EGFR inhibitors for disease treatment

Abstract

The present invention relates to compounds that target kinases such as EGFR, pharmaceutical compositions containing such compounds, and methods for using such compounds for the treatment of diseases such as cancer.

Description

[Technical Field]

[0001] Related applications This application claims the interests of U.S. Provisional Application 63 / 463,498 filed 2 May 2023, U.S. Provisional Application 63 / 627,624 filed 31 January 2024, and U.S. Provisional Application 63 / 636,734 filed 20 April 2024, and incorporates all of the disclosures thereof in their entirety by reference herein.

[0002] Technical field The present invention relates to compounds that target kinases such as EGFR, pharmaceutical compositions containing such compounds, and methods for using such compounds for the treatment of diseases such as cancer. [Background technology]

[0003] background Protein kinases are tightly regulated signaling proteins that organize the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G, et al., The protein kinase complement of the human genome. Science. 2002, 298: 1912-34). Dysregulation of kinase activity is associated with many diseases, including cancer, as well as cardiovascular diseases, degenerative diseases, immunological 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 kinase gain-and-loss mutations, gene amplification and deletions, splicing changes, and translocations (Wilson LJ, et al., New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res. 2018, 78: 15-29). Due to the crucial role of kinases in cancer and other diseases, they have become attractive targets for drug invention, and 62 small molecule kinase inhibitors have been approved, 55 of which are for cancer-targeted therapy (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2021 Update. Pharmacol Res 2021, 165: 105463). While kinase inhibitors have achieved dramatic success in cancer-targeted 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. Cancers (Basel), 2020, 12: 731). Resistance can also originate from a subpopulation of resistant / persistent cells that survive in the presence of the treatment agent. Various processes, including pathway rebound via the disengagement of negative feedback loops, transcriptional rewiring via chromatin remodeling, and autocrine / paracrine communication between tumor cells and within the tumor microenvironment, contribute to the emergence of resistant / persistent cells (Swayden M, et al., Tolerant / Persister Cancer Cells and the Path to Resistance to Targeted Therapy. Cells 2020, 9, 2601). Therefore, it is desirable to invent kinase inhibitors that target kinase oncogenic drivers, not only overcoming the most frequent resistance mutations but also targeting resistance-conserving cancer cells to overcome resistance, thereby achieving good efficacy and long-term disease control.

[0004] Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide (World Health Organization. Cancer Fact Sheet 2017). EGFR mutation activation has been reported in approximately 10-15% of cases in Caucasian adenocarcinoma patients and 50% of cases in Asian patients (Chan BA, Hughes BG, Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res 2015; 4: 36-54). The two most frequent EGFR alterations seen in NSCLC tumors are a short intraframe deletion (del19) in exon 19 of the EGFR gene and the L858R single missense mutation in exon 21 (Konduri K. et al., EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. Cancer Discovery 2016, 6: 601-11).

[0005] First-generation reversible EGFR inhibitors, erlotinib and gefitinib, are superior to chemotherapy in patients with advanced EGFR mutation-positive (Del19 or L858R) NSCLC and are used as the first-line standard of care in this situation. However, most patients develop resistance to gefitinib or erlotinib, and 50%–70% of tumors acquire the EGFR T790M gatekeeper mutation over time (Sequist LV, et al., Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3: 75ra26). The second-generation EGFR inhibitors afatinib and dacomitinib are covalent, irreversible EGFR inhibitors that also inhibit HER2 and ERB4 of the ERB family (Li D, et al., BIBW2992, an irreversible EGFR / HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702-11; Ou SH, Soo RA. Dacomitinib in lung cancer: a "lost generation" EGFR tyrosine-kinase inhibitor from a bygone era? Drug Des Devel Ther 2015; 9: 5641-53).

[0006] Afatinib and dacomitinib are more potent EGFR inhibitors approved as first-line treatments for advanced EGFR mutation-positive (Del19 or L858R) NSCLC, offering longer progression-free survival (PFS) compared to gefitinib and erlotinib, although EGFR T790M is acquired over time with afatinib treatment (Tanaka K, et al., Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Onco-target 2017; 8: 68123-30). EGFR T790M confers resistance to dacomitinib in in vitro studies (Kobayashi Y, et al., EGFR T790M and C797S mutations as mechanisms of acquired resistance to dacomitinib. J Thorac Oncol 2018; 13: 727-31). The third-generation EGFR inhibitor osimertinib is also an irreversible inhibitor that targets both EGFR activating mutations (Del19 and L858R) and the T790M resistance double mutation, and is more selective than wild-type EGFR (Finlay MR, et al., Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild-type form of the receptor. J Med Chem 2014; 57: 8249-67).Osimertinib was initially approved for patients with metastatic EGFR T790M mutation-positive NSCLC after failure of first-line EGFR inhibitors, and subsequently approved in first-line status for patients with EGFR mutation-positive NSCLC following the Phase III FLAURA trial, which included a direct comparison trial with erlotinib or gefitinib (Soria JC, et al., Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378: 113-25). The C797S mutation at the covalent EGFR residue with the irreversible EGFR inhibitor osimertinib has been detected in osimertinib-resistant patients (Ramalingam SS, et al., Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Presented at the ESMO 2018). EGFR mutations (L858R or exon 19 deletion (Ex19del)) are classified as classical or common EGFR mutations that show significant efficacy with currently approved EGFR inhibitors. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] Therefore, there is an urgent medical need to develop holistic EGFR inhibitors that are effective against classical EGFR mutations, including L858R, Δ746-750, Δ746-750 / C979S, L858R / T790M, L858R / T790M / C979S, and D770_N771insNPG, while maintaining better selectivity than wild-type EGFR. [Means for solving the problem]

[0008] overview In one embodiment, the present invention relates to formula I [ka] 〔Wherein, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、A, B, m, n, p, and q are as described herein.〕 relates to a compound of or a pharmaceutically acceptable salt, solvate, hydrate or co-crystal thereof.

[0009] In another aspect, the present invention relates to a compound of formula II

Chemical formula

[0010] In another aspect, the present invention relates to a compound of formula III

Chemical formula

[0011] In other embodiments, the present invention relates to formula IV [ka] [In the formula, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 A and B are as described herein. This relates to compounds or pharmaceutically acceptable salts, solvates, hydrates, or cocrystals thereof.

[0012] In one embodiment of the above-described aspect, the compounds of formulas (I) to (IV) are compounds selected from those specifically described or illustrated in the detailed description below.

[0013] In a further embodiment, the present invention relates to a pharmaceutical composition comprising at least one compound of formulas (I) to (IV) or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof. The pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable additives.

[0014] In a further embodiment, the present invention relates to compounds of formulas (I) to (IV) or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof for use as pharmaceuticals.

[0015] In a further embodiment, the present invention relates to a method for treating a disease such as cancer, comprising administering an effective amount of at least one compound of formulas (I) to (IV) or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof to a subject requiring such treatment.

[0016] In a further embodiment, the present invention relates to the use of compounds of formulas (I) to (IV) or pharmaceutically acceptable salts, solvates, hydrates or cocrystals thereof in the manufacture of pharmaceuticals for the treatment of diseases such as cancer, and to the use of such compounds and salts for the treatment of such diseases.

[0017] In a further embodiment, the present invention relates to a method for inhibiting a tyrosine kinase such as EGFR, comprising certain mutations described herein, comprising contacting a cell containing one or more kinases with an effective amount of at least one compound of formulas (I) to (IV) or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, and / or at least one pharmaceutical composition of the present invention, wherein the contact is in vitro, ex vivo, or in vivo.

[0018] Further embodiments, characteristics, and advantages of the present invention will become apparent from the following detailed description and through the implementation of this disclosure. Compounds of the present invention may be described as embodiments in any of the following numbered clauses. It will be understood that any of the embodiments described herein may be combined with any other embodiments described herein, provided that the embodiments do not conflict with each other.

[0019] 1. Equation I [ka] [During the ceremony, Rings A and B are independently 5-membered heteroarylenes; Each R 1 and R 2 When present, they independently contain deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, and C6-C 10 Aryl, 5-10 member heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a, -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a , -NR b , -NR a , -NR b , -NR a , -NR a R b , -NR a , -NR b , -NR a , -NR b , -NR a , -NR a R b , -NR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)2NR a R b , -P(O)OR a , -P(O)2OR a , -CN, or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 ,-PRc R d ,-P(O)R c R d ,-P(O)2R c R d ,-P(O)NR c R d -P(O)2NR c R d , -P(O)OR c -P(O)2OR c Substituted with -CN or -NO2; Each R 3 , R 4 , R 5 , and R 6 These are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a , -SR a ,-S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a Rb , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a -C(O)NR a R b ,-PR a R b ,-P(O)R a R b ,-P(O)2R a R b ,-P(O)NR a R b -P(O)2NR a R b , -P(O)OR a -P(O)2OR a -CN, or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f , -SR e ,-S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NRe S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN, or -NO2; or R 3 , R 4 , R 5 , and R 6 These two atoms, together with one or more carbon atoms to which they are bonded, form a C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl group, where each hydrogen atom in the C3-C6 cycloalkyl and 3-7 membered heterocycloalkyl groups can be 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 Rf , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; R 7 H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, -C(O)R c , or -C(O)NR c R d Here, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently -OR as desired. 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)2NRc R d , -P(O)OR c -P(O)2OR c Substituted with -CN, or -NO2; or R 7 and R 3 , R 4 , R 5 , or R 6 Each of these atoms, together with the atom to which it is bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the 4- to 7-membered heterocycloalkyl group can be 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 e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e Rf ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2;

[0020] R 8 H, -S(O)2R 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 ,-P(O)2R c R d -P(O)2NR c R d , or -P(O)2OR c and; R 9 H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member 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 Rb , -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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 Substituted with -CN or -NO2; Each R a , R b, R c , R d , R e , and R f These are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, and C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Selected from the group consisting of aryls, 5-10 membered heteroaryls, and C1-C6 alkylene-5-10 membered heteroaryls; or R a and R b or R c and R d or R e and R f These atoms, together with the atoms to which they are bonded, form a 3-7 member heterocycloalkyl group, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10In aryl, 5-10 membered heteroaryl, and C1-C6 alkylenes, each hydrogen atom in the 5-10 membered heteroaryl is independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2 -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O) N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2,Substituted with -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; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 1, 2, 3, or 4; and q is 1, 2, or 3. Compounds thereof or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0021] 2. Formula II [ka] [During the ceremony, each [ka] These are independently carbon-carbon single bonds or carbon-carbon double bonds. A compound of Clause 1 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal having the same properties.

[0022] 3. Formula III [ka] [During the ceremony, each [ka] These are independently carbon-carbon single bonds or carbon-carbon double bonds; X 1 , X 2 , and X 3 -O-, -S-, =C(H)-, =C(R) 1 )-, -N(H)-, -N(R1 )- or =N-, however X 1 , X 2 , and X 3 At least one of them is =C(H)- or =C(R 1 ) - not; and / or Y 1 , Y 2 , and Y 3 -O-, -S-, =C(H)-, =C(R) 2 )-, -N(H)-, -N(R 2 )- or = N-, however Y 1 , Y 2 , and Y 3 At least one of them is =C(H)- or =C(R 2 ) - It's not. A compound of clause 1 or 2 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal having the above.

[0023] 4. Formula IV [ka] A compound of Clause 3 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal having the same properties.

[0024] 5. X 2 is =N- or -N(R 1 )- and X 1 and X 3 -O-, -S-, =C(H)-, =C(R) 1 )-, -N(H)-, or -N(R 1 )-and; and / or Y 2 is = N-, and Y 1 and Y 3 -O-, -S-, =C(H)-, =C(R) 2 )-, -N(H)-, or -N(R 2 )-is, Compounds of clause 3 or 4 or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0025] 6. Ring A [ka] Selected from the group consisting of, Here, each [ka] This represents a covalent bond point. Any compound specified in clauses 1 to 4, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0026] 7. Ring A is [ka] Selected from the group consisting of, Here, each [ka] represents a covalent bond point; Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0027] 8. Ring A is [ka] Selected from the group consisting of, Here, each [ka] represents a covalent bond point; Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0028] 9. Ring B is [ka] Selected from the group consisting of, Here, each [ka] represents a covalent bond point; Any compound specified in clauses 1-4 or 6, or any pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0029] 10. Ring B is [ka] Selected from the group consisting of, Here, each [ka] represents a covalent bond point; Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0030] 11. p is 2 or 3, part [ka] R is ethylene or propylene, where each R 3 and R 4 These are independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a , -SR a ,-S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b , -NRa R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a -C(O)NR a R b ,-PR a R b ,-P(O)R a R b ,-P(O)2R a R b ,-P(O)NR a R b -P(O)2NR a R b , -P(O)OR a -P(O)2OR a , -CN, or -NO2; or R 3 and R 4 At least one of them, together with one or more carbons to which they are bonded, form a C3-C6 cycloalkyl or 4-7 membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 4-7 membered heterocycloalkyl 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)Re -S(O)2R e -S(O)NR e R f -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN, or -NO2; or R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the formed 4- to 7-membered heterocycloalkyl group can be 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 e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; and each [ka] represents a covalent bond point; Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0031] 12. One R 3 This is a C1-C6 alkyl group, where each hydrogen atom in the C1-C6 alkyl group can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f , -SR e ,-S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f、 -P(O)OR e 、 -P(O)₂OR e 、 is substituted with -CN or -NO₂; and / or two Rs 3 and R 4 are integrated with one or more carbons to which they are attached to form C₃-C₆ cycloalkyl or 4-7 member heterocycloalkyl, where each hydrogen atom in C₃-C₆ cycloalkyl and 4-7 member heterocycloalkyl is independently optionally -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)₂R e 、 -OS(O)NR e R f 、 -OS(O)₂NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)₂R e 、 -S(O)NR e R f 、 -S(O)₂NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)₂R f 、 -NR e S(O)NR e R f 、 -NR e S(O)₂NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN, or -NO2 substituted; and / or R 7 and R 3 or R 4 at least one of them is integrated with the atom to which they are attached to form a 4- to 7-member heterocycloalkyl, where each hydrogen atom in the 4- to 7-member heterocycloalkyl is independently optionally -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NRe R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)₂R e R f 、 -P(O)NR e R f 、 -P(O)₂NR e R f 、 -P(O)OR e 、 -P(O)₂OR e 、 -CN, or -NO₂ substituted; and any remaining R 3 and R 4 is H or deuterium, A compound of any of the preceding clauses or a pharmaceutically acceptable salt, solvate, hydrate or co-crystal thereof.

