)OR f NR e C(O)NR e R f NR e S(O)R f -NR e S(O)2R f NR e S(O)NR e R f NR e S(O)2NR e R f C(O)R e C(O)OR e C(O)NR e R f -PR e R f -P(O)R e R f P(O)2R e R f 、P(O)NR e R f -P(O)2NR e R f P(O)OR e -P(O)2OR e -CN or NO2 substitution; Each R a R b R c R d R e and R f Independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl, 5- to 10-membered heteroaryl and C1C6 alkylene-5- to 10-membered heteroaryl, or R a and R b or R c and R d or R e and R f Together with the carbon atom it is attached to, it forms 3 to 7-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3 to 7-membered heterocyclic alkyl, and C6-C 10 Aryl, C1-C6 alkylene-C6C 10 Each hydrogen atom in an aryl, 5- to 10-membered heteroaryl, or C1C6 alkylene group is independently optionally replaced by a deuterium, halogen, C1-C6 alkyl, C1C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O) (H or C1-C6 alkyl), -OC(O)N (H or C1-C6 alkyl)2, -OC(O)N (C2-C6 alkylene), OS(O)- (H or C1C6 alkyl), OS(O)2- (H or C1-C6 alkyl), OS(O)N (H or C1-C6 alkyl)2, OS(O)N (C2-C6 alkylene), OS(O)2N (H or C1-C6 alkyl)2, OS( O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), S(O)(H or C1C6 alkyl), S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, S(O)N(C2-C6 alkylene), S(O)2N(H or C1C6 alkyl)2, S(O)2N(C2C6 alkylene), N(H or C1C6 alkyl)2, N(C2C6 alkylene), N(H or C1C6 alkyl)C(O)-(H or C1-C6 alkyl), N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), N(H or C1C6 alkyl)C(O)N( H or C1-C6 alkyl)2, N(H or C1C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1C6 alkyl)S(O)-(H or C1C6 alkyl), -N(H or C1C6 alkyl)S(O)2(H or C1C6 alkyl), N(H or C1C6 alkyl)S(O)N(H or C1C6 alkyl)2, N(H or C1C6 alkyl)S(O)N(C2C6 alkylene), N(H or C1C6 alkyl)S(O)2N(H or C1C6 alkyl)2, N(H or C1C6 alkyl)S(O)2N(C2C6 alkylene), -C(O)-(H or C1C6 alkyl), -C(O)O (H or C1C6 alkyl), C(O)N(C2C6 alkylene), -P(H or C1C6 alkyl)2, -P(C2C6 alkylene), -P(O)(H or C1C6 alkyl)2, -P(O)(C2C6 alkylene), P(O)2(H or C1C6 alkyl)2, P(O)2(C2C6 alkylene), P(O)N(H or C1C6 alkyl)2, P(O)N(C2C6 alkylene), -P(O)2N(H or C1C6 alkyl)2, -P(O)2N(C2C6 alkylene), P(O)O(H or C1C6 alkyl), -P(O)2O(H or C1C6 alkyl), -CN or -NO2 substitution; m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 3, 4, 5, 6, or 7; and q is 0, 1, or 2; The compound described does not have the following formula , , , , , , , , , or .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having formula II Each of them "Independently and optionally, it is a carbon-carbon single bond or a carbon-carbon double bond, and ring A is a 5-membered heteroaryl group." 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having formula III in Cyclone B is a 5-membered heteroaryl group; X 1 X 2 and X 3 Each is independently -O-, -S-, =C(H)-, =C(R)-. 1 -, -N(H)-, -N(R) 1 )- or = N- and ring A is a 5-membered heteroaryl group, provided that X 1 X 2 and X 3 At least one of them is not =C(H)- or =C(R) 1 )-;and Each "Independently and optionally, it is a carbon-carbon single bond or a carbon-carbon double bond." 4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having formula III in Y 1 and Y 2 Each is independently -O-, -S-, =C(H)-, =C(R)-. 2b -, -N(H)-, -N(R) 2b )- or = N- and ring B is a 5-membered heteroaryl group, provided that Y 1 and Y 2 At least one of them is not =C(H)- or =C(R) ab )-;and In ring A "Optionally, a carbon-carbon single bond or a carbon-carbon double bond, in ring B." "It is a carbon-carbon single bond, and one of the bonds in ring B." It is a carbon-carbon double bond.

5. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , and , Each of them " " indicates a covalent connection point.

6. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein ring A is a 5-membered heteroaryl group selected from the group consisting of: , , , , , , , , , , , , , , , and , Each of them " " indicates a covalent connection point.

7. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group selected from the group consisting of: , , , , , , and , Each of them " " indicates a covalent connection point.

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

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

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

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2 or 8 to 10, wherein ring A is or Each of them " " indicates a covalent connection point.

12. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein ring B is a 5-membered heteroaryl group.

13. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein ring B is a 5-membered heteroaryl group selected from the group consisting of: , , , , , , and , Each of them " " indicates a covalent connection point.

14. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein ring B is a 5-membered heteroaryl group of the following formula. , , , , , or , Each of them " " indicates a covalent connection point.

15. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein R 3 It is H, methyl, ethyl, isopropyl, or cyclopropyl.

16. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein R 4 It is H, fluorine, chlorine or methyl.

17. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein R 5 It is H.

18. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein each L is independently -O-, -C(R) 7 (R) 8 )- or N(R 6 -, the condition is (L) p It does not contain -OO-, -NO-, or -NN- bonds, and (L) p With -NR 3 - Connection points do not form -ON- or -NN- bonds.

19. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein (L) p It is -O(C(R) 7 (R) 8 ))2-or-O(C(R) 7 (R) 8 ))3-.

20. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein, when present, R 6 It is H, methyl, or ethyl.

21. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein each R 7 and R 8 It is either H or methyl on its own.

22. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein (L) p It is -OC((H)(CH3))-CH2-.

23. The compound according to claim 1, wherein the compound is selected from the group consisting of (2S)-1-{(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol; (2S)-2-{(10S,17E)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-1-ol; (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol; (2S)-1-[(10S,17E)-16-ethoxy-6-(methoxymethyl)-8,10-dimethyl-12-(prop-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol; (2S)-1-{(10S,17E)-6-(methoxymethyl)-8,10,12-trimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol; (2S)-1-[(10S,17E)-12-cyclopropyl-16-ethoxy-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol; (2S)-1-{(10S,17E)-6-[difluoro(methoxy)methyl]-12-ethyl-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol; (2S)-1-{(10S,17E)-6-[(difluoromethoxy)methyl]-12-ethyl-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol; (2S)-1-{(10S,17E)-6-(ethoxymethyl)-12-ethyl-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol; (2S)-1-{(10S,17E)-6-[(cyclopropoxymethyl]-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol; (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-6-{[(prop-2-yl)oxy]methyl}-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecane-14-yl]prop-2-ol; (2S)-1-{(10S,17E)-6-[(difluoromethoxy)methyl]-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol; (2S)-1-[(10S,17E)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol; (2S)-1-{(10S,17E)-6-(ethoxymethyl)-12-ethyl-20-fluoro-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol; (2S)-1-{(10S,17E)-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol; (2S)-1-{(10S,17E)-6-(ethoxymethyl)-12-ethyl-19-fluoro-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol; (2S)-1-[(10S,17E)-16-ethoxy-6-(ethoxymethyl)-12-ethyl-19-fluoro-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol; (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-19-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol; (10S,17E)-20-fluoro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine heterocyclic pentadecene; (10S,17E)-20-fluoro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine heterocyclic pentadecene; (2S)-1-{(10S,17E)-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-16-[(prop-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl}prop-2-ol; (2S)-1-[(10S,17E)-16-ethoxy-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-2-ol; (10S,17E)-20-chloro-6,8,10,12,14,16-hexamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine heterocyclic pentadecene; (10S,17E)-20-chloro-6-(methoxymethyl)-8,10,12,14,16-pentamethyl-2,10,11,12,13,14-hexahydro-8H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazine-heterocyclic pentadecene; (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-20-fluoro-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-ethylene-bridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-1-ol; and (2S)-2-[(10S,17E)-16-ethoxy-20-fluoro-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-3,5-vinylbridged tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazolidinylpentadecanyl-14-yl]prop-1-ol; Or its pharmaceutically acceptable salt.

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

25. A method of treating a subject's disease, comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 23 or the pharmaceutical composition according to claim 24.

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

27. Use of a compound according to any one of claims 1 to 23 for preparing a medicament for treating a disease in a subject.

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