[0032] 13. One R 3 is C₁-C₆ alkyl, where each hydrogen atom in C₁-C₆ alkyl is independently optionally deuterium, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -OR e 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)₂R e 、 -OS(O)NR e R f 、 -OS(O)₂NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)₂R e 、 -S(O)NR e R f 、 -S(O)₂NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)Rf , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; and / or R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the 4- to 7-membered heterocycloalkyl group can be 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 eC(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; and any remaining R 3 and R 4 is either H or deuterium; Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0033] 14. R 3 One of them is a C1-C6 alkyl group; and any remaining R 3 and R 4 is either H or deuterium; Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0034] 15. R 3 One of them is a C1-C6 alkyl group; R 7 and R 4 One of them, together with the atom to which they are bonded, forms a 4-7 member heterocycloalkyl group; and any remaining R3 and R 4 is either H or deuterium; Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0035] 16. R 3 One of them is methyl, and any remaining R 3 and R 4 is either H or deuterium; Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0036] 17. R 7 is H, C1-C6 alkyl, C3-C6 cycloalkyl, or -C(O)R c is; or R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a 4-7 membered heterocycloalkyl group; where each hydrogen atom in the C1-C6 alkyl, C3-C6 cycloalkyl, and 4-7 membered heterocycloalkyl groups 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 Substituted with -CN or -NO2, Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0037] 18. Part [ka] is the formula [ka] These are, and here, each [ka] The ∫ represents a covalent bond, and each hydrogen atom is independently substituted with deuterium as desired. Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0038] 19. R 5 and R 6 Each of these is H, Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0039] 20. Part [ka] is the formula [ka] These are, and here, each [ka] The ∫ represents a covalent bond, and each hydrogen atom is independently substituted with deuterium as desired. Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0040] 21. R 8 is H or C1-C6 alkyl, Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0041] 22. R 9 is H, deuterium, halogen, C1-C6 alkyl, or -OR a Here, each hydrogen atom in the C1-C6 alkyl group is independently substituted with deuterium as desired. Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0042] 23. R 9is H, deuterium, halogen, -OCH3, -CH3, or -CD3. Any of the compounds specified in the preceding clause or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0043] twenty four. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound of Clause 1 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal, selected from the group consisting of the above.

[0044] twenty five. [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound of Clause 1 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal, selected from the group consisting of the above.

[0045] 26. A pharmaceutical composition comprising a compound of any of the preceding clauses or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, and optionally one or more additives.

[0046] 27. A method for treating a target disease, comprising administering a therapeutically effective amount of any compound from clauses 1 to 25 or a pharmaceutically acceptable salt, solvate, hydrate or cocrystal thereof, or a pharmaceutical composition from clause 26.

[0047] 28. Any compound specified in Clauses 1 to 25 or any pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, for use in methods of treating diseases in a subject.

[0048] 29. Use of any compound specified in Clauses 1 to 25 or any pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof in the manufacture of a medicament for the treatment of a disease in a subject. [Modes for carrying out the invention]

[0049] Detailed description Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described, as they may naturally vary. It should also be understood that the terms used herein are for the purpose of describing specific embodiments only, and are not intended to be limiting, as the scope of the present invention is limited only by the appended claims.

[0050] For the sake of brevity, disclosures of publications cited in this specification, including patents, are incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention pertains. All patents, applications, published applications, and other publications cited herein are incorporated herein by reference in their entirety. If any definition set forth in this section conflicts with or otherwise inconsistent with any definition set forth in any patent, 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.

[0051] The singular expressions used herein and in the attached claims include plural subjects unless otherwise indicated by the context. It should be further noted that claims may be drafted to exclude any arbitrary elements; that is, this statement is intended to be a prerequisite for using exclusive terms such as “only” or “solely,” or for using “negative” restrictions, in relation to the description of elements of the claims.

[0052] The terms "include," "contain," and "contain" used here are used in their open, non-restrictive sense.

[0053] To provide a more precise description, some quantitative expressions presented herein are not limited by the term “approximately.” Whether the term “approximately” is explicitly used or not, all numbers presented herein mean the actual values, and also approximations of such values ​​that can be inferred based on the ordinary art of the art, including equivalents, and approximations of such values ​​by experimental and / or measurement conditions. Where yields are expressed as percentages, such yields mean the mass of an entity relative to the maximum amount of that entity that would be obtained under specific stoichiometric conditions. Concentrations expressed as percentages mean mass ratios unless otherwise indicated.

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which the invention pertains. Any methods and materials similar to or equivalent to those described herein may also be used in carrying out or testing the invention, but preferred methods and materials are described below. All publications described herein are incorporated herein by reference to disclose and describe the methods and / or materials cited in those publications.

[0055] Unless otherwise indicated, the methods and techniques of these embodiments are carried out in the customary manner described in the various general and more specific references that are generally known in the art and cited herein. See, for example, Loudon, *Organic Chemistry*, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, *March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, Fifth Edition, Wiley-Interscience, 2001.

[0056] The chemical names of the compounds described herein are generally derived using commercially available software such as ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0057] To the extent used herein and in relation to the chemical structures described in the various embodiments described herein, "*", "**", and [ka] Each of these identifiers represents a bond point of a chemical group or chemical structure shown in an adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure AB in which A and B are bonded by a covalent bond, in one embodiment, the portion of AB defined by group or chemical structure A is [ka] It can be expressed by, here, [ka] Each of these represents a bond to A and a covalent bond to B. Alternatively, in one embodiment, the portion of AB defined by the group or chemical structure B is [ka] It can be expressed by, here, [ka] Each of these represents a bond to B and a covalent bond point to A.

[0058] For clarity, it is recognized that certain properties of the present invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various properties of the present invention described in the context of a single embodiment may be provided separately or in any suitable subcombination. All combinations of the chemical groups represented by the variable groups and the associated embodiments are specifically encompassed and expressly disclosed by the present invention to the same extent as each and all combinations are individually and expressly disclosed, insofar as such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). Furthermore, all subcombinations of the chemical groups listed in embodiments describing such variable groups are also encompassed and expressly disclosed by the present invention to the same extent as each and all subcombinations of the chemical groups are individually and expressly disclosed.

[0059] chemistry definition The term "alkyl" refers to a linear or branched monovalent hydrocarbon group. The term "alkylene" refers to a linear or branched divalent hydrocarbon group. In one embodiment, the number of atoms in "alkyl" or "alkylene" is set to a specific range of atoms, for example, C1-C20 Alkyl or C1-C 20 Alkylene, C1-C 12 Alkyl or C1-C 12 It may be advantageous to limit the group to alkylene, or C1-C6 alkyl or C1-C6 alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that are considered equivalent to any of the above examples in light of the usual art and the teachings provided herein. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n-propylene ((-CH2-)3), isopropylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), and the like. It is recognized that the alkyl or alkylene group may be unsubstituted or substituted as described herein. The alkyl or alkylene group is any of the substituents in the various embodiments described herein, and may be substituted with one or more such substituents.

[0060] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group having one or more double bonds. In one embodiment, the number of atoms in the "alkenyl" is limited to a specific range of atoms, for example, C2-C2 20 Alkenyl, C2-C 12 It may be advantageous to limit the group to alkenyls or C2-C6 alkenyls. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and buto-3-en-1-yl. Cis and trans isomers and mixtures thereof fall within the scope of this term. It is recognized that alkenyls may be unsubstituted or substituted as described herein. The alkenyl group may be substituted with any of the substituents in the various embodiments described herein, including one or more such substituents.

[0061] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having one or more triple bonds. In one embodiment, the number of atoms in "alkynyl" is limited to a specific range of atoms, for example, C2-C2 20 Alkinyl, C2-C 12 It may be advantageous to limit the group to an alkynyl or C2-C6 alkynyl group. Examples of alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH), and buto-3-in-1,4-diyl (-C≡C-CH2CH2-). It is recognized that the alkynyl group may be unsubstituted or substituted, as described herein. The alkynyl group may be substituted with one or more substituents in any of the various embodiments described herein.

[0062] The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic monovalent carbon ring. In some embodiments, it may be advantageous to limit the number of atoms in the "cycloalkyl" to a specific range of atoms, e.g., having 3 to 12 ring atoms. Polycyclic carbon rings include condensed, bridging, and spiropolycyclic systems. Examples of cycloalkyl groups include the monovalent radicals of the following entities: [ka] In particular, the cyclopropyl portion is structural formula [ka] This can be described as follows. It is recognized that the cycloalkyl group may be unsubstituted or substituted as described herein. The cycloalkyl group may be any of the substituents in the various embodiments described herein, and may contain one or more such substituents.

[0063] The term "oxo" refers to the carbonyl oxygen.

[0064] The term "halogen" or "halo" refers to chlorine, fluorine, bromine, or iodine.

[0065] The term "haloalkyl" refers to an alkyl group having one or more halo substituents. Examples of haloalkyl groups include -CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F. The term "aryl" refers to a monocyclic or fused polycyclic group of all carbon atoms having a fully conjugated π-electron system. In some embodiments, the number of atoms in "aryl" is defined as a range of atoms, for example, a monocyclic or fused polycyclic group of all carbon atoms (C6-C6) with 6 to 14 carbon atoms. 14 Aryl groups, or monocyclic or fused polycyclic groups of 6-10 carbon atoms (C 6- C 10 It may be advantageous to limit the group to aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, and anthracenyl. It is recognized that the aryl group may be unsubstituted or substituted, as described herein. The aryl group may be substituted with one or more substituents in any of the substituents in the various embodiments described herein.

[0066] The term “heterocycloalkyl” refers to a monovalent monocyclic or polycyclic ring structure that is saturated or partially saturated and has one or more non-carbon ring atoms. In some embodiments, the number of atoms in the “heterocycloalkyl” may be advantageous to be within a specific range of ring atoms, e.g., 3 to 12 ring atoms (3 to 12 members), or 3 to 7 ring atoms (3 to 7 members), or 3 to 6 ring atoms (3 to 6 members), or 4 to 6 ring atoms (4 to 6 members), 5 to 7 ring atoms (5 to 7 members), or 4 to 10 ring atoms (4 to 10 members). In some embodiments, it may be advantageous to limit the number and type of ring heteroatoms in the “heterocycloalkyl” to a specific range or type of heteroatoms, e.g., 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of monocyclic heterocycloalkyl groups include, but are not limited to, tetrahydrofuran, pyrrolidine, and morpholine. Polycyclic ring systems include condensation, bridging, and spiro systems. In some embodiments, it may be advantageous to limit the number of atoms in the bicyclic "heterocycloalkyl" to a specific range of ring atoms, e.g., 5 to 10 ring atoms (5 to 10 members) or 6 to 10 ring atoms (6 to 10 members). The ring structure may optionally include oxo or imino groups on the carbon ring members or up to two oxo groups on the sulfur ring members. Examples of condensed bicyclic, bridging bicyclic, and spiro-bicyclic heterocycloalkyl groups include, but are not limited to, pyrrolidine, 2,5-diazabicyclo[2.2.2]octane, and 1-oxaspiro[4.5]decane. Examples of heterocycloalkyl groups include the monovalent radicals of the following entities: [ka]

[0067] A three-membered heterocycle may contain at least one heteroatomic ring atom, where the heteroatomic ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of three-membered heterocycle groups include the monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatomic ring atom, where the heteroatomic ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include the monovalent and divalent radicals of azithidine, oxytenane, and thiethane. A five-membered heterocycle may contain up to four heteroatomic ring atoms, where (a) at least one ring atom is oxygen and sulfur, and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur, and up to four ring atoms are nitrogen. Non-limiting examples of 5-membered heterocyclic groups include the monovalent and divalent radicals of pyrrolidine, tetrahydrofuran, 2,5-dihydro-1H-pyrrole, pyrazolidine, thiazolidin, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene-1,1-dioxide, imidazolidine-2-one, pyrrolidine-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2-one, and oxazolidine-2-one. A 6-membered heterocycle may contain up to 4 heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and 0, 1, 2 or 3 ring atoms are nitrogen, or (b) 0 ring atoms are oxygen or sulfur and up to 4 ring atoms are nitrogen. Non-restrictive examples of six-membered heterocyclic groups include monovalent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazine-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A "heterobicyclic" is a condensed bicyclic system containing one heterocyclic ring fused to a cycloalkyl or other heterocyclic ring.

[0068] As described herein, certain embodiments may include a heteroatom-C2-C6 alkylene moiety (e.g., -N(C2-C6 alkylene) or -P(O)2(C2-C6 alkylene)). For example, -heteroatom-(C2-C6 alkylene) represents a cyclic group in which a heteroatom atom (e.g., nitrogen, phosphorus, etc.) forms two covalent bonds with a C2-C6 alkylene group (e.g., [ka] ). For example, -OC(O)N(C2-C6 alkylene) has a structural formula [ka] It can be described by [this method].

[0069] It is recognized that the heterocycloalkyl group may be unsubstituted or substituted, as described herein. The heterocycloalkyl group may be substituted with one or more substituents in any of the substituents in the various embodiments described herein.

[0070] The term "heteroaryl" refers to a monovalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (a ring structure having a carbon atom and a heteroatom selected from up to four nitrogen, oxygen, and sulfur atoms) that is completely unsaturated and has 3 to 12 ring atoms per heterocycle. The term "heteroarylene" refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (a ring structure having a carbon atom and a heteroatom selected from up to four nitrogen, oxygen, and sulfur atoms) that has 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 "heteroarylene" to a specific range of atomic members, for example, a 5-10 member heteroaryl or a 5-10 member heteroarylene. In some cases, a 5-10 membered heteroaryl group may be a monocyclic or fused bicyclic ring having 5-10 ring atoms, where at least one ring atom is a heteroatom such as N, O, or S. In some cases, a 5-10 membered heteroarylene group may be a monocyclic or fused bicyclic ring having 5-10 ring atoms, where at least one ring atom is a heteroatom such as N, O, or S. The ring structure may optionally include an oxo group or imino group on a carbon ring member or up to two oxo groups on a sulfur ring member. A descriptive example of a 5-10 membered heteroaryl group includes the monovalent radical of the following entity, while an example of a 5-10 membered heteroarylene group includes the divalent radical of the following entity, in the form of a properly engaged moiety: [ka]

[0071] In one embodiment, the “monocyclic” heteroaryl may be an aromatic five-membered or six-membered heterocycle. A five-membered heteroaryl or heteroarylene may contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur, and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur, and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include monovalent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-limiting examples of five-membered heteroarylene groups include divalent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six-membered heteroaryl or heteroarylene may contain up to four heteroatomic ring atoms, where (a) at least one ring atom is oxygen and sulfur, and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur, and up to four ring atoms are nitrogen. Non-limiting examples of a six-membered heteroaryl group include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of a six-membered heteroarylene group include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A "bicyclic heteroaryl" or "bicyclic heteroarylene" refers to a fused bicyclic system containing one heteroaryl ring fused to a phenyl or other heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include the monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinoline-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.Non-limiting examples of bicyclic heteroarylene groups include the divalent radicals of azindazole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthiridine, 1,8-naphthiridine, isoquinoline-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.

[0072] In particular, the pyrazolyl portion is in the structural formula [ka] This can be described by the structural formula. In particular, an example of the pyrazolylene portion is shown in the structural formula. [ka] It can be described by [this method].

[0073] In particular, the azaidazolylene or pyrazolopyridylene moiety, such as the 1H-pyrazolo[3,4-c]pyridylene moiety, is structural formula [ka] It can be described by [this method].

[0074] It is recognized that the heteroaryl group may be unsubstituted or substituted, as described herein. The heteroaryl group may be substituted with one or more substituents in any of the substituents in the various embodiments described herein.

[0075] It is recognized that the heteroaryl or heteroarylene group may be unsubstituted or substituted, as described herein. The heteroaryl or heteroarylene group may be substituted with one or more substituents in any of the substituents in the various embodiments described herein.

[0076] The term used here, "each atom bonded to" refers to two substituents bonded to two separate atoms (for example, R 7 and R3 , R 4 , R 5 , or R 6 One of them) becomes one, [ka] This means forming a 4- to 7-membered heterocycloalkyl group as defined by the claims, such as those mentioned above. In particular, the term "each atom forming a 4- to 7-membered heterocycloalkyl group together with the atom to which it is bonded" means, for example, [ka] R on different ring atoms 7 and R 3 , R 4 , R 5 , or R 6 This means that one of these atoms forms a 4- to 7-membered ring with these ring atoms.

[0077] For example, the term "forming a 4- to 7-membered heterocycloalkyl group together with the atom to which each is bonded" used in relation to the embodiments described herein includes compounds represented as follows: [ka]

[0078] The term "substituted" means that a particular group or part has one or more substituents. The term "unsubstituted" means that a particular group does not have substituents. When the term "substituted" is used to describe a structural system, substitution means that it occurs at any position possible by the valence of any atom in the system. In one embodiment, "substituted" means that a particular group or part has one, two, or three substituents. In another embodiment, "substituted" means that a particular group or part has one or two substituents. In yet another embodiment, "substituted" means that a particular group or part has one substituent.

[0079] As used here, "independently" means that the event or situation described below should be interpreted in isolation from other similar events or situations. For example, in a situation where several equivalent hydrogen groups are optionally substituted with other groups described in a given situation, the use of "independently as desired" means that each hydrogen atom of a group may be substituted with another group, and the groups substituting the hydrogen atoms may be the same or different. Or, for example, when there are multiple groups and all of them can be selected from a set of possibilities, the use of "independently" means that each group can be separately selected from a set of possibilities with any other group, and the groups selected in that situation may be the same or different.

[0080] Any formulas presented herein are intended to represent a compound and / or a variation or form of that structural formula. For example, any formulas presented herein are intended to include a racemate, or one or more enantiomers, diastereomers, or geometric isomers, or mixtures thereof. Furthermore, any formula presented herein is also intended to refer to a hydrate, solvate, or polymorph of such a compound, or mixtures thereof.

[0081] Any formula shown herein is also intended to represent the unlabeled and isotopically labeled forms of the compound. The isotopically labeled compound has the structure described by the formulas shown herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present invention are, 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 It contains isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. Such isotope-labeled compounds are used in metabolic studies (preferably).14 (At C) Reaction kinetics research (for example) 2 H or 3 Deuterium (i.e., H) is useful in detection or contrast techniques including drug or substrate tissue distribution assays [e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] or in radioactive treatment of patients. Furthermore, deuterium (i.e., 2 Substitution with heavier isotopes such as H) may provide certain therapeutic advantages due to greater metabolic stability, such as extended in vivo half-life or reduced required dose. The isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by replacing the non-isotopically labeled reagents with readily available isotope-labeled reagents by performing the procedures disclosed in the scheme or the examples and production below.

[0082] The present invention also includes compounds represented by formulas (I) to (IV), preferably pharmaceutically acceptable salts thereof and specific compounds exemplified herein, pharmaceutical compositions comprising such salts, and methods of using such salts.

[0083] "Pharmacologically acceptable salts" are intended to mean salts of free acids or bases of the compounds described herein that are non-toxic, biologically acceptable, or otherwise biologically appropriate for administration to a subject. See, in general, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissue of the subject without excessive toxicity, irritation, or allergic response. The compounds described herein may have a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and thus react with several inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0084] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, capronates, heptanoates, propiolates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-diates, hexin-1, This includes 6-diates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfons, methylsulfons, propylsulfons, besilates, xylenesulfons, naphthalene-1-sulfons, naphthalene-2-sulfons, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0085] For compounds of formulas (I) to (IV) containing basic nitrogen, pharmaceutically acceptable salts are obtained by any suitable method available in the art, for example, by adding a free base to an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, or an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidylic acid, or glucuronic acid. It can be produced by processing with galacturonic acid, alpha-hydroxy acids, such as mandelic acid, citric acid, or tartaric acid, amino acids, such as aspartic acid or glutamic acid, aromatic acids, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, sulfonic acids, such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any suitable mixture of acids, such as those exemplified herein, and any other acids and mixtures thereof that are considered equivalents or acceptable substitutes in light of the ordinary level of skill in this art.

[0086] The present invention also relates to pharmaceutically acceptable prodrugs of the compounds of formulas (I) to (IV), and methods of treatment using such pharmaceutically acceptable prodrugs. The term “prodrug” refers to a precursor of the designated compound that, after administration to a subject, yields the compound in vivo or under physiological conditions via chemical or physiological means such as solvolysis or enzymatic cleavage (for example, a prodrug brought to physiological pH is converted to the compounds of formulas (I) to (IV)). A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, bioacceptable, and otherwise biosuitable for administration to a subject. Explanatory procedures for the selection and manufacture of suitable prodrug derivatives are described, for example, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985.

[0087] The present invention also relates to pharmaceutically active metabolites of the compounds of formulas (I) to (IV), and the use of such metabolites in the methods of the present invention. “pharmaceutically active metabolite” means the pharmacologically active product of the in vivo metabolism of the compounds of formulas (I) to (IV) or their salts. Prodrugs and active metabolites of the compounds can be determined using routine techniques known or available in the art. For example, Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; see Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

[0088] The term "EGFR inhibitor" as used herein includes, but is not limited to, compounds that can inhibit the protein encoded by the EGFR gene. EGFR inhibitors include, but are not limited to, compounds that can inhibit the protein encoded by classical EGFR mutations, rare mutations, and secondary resistance mutations. Examples of EGFR mutations include, but are not limited to, L858R, Δ746-750, Δ746-750 / C979S, L858R / T790M, L858R / T790M / C979S, and D770_N771insNPG, as well as other emerging and established resistance mutations. It will be recognized by those skilled in the art that descriptions of inhibition of EGFR mutations such as EGFR L858R refer to inhibition of the protein encoded by a single missense mutation in exon 21 of the EGFR gene.

[0089] Representative Embodiments In one embodiment, the present invention is represented by formula I [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 A, B, m, n, p, and q are as described herein. The present invention provides compounds or pharmaceutically acceptable salts, solvates, hydrates, or cocrystals thereof.

[0090] In one embodiment, the present invention is represented by formula II [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 A, B, m, n, p, and q are as described herein. This relates to compounds or pharmaceutically acceptable salts, solvates, hydrates, or cocrystals thereof.

[0091] In one embodiment, the present invention is represented by Formula III [ka] [In the formula, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9A, B, p, and q are as described herein. This relates to compounds or pharmaceutically acceptable salts, solvates, hydrates, or cocrystals thereof.

[0092] In one embodiment, the present invention is represented by formula IV [ka] [In the formula, X 1 , X 2 , X 3 , Y 1 , Y 2 , Y 3 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 A and B are as described herein. This relates to compounds or pharmaceutically acceptable salts, solvates, hydrates, or cocrystals thereof.

[0093] For one reason, X 1 , X 2 , and X 3 These are independently -O-, -S-, =C(H)-, and =C(R 1 )-, -N(H)-, -N(R 1 )- or =N-, and ring A is a 5-membered heteroarylene, however X 1 , X 2 , and X 3 At least one of them is =C(H)- or =C(R 1 )-not. In one embodiment, X 2 is =N- or -N(R 1 )- and X 1 and X 3 These are independently -O-, -S-, =C(H)-, and =C(R 1 )-, -N(H)-, or -N(R 1 )- and ring A is a 5-membered heteroarylene. In one embodiment, X 2 is =N- or -N(R 1 )- and X1 and X 3 These are independently =C(H)- and =C(R 1 )- and ring A is a 5-membered heteroarylene. In one embodiment, X 1 , X 2 , and X 3 Each of them independently corresponds to -N(R 1 )-, =N-, =C(R 1 )- and ring A is a 5-membered heteroarylene, however X 1 , X 2 , and X 3 At least one of them is =C(R 1 )-isn't it.

[0094] In one embodiment, Y 1 , Y 2 , and Y 3 These are independently -O-, -S-, =C(H)-, and =C(R 2 )-, -N(H)-, -N(R 2 )- or =N-, and ring B is a 5-membered heteroarylene, however Y 1 , Y 2 , and Y 3 At least one of them is =C(H)- or =C(R 2 )-not. In one embodiment, Y 1 , Y 2 , and Y 3 These are independently =C(H)- and =C(R 2 )-,-N(R 2 )- or =N-, and ring B is a 5-membered heteroarylene, however Y 1 , Y 2 , and Y 3 At least one of them is =C(H)- or =C(R 2 )-not. In one embodiment, Y 2 is = N-, and Y 1 and Y 3 These are independently -O-, -S-, =C(H)-, and =C(R 2 )-, -N(H)-, or -N(R 2)- and ring B is a 5-membered heteroarylene. In one embodiment, ring A and ring B are each independently a 5-membered heteroarylene.

[0095] In one demonstration, ring A is [ka] A group consisting of is selected, where each [ka] represents a covalent bond. In one embodiment, ring A is pyrazolylene. In one embodiment, ring A is [ka] A group consisting of is selected, where each [ka] represents a covalent bond point. In one embodiment, ring A is [ka] A group consisting of is selected, where each [ka] represents a covalent bond point. In one embodiment, ring A is [ka] And here, each [ka] represents a covalent bond point. In one embodiment, ring A is [ka] And here, each [ka] represents a covalent bond point. In one embodiment, ring A is [ka] A group consisting of is selected, where each [ka] represents a covalent bond point. In one embodiment, ring A is [ka] A group consisting of is selected, where each [ka] represents a covalent bond point. In one embodiment, ring A is [ka] A group consisting of is selected, where each [ka] represents a covalent bond point.

[0096] One appeal, ring B is [ka] A group consisting of is selected, where each [ka] represents a covalent bond. In one embodiment, ring B is pyrazolylene. In one embodiment, ring B is [ka] A group consisting of is selected, where each [ka] represents a covalent bond point. In one embodiment, ring B is [ka] A group consisting of is selected, where each [ka] represents a covalent bond point. In one embodiment, ring B is [ka] And here, each [ka] represents a covalent bond point. In one embodiment, ring B is [ka] And here, each [ka] represents a covalent bond point. In one embodiment, ring B is [ka] And here, each [ka] represents a covalent bond point. In one embodiment, ring B is [ka] A group consisting of is selected, where each [ka] represents a covalent bond point. In one embodiment, ring B is [ka] A group consisting of is selected, where each [ka] represents a covalent bond point. In one embodiment, [ka] And in the formula, each [ka] represents a covalent bond point.

[0097] In one demonstration, rings A and B are pyrazolylenes.

[0098] In one embodiment, m is 0, 1, 2, or 3. In one embodiment, m is 0, 1, or 2. In one embodiment, m is 0 or 1. In one embodiment, m is 1 or 2. In one embodiment, m is 2 or 3. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3.

[0099] In one embodiment, n is 0, 1, 2, or 3. In one embodiment, n is 0, 1, or 2. In one embodiment, n is 0 or 1. In one embodiment, n is 1 or 2. In one embodiment, n is 2 or 3. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3.

[0100] One way of doing this is for each R 1 and R 2 When present, they independently contain deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, and C6-C 10 Aryl, 5-10 member 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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 ,-PRc R d ,-P(O)R c R d ,-P(O)2R c R d ,-P(O)NR c R d -P(O)2NR c R d , -P(O)OR c -P(O)2OR c It is substituted with -CN or -NO2.

[0101] One way of doing this is for each R 1 and R 2 When present, they independently contain deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, and C6-C 10 Aryl, 5-10 member 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, or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=N)NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d , -SR c ,-S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d , -NR c R d , -NR c C(O)R d ,-N(C(O)R c )(C(O)R d ), -NRc C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c -C(O)NR c R d -C(=N)NR c R d ,-PR c R d ,-P(O)R c R d ,-P(O)2R c R d ,-P(O)NR c R d -P(O)2NR c R d , -P(O)OR c -P(O)2OR c It is substituted with -CN or -NO2.

[0102] One way of doing this is for each R 1 and R 2 When present, they independently include halogens, C1-C6 alkyls, C2-C6 alkenyls, C2-C6 alkynyls, C3-C6 cycloalkyls, 3-7 member heterocycloalkyls, and C6-C 10 Aryl, 5-10 member 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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c -OC(O)R c -OC(O)NRc R d 、-OC(=N)NR c R d 、-OS(O)R c 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=N)NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=N)NR c R d 、-PR c R d 、-P(O)R c R d 、-P(O)2R c R d 、-P(O)NR c R d 、-P(O)2NR c Rd , -P(O)OR c -P(O)2OR c It is substituted with -CN or -NO2.

[0103] One way of doing this is for each R 1 and R 2 When present, they independently include halogens, C1-C6 alkyls, C2-C6 alkenyls, C2-C6 alkynyls, C3-C6 cycloalkyls, 3-7 member heterocycloalkyls, and -OR a -OC(O)R a -OC(O)NR a R b Here, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally a halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c It is substituted with -CN or -NO2. In one embodiment, each R 1 and R 2 When present, they independently include halogens, C1-C6 alkyls, C2-C6 alkynyls, and -OR a , or -CN, where each hydrogen atom in the C1-C6 alkyl and C2-C6 alkynyl is independently a halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -OR c , or replaced with -CN. In one embodiment, each R 1 and R 2 When present, they independently include halogens, C1-C6 alkyls, C2-C6 alkynyls, and -OR a , or -CN, where each hydrogen atom in the C1-C6 alkyl or C2-C6 alkynyl is independently -OR as desired. c Alternatively, it is replaced with -CN.

[0104] One way of doing this is for each R 1 When present, they independently form C1-C6 alkyl, -OR a, or -CN, where each hydrogen atom in the C1-C6 alkyl group is independently -OR as desired. c Or it is replaced with -CN. In one embodiment, each R 1 When present, they independently form C1-C6 alkyl, -OR a , or -CN, where each hydrogen atom in the C1-C6 alkyl group is independently substituted with -OH or -CN as desired.

[0105] One way of doing this is for each R 2 When present, R is independently a halogen, a C1-C6 alkyl, or a C2-C6 alkynyl. In one embodiment, each R 2 When present, it is independently halogen, methyl, ethyl, or ethyne.

[0106] One way of doing this is for each R a R is a C1-C6 alkyl group, where each hydrogen atom in the C1-C6 alkyl group is independently substituted with deuterium or -CN as desired. In one embodiment, each R a is methyl, ethyl, or propyl, where each hydrogen atom in the C1-C6 alkyl group is independently substituted with deuterium or -CN as desired.

[0107] One way of doing this is for each R c H is H.

[0108] One way of doing this is for each R 3 , R 4 , R 5 , and R 6 These are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2Ra , -SR a ,-S(O)R a -S(O)2R a -S(O)NR a R b -S(O)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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f , -SR e ,-S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN, or -NO2; or R 3 , R 4 , R 5 , and R6 These two atoms, together with one or more carbon atoms to which they are bonded, form a C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl group, where each hydrogen atom in the C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl group can be 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 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 eR f , -P(O)OR e -P(O)2OR e It is substituted with -CN or -NO2. In one embodiment, each R 3 , R 4 , R 5 , and R 6 R is independently H or C1-C6 alkyl. In one embodiment, each R 3 , R 4 , R 5 , and R 6 R is independently H, methyl, or ethyl. In one embodiment, each R 3 , R 4 , R 5 , and R 6 It is independently either H or methyl.

[0109] One way of doing this is for each R 3 and R 4 R is independently H, methyl, or ethyl. In one embodiment, each R 3 and R 4 R is independently H or methyl. In one embodiment, R 3 One of them is methyl, and any remaining R 3 and R 4 is H or deuterium. In one example, R 3 One of them is a C1-C6 alkyl group; R 7 and R 4 One of them, together with the atom to which they are bonded, forms a 4-7 member heterocycloalkyl group; and any remaining R 3 and R 4 is either H or deuterium.

[0110] One reason, R 5 and R 6 Each of these is H.

[0111] One reason, R 7 H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 member heterocycloalkyl, C6-C10 Aryl, 5-10 member heteroaryl, -C(O)R c , or -C(O)NR c R d Here, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently -OR as desired. 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 Rd , -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 Substituted with -CN, or -NO2; or R 7 and R 3 , R 4 , R 5 , or R 6 Each of these atoms, together with the atom to which it is bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the 4- to 7-membered heterocycloalkyl group can be 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 Rf , -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 It is substituted with -CN or -NO2.

[0112] One reason, R 7 H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 member heterocycloalkyl, C6-C 10 The aryl group is a 5-10 member heteroaryl group, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 member heterocycloalkyl, or C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently -OR as desired. c -OC(O)R c -OC(O)NR c R d -OC(=N)NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c Rd , -SR c ,-S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d , -NR c R d , -NR c C(O)R d ,-N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c -C(O)NR c R d -C(=N)NR c R d ,-PR c R d ,-P(O)R c R d ,-P(O)2R c R d ,-P(O)NR c R d -P(O)2NR c R d , -P(O)OR c -P(O)2OR c Substituted with -CN, or -NO2; or R 7 and R 3 , R 4 , R 5 , or R 6Each of these atoms, together with the atom to which it is bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the 4- to 7-membered heterocycloalkyl group can be 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 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 It is substituted with -CN or -NO2.

[0113] One reason, R 7 H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 member heterocycloalkyl, C6-C 10 The aryl group is a 5-10 member heteroaryl group, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 member heterocycloalkyl, or C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently -OR as desired. c -OC(O)R c -OC(O)NR c R d -OC(=N)NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d , -SR c ,-S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d , -NR c R d , -NR c C(O)R d ,-N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d, -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c -C(O)NR c R d -C(=N)NR c R d ,-PR c R d ,-P(O)R c R d ,-P(O)2R c R d ,-P(O)NR c R d -P(O)2NR c R d , -P(O)OR c -P(O)2OR c Substituted with -CN, or -NO2; or R 7 and R 3 , R 4 , R 5 , or R 6 Each of these atoms, together with the atom to which it is bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the 4- to 7-membered heterocycloalkyl group can be 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 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 It is substituted with -CN or -NO2.

[0114] One reason, R 7 is H, C1-C6 alkyl, C3-C6 cycloalkyl, or -C(O)R c is; or R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group. In one embodiment, R 7 R is H, C1-C6 alkyl, or C3-C6 cycloalkyl. In one embodiment, R 7 and R 3 , R 4 , R 5 , or R 6 Each of these atoms, together with the atom to which it is bonded, forms a 4- to 7-membered heterocycloalkyl group. In one embodiment, R 7is H, methyl, ethyl, propyl, or cyclopropyl. In one embodiment, R 7 is H, C1-C6 alkyl, or C3-C6 cycloalkyl. In one embodiment, R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group. In one embodiment, R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a five-membered heterocycloalkyl group.

[0115] One reason, R 7 is H, C1-C6 alkyl, C3-C6 cycloalkyl, or -C(O)R c is; or R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group; where each hydrogen atom in the C1-C6 alkyl, C3-C6 cycloalkyl, and 4- to 7-membered heterocycloalkyl groups 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 cC(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 It is substituted with -CN or -NO2.

[0116] In one embodiment, p is 2 or 3, and part [ka] R is ethylene or propylene, where each R 3 and R 4These are independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a , -SR a ,-S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a -C(O)NR a R b ,-PR a R b ,-P(O)R a R b ,-P(O)2R a R b ,-P(O)NR a R b -P(O)2NR a R b, -P(O)OR a -P(O)2OR a , -CN, or -NO2; or R 3 and R 4 At least one of them, together with one or more carbons to which they are bonded, form a C3-C6 cycloalkyl or 4-7 membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl and 4-7 membered heterocycloalkyl can be 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 e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN, or -NO2; or R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the formed 4- to 7-membered heterocycloalkyl group can be 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 e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e-C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; and each [ka] represents a covalent bond point.

[0117] In one embodiment, part [ka] is ethylene, where each R 3 and R 4 is independently H or C1-C6 alkyl; and / or R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group.

[0118] In one embodiment, part [ka] is an expression [ka] These are, and here, each [ka] The ∫ represents a covalent bond, and each hydrogen atom is independently substituted with deuterium as desired.

[0119] In one embodiment, part [ka] is an expression [ka] These are, and here, each [ka] represents a covalent bond, and each hydrogen is independently substituted with deuterium as desired. In one embodiment, partial [ka] is an expression [ka] These are, and here, each [ka] The ∫ represents a covalent bond, and each hydrogen atom is independently substituted with deuterium as desired.

[0120] In one embodiment, p is 1, 2, 3, or 4. In one embodiment, p is 1, 2, or 3. In one embodiment, p is 2, 3, or 4. In one embodiment, p is 1 or 2. In one embodiment, p is 2 or 3. In one embodiment, p is 3 or 4. In one embodiment, p is 1. In one embodiment, p is 2. In one embodiment, p is 3. In one embodiment, p is 4.

[0121] In one embodiment, part [ka] is an expression [ka] These are, and here, each [ka] The ∫ represents a covalent bond, and each hydrogen atom is independently substituted with deuterium as desired.

[0122] In one embodiment, q is 1, 2, or 3. In one embodiment, q is 1 or 2. In one embodiment, q is 2 or 3. In one embodiment, q is 1. In one embodiment, q is 2. In one embodiment, q is 3.

[0123] One reason, R 8 H, -S(O)2R 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 ,-P(O)2R c R d -P(O)2NR c R d , or -P(O)2OR c That is the case.

[0124] One reason, R 8 H, deuterium, -S(O)2R c -S(O)2NR c R d , -C(O)R c , -C(O)OR c -C(O)NR c R d -C(=N)NR c R d ,-P(O)2R c R d -P(O)2NR c R d -P(O)2OR c In one example, R 8 is H or C1-C6 alkyl. In one embodiment, R 8H, -S(O)2R c -S(O)2NR c R d , -C(O)R c , -C(O)OR c -C(O)NR c R d -C(=N)NR c R d ,-P(O)2R c R d -P(O)2NR c R d -P(O)2OR c In one example, R 8 is H or C1-C6 alkyl. In one embodiment, R 8 H is H.

[0125] One reason, R 9 H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a , -SR a ,-S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR aS(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a -C(O)NR a R b ,-PR a R b ,-P(O)R a R b ,-P(O)2R a R b ,-P(O)NR a R b -P(O)2NR a R b , -P(O)OR a -P(O)2OR a -CN, or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 Rd , -NR c C(O)R d ,-N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=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 It is substituted with -CN or -NO2.

[0126] One reason, R 9 is H, deuterium, halogen, C1-C6 alkyl, or -OR a Here, each hydrogen atom in the C1-C6 alkyl group is independently substituted with deuterium as desired. In one embodiment, R 9H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member 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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=N)NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d , -SR c ,-S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d , -NR c R d , -NR c C(O)R d ,-N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c, -C(O)OR c -C(O)NR c R d -C-(=N)NR c R d ,-PR c R d ,-P(O)R c R d ,-P(O)2R c R d ,-P(O)NR c R d -P(O)2NR c R d , -P(O)OR c -P(O)2OR c It is substituted with -CN or -NO2. In one embodiment, R 9 is H, deuterium, halogen, C1-C6 alkyl, where each hydrogen atom in the C1-C6 alkyl is independently substituted with deuterium as desired. In one embodiment, R 9 R is a C1-C6 alkyl group, where each hydrogen atom in the C1-C6 alkyl group is independently substituted with deuterium as desired. In one embodiment, R 9 is H, deuterium, halogen, -CH3, or -CD3. In one embodiment, R 9 is H, deuterium, halogen, -OCH3, -CH3, or -CD3.

[0127] One way of doing this is for each R a , R b , R c , R d , R e , and R f These are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, and C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Selected from the group consisting of aryls, 5-10 membered heteroaryls, and C1-C6 alkylene-5-10 membered heteroaryls; or R a and R b or R c and Rd or R e and R f These atoms, together with the atoms to which they are bonded, form a 3-7 member heterocycloalkyl group, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10In aryl, 5-10 membered heteroaryl, and C1-C6 alkylenes, each hydrogen atom in the 5-10 membered heteroaryl is independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2 -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O) N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2,Substituted with -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.

[0128] One reason, R 9 Deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member 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)2NRa R b , -C(O)R a , -C(O)OR a -C(O)NR a R b ,-PR a R b ,-P(O)R a R b ,-P(O)2R a R b ,-P(O)NR a R b -P(O)2NR a R b , -P(O)OR a -P(O)2OR a -CN, or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 , -NRc 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 It is substituted with -CN or -NO2.

[0129] One reason, R 9 These are halogens, C1-C6 alkyls, C2-C6 alkenyls, C2-C6 alkynyls, C3-C6 cycloalkyls, 3-7 member heterocycloalkyls, and C6-C 10 Aryl, 5-10 member 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 aR 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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR d )NRc R d 、-OS(O)R c 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=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 It is substituted with -CN or -NO2.

[0130] One reason, R 9 is halogen, -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)2NRa R b , -P(O)OR a -P(O)2OR a It is -CN or -NO2.

[0131] One reason, R 9 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 The aryl group is a 5-10 member heteroaryl group, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, or C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 It is substituted with -CN or -NO2. In one embodiment, R 9 This is a C1-C6 alkyl group, where each hydrogen atom in the C1-C6 alkyl group can be independently and optionally 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 Substituted with -CN or -NO2

[0132] One reason, R 8 and R 9 Each of them is H. In another embodiment, R 8 H is R 9 is not H. For example, in one embodiment, R 8H is R 9 These are as described herein and may be deuterium, optionally substituted C1-C6 alkyl (e.g., methyl or -CD3), or optionally substituted alkoxy (i.e., -O-C1-C6 alkyl) (e.g., methoxy).

[0133] One reason, R 8 H is R 9 The following is stated: deuterium, optionally substituted C1-C6 alkyl (e.g., methyl or -CD3) or optionally substituted alkoxy (e.g., -O-C1-C6 alkyl such as methoxy), m is 2, and 1 R 1 is a C1-C6 alkyl group which is optionally substituted (e.g., unsubstituted such as methyl, hydroxysubstituted such as -CH(CH3)(CH2OH) or ethanol, or heterocycloalkyl substituted such as -ethylene-pyrrolidinyl), and other R 1 The element is optionally substituted C1-C6 alkyl (e.g., ethyl, optionally substituted -N(H or C1-C6 alkyl)-C1-C6 alkyl) or optionally substituted -O-C1-C6 alkyl (e.g., ethoxy or -O-CH2CN).

[0134] One reason, R 8 H is R 9 is a optionally substituted C1-C6 alkyl (e.g., methyl or -CD3) or an optionally substituted alkoxy (e.g., -O-C1-C6 alkyl such as methoxy), m is 2, and 1 R 1 is a C1-C6 alkyl group which is optionally substituted (e.g., unsubstituted such as methyl, hydroxysubstituted such as -CH(CH3)(CH2OH) or ethanol, or heterocycloalkyl substituted such as -ethylene-pyrrolidinyl), and other R 1is optionally substituted C1-C6 alkyl (e.g., ethyl, optionally substituted -N(H or C1-C6 alkyl)-C1-C6 alkyl) or optionally substituted -O-C1-C6 alkyl (e.g., ethoxy or -O-CH2CN), n is 2, and each R 2 The C1-C6 alkyl group is optionally substituted (e.g., unsubstituted such as methyl, -CH(CH3)(CH2OH), or hydroxysubstituted such as ethanol).

[0135] In one embodiment, each of ring A and ring B is a pyrazole, and both m and n are independently 1, 2, or 3. For example, m can be 1 or 2, and n can be 1 or 2. In one embodiment, each of ring A and ring B is a pyrazole, m is 1 or 2, and n is 2. In one embodiment, each of ring A and ring B is a pyrazole, m is 1, and n is 2. In one embodiment, each of ring A and ring B is a pyrazole, m is 2, and n is 2.

[0136] In one embodiment, p is 2 or 3, q ​​is 1 or 2, and R 7 Except that it is not H, it is as described here. For example, in one embodiment, p is 2 or 3, q ​​is 1 or 2, and R 7 The C1-C6 alkyl group (e.g., methyl, ethyl, or isopropyl) or the C3-C6 cycloalkyl group (e.g., cyclopropyl).

[0137] In one embodiment, each of ring A and ring B is a pyrazole, and each of m and n is independently 1, 2, or 3; R 8 H is H; and R 9 These are halogens, C1-C6 alkyls, C2-C6 alkenyls, C2-C6 alkynyls, C3-C6 cycloalkyls, 3-7 member heterocycloalkyls, and C6-C 10 Aryl, 5-10 member 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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -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 ,-PRc R d ,-P(O)R c R d ,-P(O)2R c R d ,-P(O)NR c R d -P(O)2NR c R d , -P(O)OR c -P(O)2OR c Substituted with -CN or -NO2; p is 2 or 3, q ​​is 1 or 2, R 7 The C1-C6 alkyl group (e.g., methyl, ethyl, or isopropyl) or the C3-C6 cycloalkyl group (e.g., cyclopropyl).

[0138] One way of doing this is for each R a , R b , R c , R d , R e , and R f These are independently selected from the group consisting of H, deuterium, and C1-C6 alkyl groups.

[0139] In one embodiment, the present invention relates to 2-[(10R,17E)-16-ethoxy-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(11S,17E)-16-ethoxy-6,8,11-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(10R,17E)-8,10-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(11S,17E)-8,11-dimethyl-12-(propan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(10S,17E)-8,10,12-trimethyl-16-[(propane-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(10R,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(11S,17E)-16-ethoxy-12-ethyl-8,11-dimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(10S,17E)-16-ethoxy-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(10S,17E)-12-ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(10R,17E)-12-ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(10S,17E)-16-ethoxy-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(10R,17E)-16-ethoxy-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(10S,17E)-12-ethyl-6,8,10,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(10R,17E)-12-ethyl-6,8,10,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(11S,17E)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(10R,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(11R,17E)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; 2-[(10R,17E)-6,8,10,16-tetramethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(10S,17E)-6,8,10,16-tetramethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; {[(10S,17E)-14-(2-hydroxyethyl)-6,8,10,12-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; {[(10S,17E)-12-ethyl-14-(2-hydroxyethyl)-6,8,10-trimethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; (2S)-2-[(10R,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(11S,17E)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; 2-[(10S,17E)-12-cyclopropyl-16-ethoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; {[(11S,17E)-14-(2-hydroxyethyl)-6,8,11,12-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; 2-[(8aR,9S,19E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethane-1-ol; 2-[(8aR,9R,19E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethane-1-ol; 2-[(10S,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; (2S)-2-[(10R,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; {[(10R,17E)-12-ethyl-14-(2-hydroxyethyl)-6,8,10-trimethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; 2-[(8aR,19E)-1-ethoxy-11,13-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethane-1-ol; 2-[(10S,17E)-6,8,10,12,16-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; {[(10R,17E)-14-(2-hydroxyethyl)-6,8,10,12-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; {[(8aR,19E)-3-(2-hydroxyethyl)-11,13-dimethyl-3,4,7,8,8a,9,11,17-octahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-1-yl]oxy}acetonitrile; 2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; (2S)-2-[(10S,17E)-6,8,10,12,16-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (10S,17E)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,12-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-carbonitride; {[(11R,17E)-14-(2-hydroxyethyl)-6,8,11,12-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; {[(8aR,19E)-3-(2-hydroxyethyl)-9,11,13-trimethyl-3,4,7,8,8a,9,11,17-octahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-1-yl]oxy}acetonitrile; {[(10S,17E)-14-[(2S)-1-hydroxypropane-2-yl]-6,8,10,12-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; 2-[(10R,17E)-12,16-diethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; (2S)-2-[(8aR,9S,19E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]propan-1-ol; {[(10R,17E)-12-ethyl-14-[(2S)-1-hydroxypropane-2-yl]-6,8,10-trimethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; (2S)-2-[(17E)-16-ethoxy-6,8,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; 2-[(10S,17E)-16-ethyl-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; (2S)-2-[(10S,17E)-16-ethyl-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; 2-[(10S,17E)-12,16-diethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; {[(8aR,19E)-3-[(2S)-1-hydroxypropan-2-yl]-11,13-dimethyl-3,4,7,8,8a,9,11,17-octahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-1-yl]oxy}acetonitrile; (2S)-2-[(8aR,19E)-1-ethoxy-11,13-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]propan-1-ol; {[(17E)-12-ethyl-14-[(2S)-1-hydroxypropan-2-yl]-6,8-dimethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; {[(10S,17E)-12-ethyl-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10-trimethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-16-yl]oxy}acetonitrile; 2-[(17E)-16-ethoxy-6,8,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(17E)-16-ethoxy-6,8,12-trimethyl-2,6,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:3'',4''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; {[(17E)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,12-trimethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; (17E)-8,15,16-trimethyl-2,10,11,12,13,15-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; (17E)-8,12,15,16-tetramethyl-2,10,11,12,13,15-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; 2-[(10S,17E)-16-ethoxy-6,12-diethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-6-ethynyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; 2-[(10S,17E)-16-ethoxy-6-ethynyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-6-ethyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-1-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol; (2S)-2-[(10S,17E)-16-[( 2 H5)ethyloxy]-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; (2R)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2R)-2-[(10R,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S,17E)-16-(ethylamino)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(11R,17E)-16-ethoxy-6,8,11,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; 2-[(17E)-16-ethoxy-6,12-dimethyl-2,6,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:3'',4''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; (2S)-2-[(10S,17E)-16-[ethyl(methyl)amino]-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; (2S)-1-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol; (2S)-2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(11R,17E)-12-cyclopropyl-16-ethoxy-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; 1-[(10S,17E)-16-ethoxy-14-[(2S)-1-hydroxypropane-2-yl]-6,8,10-trimethyl-2,8,10,11,13,14-hexahydro-12H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-12-yl]ethane-1-one; 2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(11R,17E)-12-cyclopropyl-16-ethoxy-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 1-[(10S,17E)-16-ethoxy-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10-trimethyl-2,8,10,11,13,14-hexahydro-12H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-12-yl]prop-2-en-1-one; (10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-14-[(2S)-1-(pyrrolidine-1-yl)propan-2-yl]-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; (10S,17E)-14-[(2S)-1-(azetidine-1-yl)propan-2-yl]-16-ethoxy-6,8,10,12-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; (10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-14-[(2S)-1-(morpholine-4-yl)propan-2-yl]-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]-N-methylpropane-1-amine; (2S)-2-[(10S,17E)-6,16-diethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-14-[(2S)-1-(piperidine-1-yl)propan-2-yl]-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]-N,N-dimethylpropane-1-amine; (3S)-1-{(2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propyl}pyrrolidine-3-ol; (3R)-1-{(2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propyl}pyrrolidine-3-ol; 1-{[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]methyl}cyclopropane-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-6-(methoxymethyl)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; and (10S,17E)-6,8,10,12,15,16-Hexamethyl-2,10,11,12,13,15-Hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; The present invention provides compounds of formulas (I) to (IV) selected from the group consisting of the above, or pharmaceutically acceptable salts, solvates, hydrates, or cocrystals thereof.

[0140] In one embodiment, the present invention relates to 2-[(10S,17E)-16-ethoxy-12-ethyl-8,10,20-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(10S,17E)-16-ethoxy-8,10,12,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-30n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(10R,17E)-16-ethoxy-12-ethyl-8,10,20-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(10R,17E)-16-ethoxy-8,10,12,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(10S,17E)-8,10,12,20-tetramethyl-16-[(propane-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-8,10,12,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; 2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(10S,17E)-8,10,12,16,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; {[(10S,17E)-14-[(2S)-1-hydroxypropane-2-yl]-6,8,10,12,20-pentamethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-16-yl]oxy}acetonitrile; (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; (2S)-2-[(10S,17E)-6,8,10,12,16,20-Hexamethyl-2,8,10,11,12,13-Hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; {[(10S,17E)-14-(2-hydroxyethyl)-6,8,10,12,20-pentamethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl(20- 2 H)-10,11,12,13-tetrahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14(2H)-yl]propan-1-ol; 2-[(17E)-16-ethoxy-6,8,12,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-20-( 2 H3)methyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-20-( 2 H3)methyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S,17E)-16-[( 2 H5)ethyloxy]-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; 2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl(20- 2 H)-2,8,10,11,12,13-Hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl(20- 2 H)-2,8,10,11,12,13-Hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl(20- 2H)-2,8,10,11,12,13-Hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-1-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-2-ol; (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S,17E)-16-(ethylamino)-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; (2R)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; (2S)-2-[(10S,17E)-16-ethoxy-20-methoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10R,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; (10S,17E)-16-ethoxy-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,12-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-20-ol; (2R)-2-[(10R,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; (2S)-2-[(10S,17E)-6,8,10,12,20-pentamethyl-16-(methylamino)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S,17E)-16-[ethyl(methyl)amino]-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; (10S,17E)-6,8,10,12,14,16,20-heptamethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; (10S,17E)-6,8,10,14,16,20-Hexamethyl-12-(propan-2-yl)-2,10,11,12,13,14-Hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; (11R,17E)-6,8,11,14,16,20-Hexamethyl-12-(propan-2-yl)-2,10,11,12,13,14-Hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; 2-[(10S,17E)-6,8,10,16,20-pentamethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; (10S,17E)-6,8,10,12,16,20-Hexamethyl-14-[2-(pyrrolidine-1-yl)ethyl]-2,10,11,12,13,14-Hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; (10S,17E)-6,8,10,12,16,20-Hexamethyl-15-[2-(pyrrolidine-1-yl)ethyl]-2,10,11,12,13,15-Hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; (2S)-2-[(10S,17E)-12-cyclopropyl-6,8,10,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(11R,17E)-12-cyclopropyl-6,8,11,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; 1-[(10S,17E)-16-ethoxy-6,8,10,14,20-pentamethyl-2,8,10,11,13,14-hexahydro-12H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-12-yl]ethane-1-one; (2S)-2-[(10R,11R,17E)-16-ethoxy-6,8,10,11,12,20-hexamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S,11R,17E)-16-ethoxy-6,8,10,11,12,20-hexamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; 2-[(10S,17E)-12-cyclopropyl-6,8,10,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 2-[(11R,17E)-12-cyclopropyl-6,8,11,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; 1-[(10S,17E)-16-ethoxy-6,8,10,14,20-pentamethyl-2,8,10,11,13,14-hexahydro-12H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-12-yl]propan-1-one; Cyclopropyl[(10S,17E)-16-ethoxy-6,8,10,14,20-pentamethyl-2,8,10,11,13,14-hexahydro-12H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-12-yl]methanone; 1-[(10S,17E)-16-ethoxy-6,8,10,14,20-pentamethyl-2,8,10,11,13,14-hexahydro-12H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-12-yl]-2-methylpropane-1-one; 1-[(10S,17E)-6-[(cyclopropyloxy)methyl]-8,10,14,20-tetramethyl-2,8,10,11,13,14-hexahydro-12H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-12-yl]-2-(dimethylamino)ethane-1-one; (2S)-2-[(10S,17E)-12-cyclopropyl-6-(methoxymethyl)-8,10,20-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(11R,17E)-12-cyclopropyl-6-(methoxymethyl)-8,11,20-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; 2-(dimethylamino)-1-[(10S,17E)-6-(methoxymethyl)-8,10,14,20-tetramethyl-2,8,10,11,13,14-hexahydro-12H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-12-yl]ethane-1-one; (17E)-6,8,12,15,16,20-Hexamethyl-2,10,11,12,13,15-Hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; 3-(dimethylamino)-1-[(10S,17E)-6-(methoxymethyl)-8,10,14,20-tetramethyl-2,8,10,11,13,14-hexahydro-12H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-12-yl]propan-1-one; (17E)-6,8,12,14,16,20-Hexamethyl-2,10,11,12,13,14-Hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (17E)-6,8,12,14,20-pentamethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-6-(methoxymethyl)-8,10,20-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; {[(10S,17E)-12-ethyl-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,20-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; (2S)-2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (17E)-6,8,12,14,20-pentamethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-carbonitride; {[(10S,17E)-12-(2,2-difluoroethyl)-14-[(2S)-1-hydroxypropane-2-yl]-6,8,10,20-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; {[(10S,17E)-12-cyclopropyl-14-[(2S)-1-hydroxypropane-2-yl]-6,8,10,20-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; {[(11R,17E)-12-cyclopropyl-14-[(2S)-1-hydroxypropane-2-yl]-6,8,11,20-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; (2S)-2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6-(methoxymethyl)-8,10,20-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(11R,17E)-12-cyclopropyl-16-ethoxy-6-(methoxymethyl)-8,11,20-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; {[(11R,17E)-12-(2,2-difluoroethyl)-14-[(2S)-1-hydroxypropane-2-yl]-6,8,11,20-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; (2S)-2-[(10S,17E)-16-ethoxy-6-(methoxymethyl)-8,10,12,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; {[(10S,17E)-12-(2-fluoroethyl)-14-[(2S)-1-hydroxypropane-2-yl]-6,8,10,20-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; {[(11R,17E)-12-(2-fluoroethyl)-14-[(2S)-1-hydroxypropane-2-yl]-6,8,11,20-tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; {[(17E)-6,8,12,14,20-pentamethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; {[(10S,17E)-6,8,10,12,14,20-Hexamethyl-2,10,11,12,13,14-Hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]Oxazacyclopentadecin-16-yl]oxyacetonitrile; (2S)-2-[(10S,17E)-16-ethoxy-6-(hydroxymethyl)-8,10,12,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-1-[(10S,17E)-6,8,10,12,16,20-Hexamethyl-2,8,10,11,12,13-Hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol; (2S)-2-[(10R,11R,17E)-16-ethoxy-6-(methoxymethyl)-8,10,11,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; (2S)-2-[(10S,11R,17E)-16-ethoxy-6-(methoxymethyl)-8,10,11,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol; {[(10R,17E)-10-(difluoromethyl)-6,8,12,14,20-pentamethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; {[(10S,17E)-10-(difluoromethyl)-6,8,12,14,20-pentamethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile; (10S,17E)-6,8,10,12,15,16,20-heptamethyl-2,10,11,12,13,15-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; 2-[(10S,11R,17E)-16-ethoxy-12-ethyl-6-(methoxymethyl)-8,10,11,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(10R,11R,17E)-16-ethoxy-12-ethyl-6-(methoxymethyl)-8,10,11,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol; (2S)-2-[(4aS,7aS,13E)-12-ethoxy-1,3,8,21-tetramethyl-3,4a,5,7,7a,8,9,16-octahydro-10H-19,17-(azenometeno)flo[3,4-b]tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-10-yl]propan-1-ol; (2S)-2-[(4aR,7aR,13E)-12-ethoxy-1,3,8,21-tetramethyl-3,4a,5,7,7a,8,9,16-octahydro-10H-19,17-(azenometeno)flo[3,4-b]tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-10-yl]propan-1-ol; 2-[(10R,11R,17E)-16-ethoxy-6-(methoxymethyl)-8,10,11,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; 2-[(10S,11R,17E)-16-ethoxy-6-(methoxymethyl)-8,10,11,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol; (10S,17E)-6-(methoxymethyl)-8,10,12,14,16,20-hexamethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin; 2-[(8aR,9S,19E)-1-ethoxy-9,11,13,21-tetramethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethane-1-ol; 2-[(8aR,9R,19E)-1-ethoxy-9,11,13,21-tetramethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethane-1-ol; (2S)-2-[(8aR,9S,19E)-1-ethoxy-9,11,13,21-tetramethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]propan-1-ol; (2S)-2-[(8aR,9R,19E)-1-ethoxy-9,11,13,21-tetramethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]propan-1-ol; and (2S)-1-[(10S,17E)-6,8,10,12,16,20-Hexamethyl-2,8,10,11,12,13-Hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol; The present invention provides compounds of formulas (I) to (IV) selected from the group consisting of the above, or pharmaceutically acceptable salts, solvates, hydrates, or cocrystals thereof.

[0141] Next are the compounds of formulas (I) to (IV): [Table 1] [Table 2] [Table 3] Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] [Table 31] This also represents descriptive embodiments of its pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

[0142] Those skilled in the art will recognize that the species listed or described herein are not exhaustive, and that further species within the scope of these defined terms may be selected.

[0143] Alternative Embodiments In one embodiment, the present invention provides compounds or methods of the following embodiments.

[0144] 1. Equation I [ka] [During the ceremony, Rings A and B are independently 5-membered heteroarylenes; Each R1 and R 2 When present, they independently contain deuterium, halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, and C6-C 10 Aryl, 5-10 member 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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 In aryls, or 5-10 membered heteroaryls, each hydrogen atom can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=N)NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d , -SR c ,-S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d , -NR c R d , -NR c C(O)R d ,-N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NRc R d , -C(O)R c , -C(O)OR c -C(O)NR c R d -C(=N)NR c R d ,-PR c R d ,-P(O)R c R d ,-P(O)2R c R d ,-P(O)NR c R d -P(O)2NR c R d , -P(O)OR c -P(O)2OR c Substituted with -CN or -NO2; Each R 3 , R 4 , R 5 , and R 6 These are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a , -SR a ,-S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR aC(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a -C(O)NR a R b ,-PR a R b ,-P(O)R a R b ,-P(O)2R a R b ,-P(O)NR a R b -P(O)2NR a R b , -P(O)OR a -P(O)2OR a -CN, or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Each hydrogen atom in aryls and 5-10 membered heteroaryls can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f , -SR e ,-S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f , -NR e Rf , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN, or -NO2; or R 3 , R 4 , R 5 , and R 6 These two atoms, together with one or more carbon atoms to which they are bonded, form a C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl group, where each hydrogen atom in the C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl group can be 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 e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; R 7 H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 member heterocycloalkyl, C6-C 10 The aryl group is a 5-10 member heteroaryl group, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 member heterocycloalkyl, or C6-C 10In aryls, or 5-10 membered heteroaryls, each hydrogen atom can be independently and optionally -OR c -OC(O)R c -OC(O)NR c R d -OC(=N)NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d , -SR c ,-S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d , -NR c R d , -NR c C(O)R d ,-N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c -C(O)NR c R d -C(=N)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 Substituted with -CN, or -NO2; or R 7 and R 3 , R 4 , R 5 , or R 6 Each of these atoms, together with the atom to which it is bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the 4- to 7-membered heterocycloalkyl group can be 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 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)ORe -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; R 8 H, -S(O)2R c -S(O)2NR c R d , -C(O)R c , -C(O)OR c -C(O)NR c R d -C(=N)NR c R d ,-P(O)2R c R d -P(O)2NR c R d , or -P(O)2OR c and; R 9 H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member 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, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 In aryls, or 5-10 membered heteroaryls, each hydrogen atom can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=N)NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c Rd -OS(O)2NR c R d , -SR c ,-S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d , -NR c R d , -NR c C(O)R d ,-N(C(O)R c )(C(O)R d ), -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c -C(O)NR c R d -C-(=N)NR c R d ,-PR c R d ,-P(O)R c R d ,-P(O)2R c R d ,-P(O)NR c R d -P(O)2NR c R d , -P(O)OR c -P(O)2OR c Substituted with -CN or -NO2; Each R a , R b , R c, R d , R e , and R f These are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, and C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Selected from the group consisting of aryls, 5-10 membered heteroaryls, and C1-C6 alkylene-5-10 membered heteroaryls; or R a and R b or R c and R d or R e and R f These atoms, together with the atoms to which they are bonded, form a 3-7 member heterocycloalkyl group, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10In aryl, 5-10 membered heteroaryl, or C1-C6 alkylene-5-10 membered heteroaryls, each hydrogen atom can be independently and optionally replaced with deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2 -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O) N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2,Substituted with -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; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 1, 2, 3, or 4; and q is 1, 2, or 3. Compounds of or pharmaceutically acceptable salts thereof.

[0145] 2. Formula II [ka] [During the ceremony, each [ka] These are independently carbon-carbon single bonds or carbon-carbon double bonds. A compound of Embodiment 1 or a pharmaceutically acceptable salt thereof having the above characteristics.

[0146] 3. Formula III [ka] [During the ceremony, each [ka] These are independently carbon-carbon single bonds or carbon-carbon double bonds; X 1 , X 2 , and X 3 -O-, -S-, =C(H)-, =C(R) 1 )-, -N(H)-, -N(R 1)- or =N- and ring A is a 5-membered heteroarylene, however X 1 , X 2 , and X 3 At least one of them is =C(H)- or =C(R 1 ) - not; and / or Y 1 , Y 2 , and Y 3 These are independently -O-, -S-, =C(H)-, and =C(R 2 )-, -N(H)-, -N(R 2 )- or =N-, and ring B is a 5-membered heteroarylene, however Y 1 , Y 2 , and Y 3 At least one of them is =C(H)- or =C(R 2 ) - It's not. A compound of Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof having the above.

[0147] 4. Formula IV [ka] A compound of Embodiment 3 or a pharmaceutically acceptable salt thereof having the same properties.

[0148] 5. X 2 is =N- or -N(R 1 )- and X 1 and X 3 -O-, -S-, =C(H)-, =C(R) 1 )-, -N(H)-, or -N(R 1 )-, and ring A is a 5-membered heteroarylene; and / or

[0149] Y 2 is = N-, and Y 1 and Y 3 These are independently -O-, -S-, =C(H)-, and =C(R 2 )-, -N(H)-, or -N(R 2 )- and ring B is a 5-membered heteroarylene, the compound of Embodiment 3 or 4.

[0150] 6. Ring A [ka] A group consisting of is selected, where each [ka] A compound of any of Embodiments 1 to 4 or a pharmaceutically acceptable salt thereof, wherein represents a covalent bond site.

[0151] 7. Ring A is [ka] A group consisting of is selected, where each [ka] A compound from any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein represents a covalent bond site.

[0152] 8. Ring A is [ka] A group consisting of is selected, where each [ka] A compound from any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein represents a covalent bond site.

[0153] 9. Ring B is [ka] A group consisting of is selected, where each [ka] A compound of any of embodiments 1 to 4 or 6 or a pharmaceutically acceptable salt thereof, wherein represents a covalent bond site.

[0154] 10. Ring B is [ka] A group consisting of is selected, where each [ka] A compound from any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein represents a covalent bond site.

[0155] 11. p is 2 or 3, part [ka] R is ethylene or propylene, where each R 3 and R 4 These are independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 member heterocycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OS(O)R a -OS(O)2R a , -SR a ,-S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -OS(O)NR a R b -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b, -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a -C(O)NR a R b ,-PR a R b ,-P(O)R a R b ,-P(O)2R a R b ,-P(O)NR a R b -P(O)2NR a R b , -P(O)OR a -P(O)2OR a , -CN, or -NO2; or R 3 and R 4 At least one of them, together with one or more carbons to which they are bonded, form a C3-C6 cycloalkyl or 4-7 membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 4-7 membered heterocycloalkyl 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 eC(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN, or -NO2; or R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the formed 4- to 7-membered heterocycloalkyl group can be 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 Rf , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; and each [ka] A compound from any of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein represents a covalent bond site.

[0156] 12. One R 3 This is a C1-C6 alkyl group, where each hydrogen atom in the C1-C6 alkyl group can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2Re -OS(O)NR e R f -OS(O)2NR e R f , -SR e ,-S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; and / or two R 3 and R 4These atoms, together with one or more carbon atoms to which they are bonded, form a C3-C6 cycloalkyl or 4-7 membered heterocycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl or 4-7 membered heterocycloalkyl can be 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 e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f, -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; and / or R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the 4- to 7-membered heterocycloalkyl group can be 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 e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2Re R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; and any remaining R 3 and R 4 Any compound of the preceding embodiment or a pharmaceutically acceptable salt thereof, wherein the element is H or deuterium.

[0157] 13. One R 3 This is a C1-C6 alkyl group, where each hydrogen atom in the C1-C6 alkyl group can be independently and optionally deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f , -SR e ,-S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NRe R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; and / or R 7 and R 3 or R 4 At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the 4- to 7-membered heterocycloalkyl group can be 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 e S(O)R f , -NR eS(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e -C(O)NR e R f ,-PR e R f ,-P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f -P(O)2NR e R f , -P(O)OR e -P(O)2OR e Substituted with -CN or -NO2; and any remaining R 3 and R 4 Any compound of the preceding embodiment or a pharmaceutically acceptable salt thereof, wherein the element is H or deuterium.

[0158] 14. R 3 One of them is a C1-C6 alkyl group; and any remaining R 3 and R 4 Any compound of the preceding embodiment or a pharmaceutically acceptable salt thereof, wherein the element is H or deuterium.

[0159] 15. R 3 One of them is a C1-C6 alkyl group; R 7 and R 4 One of them, together with the atom to which they are bonded, forms a 4-7 member heterocycloalkyl group; and any remaining R 3 and R 4 Any compound of the preceding embodiment or a pharmaceutically acceptable salt thereof, wherein the element is H or deuterium.

[0160] 16. R 3 One of them is methyl, and any remaining R 3 and R 4Any compound of the preceding embodiment or a pharmaceutically acceptable salt thereof, wherein the element is H or deuterium.

[0161] 17. R 7 is H, C1-C6 alkyl, or C3-C6 cycloalkyl; or R 7 and R 3 or R 4 Any compound of the preceding embodiment or a pharmaceutically acceptable salt thereof, wherein at least one of the atoms forms a 4- to 7-membered heterocycloalkyl group together with the atom to which they are bonded.

[0162] 18. Part [ka] is the formula [ka] These are, and here, each [ka] Any compound of the preceding embodiment or a pharmaceutically acceptable salt thereof, wherein represents a covalent bond site, and each hydrogen is independently substituted with deuterium as desired.

[0163] 19. R 5 and R 6 Any of the compounds of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein each of the elements is H.

[0164] 20. Part [ka] is the formula [ka] These are, and here, each [ka] Any compound of the preceding embodiment or a pharmaceutically acceptable salt thereof, wherein represents a covalent bond site, and each hydrogen is independently substituted with deuterium as desired.

[0165] 21. R 8 Any compound of the preceding embodiment or a pharmaceutically acceptable salt thereof, wherein the compound is H or a C1-C6 alkyl group.

[0166] 22. R 9 A compound of any of the preceding embodiments or a pharmaceutically acceptable salt thereof, wherein is H, deuterium, halogen, or C1-C6 alkyl, where each hydrogen atom in the C1-C6 alkyl is optionally substituted with deuterium.

[0167] 23. R 9 Any of the compounds of the previous embodiments or a pharmaceutically acceptable salt thereof, wherein is H, deuterium, halogen, -CH3, or -CD3.

[0168] twenty four. [ka] [ka] [ka] [ka] [ka] [ka] A compound of Embodiment 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0169] 25. A pharmaceutical composition comprising any of the compounds of the preceding embodiments and, optionally, one or more additives.

[0170] 26. A method for treating a target disease, comprising administering a therapeutically effective amount of any compound of Embodiments 1 to 24 or a pharmaceutical composition of Embodiment 25.

[0171] 27. Any compound of Embodiments 1 to 24 for use in a method of treating a disease in a subject.

[0172] 28. Use of any compound of Embodiments 1 to 24 in the manufacture of a pharmaceutical product for the treatment of a disease in a subject.

[0173] Pharmaceutical composition For therapeutic purposes, a pharmaceutical composition containing the compounds described herein may further contain one or more pharmaceutically acceptable additives. A pharmaceutically acceptable additive is a non-toxic and otherwise biocompatible substance for administration to a subject. Such additives facilitate the administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable additives include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, fillers, emulsifiers, or flavor modifiers. In preferred embodiments, the pharmaceutical composition of the present invention is a sterile composition. The pharmaceutical composition may be prepared using formulation techniques known to or available to those skilled in the art.

[0174] The present invention also intends to include sterile compositions, including compositions that comply with national and regional regulations governing the composition.

[0175] The pharmaceutical compositions and compounds described herein may be formulated in the form of pills, tablets, lozenges, suppositories, sachets, sugar-coated tablets, granules, powders, reconstituted powders, or capsules in a suitable pharmaceutical solvent or carrier, in accordance with conventional methods known in the art of manufacturing various dosage forms. The pharmaceutical compositions of the present invention may be administered by an appropriate delivery route such as oral, non-enteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0176] For oral administration, the compounds of the present invention may be provided in solid form, such as tablets or capsules, or as solutions, emulsions, or suspensions. To prepare oral compositions, the compounds of the present invention may be formulated to yield doses of, for example, about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. Oral tablets contain the active ingredient mixed with suitable pharmaceutically acceptable additives such as diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, and preservatives. Suitable inert fillers include carbonate, sodium and calcium, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, and sorbitol. Exemplary liquid oral additives include ethanol, glycerol, and water. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrants. The binder may include starch and gelatin. The lubricant, if present, may be magnesium stearate, stearic acid, or talc. Optionally, glyceryl monostearate or glyceryl distearate may be used to delay the absorption of the tablets in the gastrointestinal tract. They may be coated with substances such as those listed above, or with an enteric coating.

[0177] Oral capsules include hard and soft gelatin capsules. For the preparation of hard gelatin capsules, the active ingredient may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and diglycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0178] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be provided as lyophilized or dried products for reconstitution with water or other suitable media before use. Such liquid compositions may optionally contain pharmaceutically acceptable additives, e.g., suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous media, e.g., oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid); humectants such as lecithin; and optionally, flavorings or colorings.

[0179] For non-enteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the present invention may be provided in sterile aqueous solutions or suspensions or non-enterally acceptable oils buffered to an appropriate pH and isotonicity. Suitable aqueous media include Ringer's solution and isotonic sodium chloride. Such forms may be provided in unit-dose forms such as ampoules or disposable injection devices, multi-dose forms such as vials from which appropriate doses can be drawn, or in solid forms or pre-concentrates that can be used for the preparation of injectable formulations. Explanatory infusion doses range from about 1 to 1000 μg / kg / min of the agent mixed with the pharmaceutical carrier over a period ranging from several minutes to several days.

[0180] For nasal, inhalation, or oral administration, the pharmaceutical composition of the present invention may be administered, for example, using a spray formulation that also includes a suitable carrier. The composition of the present invention may be formulated for rectal administration as a suppository.

[0181] For topical application, the compounds of the present invention are preferably formulated as creams, ointments, or similar media suitable for topical administration. For topical administration, the compounds of the present invention may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of the drug relative to the medium. Another method for administering the agents of the present invention may utilize patch formulations for transdermal delivery.

[0182] The terms “to treat” or “treatment” as used herein encompass both “preventive” and “curative” treatments. “Preventive” treatments involve delaying the progression of a disease, its symptoms, or condition, suppressing any symptoms that may appear, or reducing the risk of the onset or recurrence of the disease or symptoms. “Cure” treatments include reducing the severity of an existing disease, symptom, or condition or preventing its worsening. Therefore, treatments include improving or preventing the worsening of existing disease symptoms, preventing the onset of further symptoms, improving or preventing the systemic causes of symptoms, blocking a disability or disease, for example, blocking the progression of a disability or disease, alleviating a disability or disease, inducing regression of a disability or disease, alleviating a condition caused by a disease or disability, or cessating the symptoms of a disease or disability.

[0183] The term "subject" refers to mammalian patients, such as humans, who require such treatment.

[0184] Exemplary diseases include cancer, pain, neurological disorders, autoimmune diseases, and inflammation. The term "cancer" as used herein includes ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumors, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. +This includes, but is not limited to, breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumors, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, spitzoid neoplasms, sarcomas, astrocytomas, low-grade brain gliomas, secretory carcinomas of the mammary gland, mammary gland analogous carcinomas, acute myeloid leukemia, congenital mesodermal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, cutaneous melanoma, squamous cell carcinoma of the head and neck, pediatric glioma CML, prostate cancer, pulmonary squamous cell carcinoma, ovarian serous adenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial cancers. In one embodiment, cancer includes 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 tumors, and anaplastic large cell lymphoma. Pain includes cancer pain, pain from chemotherapy procedures, neuralgia, pain from injury, or other sources, e.g., pain of any source or etiology. Autoimmune diseases include, for example, rheumatoid arthritis, Sjögren's syndrome, type 1 diabetes, and lupus. Exemplary neurological diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Exemplary inflammatory diseases include atherosclerosis, allergies, and inflammation due to infection or injury.

[0185] In one embodiment, the compounds and pharmaceutical compositions of the present invention specifically target tyrosine receptor kinases, particularly EGFRs having one or more mutations such as L858R, Δ746-750, Δ746-750 / C979S, L858R / T790M, L858R / T790M / C979S, and D770_N771insNPG. Therefore, these compounds and pharmaceutical compositions can be used to prevent, reverse, delay, or inhibit the activity of one or more of these kinases. In a preferred embodiment, a method for treating a target cancer is described. In another embodiment, the method is for treating lung cancer, such as non-small cell lung cancer.

[0186] In the inhibition method of the present invention, the "effective amount" is an amount sufficient to inhibit the target protein. Measurement of such target modulation can be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of situations, including in vitro assays. In such a method, the cells are cancer cells having abnormal signaling due to upregulation of EGFR, preferably including cancer cells having one or more EGFR mutations such as L858R, Δ746-750, Δ746-750 / C979S, L858R / T790M, L858R / T790M / C979S, and D770_N771insNPG, while maintaining better selectivity than wild-type EGFR.

[0187] In the treatment method of the present invention, “effective dose” is generally an amount or dose sufficient to produce the desired therapeutic benefit in a subject requiring such treatment. The effective dose or dose of the compound of the present invention can be determined by routine methods such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., mode or route of administration or drug delivery, pharmacokinetics of the drug, severity and course of infection, health status, condition, and weight of the subject, and judgment of the treating physician. Exemplary doses are in the range of approximately 0.1 mg to 1 g per day, or approximately 1 mg to 50 mg per day, or approximately 50 to 250 mg per day, or approximately 250 mg to 1 g per day. The total dose may be administered in a single dose or in divided dose units (e.g., BID, TID, QID).

[0188] If the patient's condition improves, the dose may be adjusted for prophylactic or maintenance treatment. For example, the dose, frequency, or both may be reduced as a function of symptoms to a level where the desired therapeutic or prophylactic effect is maintained. Naturally, treatment may be discontinued once symptoms have subsided to an appropriate level. However, the patient may require intermittent treatment on a long-term basis due to some recurrence of symptoms. The patient may also require chronic treatment on a long-term basis.

[0189] Drug combinations The compounds of the present invention described herein may be used in combination with one or more further active ingredients in pharmaceutical compositions or methods for the treatment of the diseases and disorders described herein. Furthermore, the further active ingredients include other therapies or agents that mitigate the adverse effects of the treatment on the intended disease target. Such combinations may be useful for increasing efficacy, improving other disease symptoms, reducing one or more side effects, or reducing the required dose of the compounds of the present invention. The further active ingredients may be administered in separate pharmaceutical compositions from the compounds of the present invention or may be incorporated together with the compounds of the present invention in a single pharmaceutical composition. The further active ingredients may be administered simultaneously with, before, or after the administration of the compounds of the present invention.

[0190] Combination formulations containing further active ingredients include activators against other targets associated with the disease, and are known or discovered to be effective in treating the diseases and disorders described herein. For example, the compositions and formulations of the present invention and methods of treatment may further include other drugs or pharmaceuticals, e.g., other activators useful for treating or alleviating the target disease or associated symptoms or conditions. For cancer indications, further 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 drugs, mitotic inhibitors, antibodies, hormone therapy, or corticosteroids. For pain indications, suitable combination formulations include anti-inflammatory agents, e.g., NSAIDs. The pharmaceutical compositions of the present invention may further include one or more such activators, and methods of treatment may further include the administration of one or more such activators in an effective amount.

[0191] Chemical synthesis method The following examples are provided for illustrative purposes only, but are not limiting to the present invention. Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified by selecting appropriate starting materials and reagents to obtain other compounds of formulas (I) to (IV).

[0192] Abbreviations: The examples described herein use materials that include, but are not limited to, those described by the following abbreviations known to those skilled in the art: [Table 32] [Table 33] [Table 34]

[0193] The proposed targets can be manufactured via conventional chemistry or according to the general scheme shown below.

[0194] The following starting materials and intermediates can be obtained from commercial sources or by known literature methods: (2S)-2-methyloxirane, (2R)-2-methyloxirane, propan-2-amine, iodoethane, 2-bromoethoxy-tert-butyl-dimethylsilane, (2R)-1-(isopropylamino)propan-2-ol, 5-bromo-1H-pyrazolo[3,4-c]pyridine, 2,5-dimethylpyrazole-3-ol, 2,4-dimethylpyridine-3-amine, 2,6-dimethylpyridine, 2-methylpyrazole-3-ol, methyl 3-methyl-1H-pyrazole-5-carboxylate (also known as methyl 5-Methyl-1H-pyrazole-3-carboxylate), 2-[tert-butyl(dimethyl)silyl]oxyethanol, (2R)-1-(ethylamino)propane-2-ol, (2S)-2-aminopropane-1-ol, (2R)-2-aminopropane-1-ol, (2R)-propane-1,2-diol, (2S)-propane-1,2-diol, (2R)-1-(isopropylamino)propane-2-ol, (2S)-1-(isopropylamino)propane-2-ol, (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid, N-methoxymethanamine, 2-(methylamino)ethanol, etanamine, 2-iodoacetonitrile, tert-butyl N-[(2R)-2-hydroxypropyl]carbamate, tert-butyl N-[(1R)-2-hydroxy-1-methyl-ethyl]carbamate, tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]carbamate, tert-butyl N-[(2S)-2-hydroxypropyl]carbamate, methyl 3-bromo-1H-pyrazole-5-carboxylate, methyl 3-hydroxy-1H-pyrazole-5-carboxylate, ethyl 3-hydroxy-1H-pyrazole-5-carboxylate, tert-butyl N-(2-bromoethyl)carbamate, (2,2,2-trifluoroacetyl)2,2,2-trifluoroacetate, N-ethyl-2,2,2-trifluoro-N-[(2S)-2-hydroxypropyl]acetamide, [(2R)-pyrrolidine-2-yl]methanol, ethyl 2,4-Dioxohexanoate, (R)-1-(ethylamino)propan-2-ol, 1,3-dimethylpyrazole-4-ol, [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate, Ethinyl(triisopropyl)silane, Cyclopropanamine, Ethyl 2,4-Dioxopentanoate, 5-(bromomethyl)-4-iodo-1,3-dimethylpyrazole, (2S)-1-(cyclopropylamino)propan-2-ol, Methyl 1H-pyrazole-5-carboxylate, Ethyl (2S)-2-hydroxypropanoate, Ethyl 3-ethoxy-1H-pyrazole-5-carboxylate, (2-hydroxyphenyl)boronic acid, 1-methylpyrazole-4-ol, tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, ethyl 5-methyl-1H-pyrazole-3-carboxylate, methyl 5-hydroxy-2-methylpyrazole-3-carboxylate, 1-iodoethane-1,1,2,2,2-d5, 2-chloro-4-methylpyridine-3-amine, 2,2,2-trifluoro-N-[(2R)-2-hydroxypropyl]-N-methylacetamide, ethyl 2,5-dimethylpyrazole-3-carboxylate, ethyl 3,3-diethoxyprop-2-enoate, 2,2,2-trifluoro-N-[(2R)-2-hydroxypropyl]-N-methylacetamide, methyl 4-methoxy-3-oxobutanoate, ethyl 1-Hydroxycyclopropanecarboxylate, 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane, 1-Methyl-1H-pyrazole-5-ol, tert-butyl (2-bromoethyl)carbamate, tert-butyl (R)-(1-oxopropan-2-yl)carbamate, 1,3-dimethyl-1H-pyrazole-5-ol, tert-butyl (R)-(2-hydroxypropyl)carbamate, propanoyl chloride, cyclopropanecarbonyl chloride, cyclopropanol, ethyl 4-chloro-3-oxobutanoate, 3-bromo-1,1-Difluoro-propan-2-ol, and 3,6-dioxabicyclo[3.1.0]hexane; benzyl(triethyl)ammonium chloride, and methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate.

[0195] General method A: Example 1 is used as an example.

[0196] Preparation of 2-[(10R,17E)-16-ethoxy-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 1) [ka]

[0197] Step 1. A solution of commercially available (2R)-2-methyloxirane (5.00 g, 86.0 mmol, 1 equivalent) and commercially available propan-2-amine (15.2 g, 258 mmol, 3 equivalents) in MeOH (80 mL) was stirred at 25°C for 14 hours. After completion, the mixture was concentrated to obtain (2R)-1-(isopropylamino)propan-2-ol (8.60 g, 73.3 mmol, 85% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 3.76 - 3.66 (m, 1H), 2.85 - 2.69 (m, 2H), 2.40 - 2.27 (m, 1H), 2.19 - 1.94 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H), 1.09 - 1.04 (m, 6H).

[0198] Step 2. To a 150 mL solution of commercially available methyl 3-hydroxy-1H-pyrazole-5-carboxylate (15 g, 105.55 mmol, 1 equivalent) and iodoethane (16.46 g, 105.55 mmol, 8.44 mL, 1 equivalent) in DMF (150 mL), K₂CO₃ (43.76 g, 316.65 mmol, 3 equivalents) was added. The mixture was stirred at 80°C for 2 hours. After completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water (200 mL x 2), dried over Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 80:20) to obtain methyl 3-ethoxy-1H-pyrazole-5-carboxylate (10.4 g, 61.12 mmol, 58% yield) as a white solid. LCMS: (M+1: 171.1)

[0199] Step 3. To a 100 mL solution of methyl 3-ethoxy-1H-pyrazole-5-carboxylate (10 g, 58.77 mmol, 1 equivalent) and commercially available 2-bromoethoxy-tert-butyl-dimethyl-silane (21.09 g, 88.15 mmol, 1.5 equivalents) in DMF (1), NaI (8.81 g, 58.77 mmol, 1 equivalent) and K2CO3 (24.37 g, 176.30 mmol, 3 equivalents) were added, and the mixture was stirred at 60°C for 16 hours. After completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with water (80 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 17:83) to obtain methyl 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-1H-pyrazole-5-carboxylate (12.7 g, 38.66 mmol, 66% yield) as a yellow liquid. LCMS: (M+1: 329.5).

[0200] Step 4. To a solution of methyl 2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxypyrazole-3-carboxylate (12 g, 36.53 mmol, 1 equivalent) in THF (120 mL), LiAlH4 (1.39 g, 36.53 mmol, 1 equivalent) was added at 0°C. The mixture was stirred at 0°C for 2 hours. After completion, the mixture was quenched with MeOH (150 mL) at 0°C, and the mixture was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0~3:1) to obtain (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-1H-pyrazole-5-yl)methanol (12.7 g, 38.66 mmol, 66% yield) as a yellow liquid. LCMS: (M+1: 301.1)

[0201] Step 5. To a solution of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxypyrazole-3-yl]methanol (7g, 23.30 mmol, 1 equivalent) in ACN (70 mL), NIS (4.72 g, 20.97 mmol, 0.9 equivalents) was added at 0°C, and the mixture was stirred at 25°C for 2 hours. After completion, the mixture was quenched at 0°C with saturated Na2SO3 (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 80:20) to obtain (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazole-5-yl)methanol (7.7 g, 18.06 mmol, 66% yield) as a yellow liquid. 1H NMR (400 MHz, MeOD) δ = 4.60 (d, J = 2.0 Hz, 2H), 4.30 - 4.25 (m, 2H), 4.23 (dt, J = 2.6, 4.8 Hz, 2H), 3.95 -3.90 (m, 2H), 3.33 (br s, 1H), 1.45 - 1.39 (m, 3H), 0.84 (d, J = 2.0 Hz, 9H), 0.02 -0.01 (m, 6H). LCMS: (M+1: 427.0).

[0202] Step 6. To a 35 mL solution of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methanol (3.5 g, 8.21 mmol, 1 equivalent) and PPh3 (2.58 g, 9.85 mmol, 1.2 equivalents) in DCM, CBr4 (3.27 g, 9.85 mmol, 1.2 equivalents) was added at 0°C. The mixture was stirred at 25°C for 1 hour. After completion, the mixture was diluted with water (50 mL) and extracted with DCM (30 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 80:20) to obtain 5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazole (2.9 g, 5.93 mmol, 72% yield) (also known as 2-[5-(bromomethyl)-3-ethoxy-4-iodopyrazole-1-yl]ethoxy-tert-butyl-dimethyl-silane) as a yellow oily substance. LCMS: (M+1: 490.8).

[0203] Step 7. To a solution of (2R)-1-(isopropylamino)propan-2-ol (4.00 g, 34.1 mmol, 1.5 equivalents) in ACN (260 mL), K2CO3 (6.29 g, 45.5 mmol, 2 equivalents) and 5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazole (11.1 g, 22.8 mmol, 1 equivalent) were added. The mixture was stirred at 50°C for 12 hours. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / THE = 1:0-5:1) to obtain (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-isopropyl-amino]propan-2-ol (11.9 g, 22.6 mmol, 99% yield) as a colorless oil. LCMS: (M+1: 526.5).

[0204] Step 8. (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methylisopropyl-amino]propan-2-ol (11.9 g, 22.6 mmol, 1 equivalent) was dissolved in DCM (120 mL) and TEA (11.5 g, 113 mmol, 5 equivalents) and MsCl (7.82 g, 68.3 mmol, 3.02 equivalents) were added. The mixture was stirred at 0°C for 30 minutes. After completion, the mixture was quenched with dilute citric acid (120 mL) and extracted with DCM (60 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain [(1R)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-isopropyl-amino]-1-methyl-ethyl]methanesulfonate (12.7 g, 21.1 mmol, 93% yield) as a white oil.

[0205] Step 9. A solution of commercially available 5-bromo-1H-pyrazolo[3,4-c]pyridine (23.0 g, 116 mmol, 1 equivalent) and t-BuOK (26.0 g, 232 mmol, 2 equivalents) in THF (300 mL) was added dropwise to a solution of I2 (32.4 g, 127 mmol, 1.1 equivalents) in THF (100 mL) at 0°C. The mixture was stirred at 0°C for 3 hours. After completion, the mixture was quenched with saturated NaHSO3 (100 mL), diluted with H2O (300 mL), and extracted with ethyl acetate (3 × 300 mL). The organic layer was washed with brine (3 × 100 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain 5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine (37.5 g, 115 mmol, 99.67% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.80 (s, 1H), 7.55 (s, 1H). LCMS: (M+1: 323.6).

[0206] Step 10. To a solution of 5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine (25.0 g, 77.1 mmol, 1 equivalent) in toluene (250 mL), TsOH (2.66 g, 15.4 mmol, 0.2 equivalents) and 3,4-dihydro-2H-pyran (DHP) (16.2 g, 192 mmol, 2.5 equivalents) were added. The mixture was stirred at 90°C for 2 hours. After completion, the mixture was washed with NH4Cl solution (2 × 100 mL), washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA = 100 / 8) to obtain 5-bromo-3-iodo-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridine (22.3 g, 54.6 mmol, 70.81% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 1H), 7.72 (s, 1H), 6.00 (dd, J = 1.6, 8.8 Hz, 1H), 3.92 - 3.84 (m, 1H), 3.80 - 3.72 (m, 1H), 2.35 - 2.26 (m, 1H), 2.06 - 1.96 (m, 2H), 1.79 - 1.66 (m, 1H), 1.63 - 1.55 (m, 2H). LCMS: (M+1: 409.8).

[0207] Step 11. To a solution of 5-bromo-3-iodo-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridine (12.0 g, 29.4 mmol, 1 equivalent), potassium vinyltrifluoroborate (19.7 g, 147 mmol, 5 equivalents), dioxane (120 mL), and H2O (24 mL), Pd(dppf)Cl2 (2.15 g, 2.94 mmol, 0.1 equivalent) and Na2CO3 (9.35 g, 88.2 mmol, 3 equivalents) were added. The mixture was stirred under N2 at 40°C for 72 hours. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA=50 / 1) to obtain 5-bromo-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine (8.6 g, 27.9 mmol, 94.89% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.06 (s, 1H), 8.30 (s, 1H), 7.01 (dd, J = 11.6, 18.0 Hz, 1H), 6.21 (d, J = 18.0 Hz, 1H), 6.03 - 5.93 (m, 1H), 5.59 (d, J = 11.6 Hz, 1H), 3.93 - 3.84 (m, 1H), 3.81 - 3.72 (m, 1H), 2.39 - 2.27 (m, 1H), 2.05 - 1.97 (m, 2H), 1.78 - 1.69 (m, 1H), 1.63 - 1.55 (m, 2H).LCMS: (M+1: 309.8).

[0208] Step 12. To a solution of 5-bromo-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine (7.00 g, 22.7 mmol, 1 equivalent) in dioxane (210 mL), K2CO3 (6.28 g, 45.4 mmol, 2 equivalents), commercially available 2,5-dimethylpyrazole-3-ol (3.06 g, 27.3 mmol, 1.2 equivalents), and [2-(2-aminophenyl)phenyl]methylsulfonyloxypalladium; ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphan (tBuBrettPhos Pd G3) (1.36 g, 1.59 mmol, 0.07 equivalents) were added under N2 conditions. The mixture was stirred at 130°C for 12 hours. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1:0-15:1) to obtain 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (5.10 g, 15.0 mmol, 66% yield) as a brown solid. LCMS: (M+1: 340.1).

[0209] Step 13. K2CO3 (6.96 g, 50.4 mmol, 3 equivalents) was added to a solution of 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (5.70 g, 16.8 mmol, 1 equivalent) and [(1R)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-isopropyl-amino]-1-methyl-ethyl]methanesulfonate (12.2 g, 20.2 mmol, 1.2 equivalents) in DMF (330 mL). The mixture was stirred at 60°C for 12 hours. After completion, the mixture was quenched with water (660 mL) and extracted with ethyl acetate (150 mL x 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:EA = 1:0~1:2) to obtain (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-isopropyl-propane-1-amine (8.83 g, 10.4 mmol, 62% yield) as a yellow solid. LCMS: (M+1: 847.7).

[0210] Step 14. (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-isopropyl-propane-1-amine(8.8 To a 445 mL solution of DMF containing 3 g (10.4 mmol, 1 equivalent), TBAC (2.90 g, 10.4 mmol, 1 equivalent), NaHCO3 (2.19 g, 26.1 mmol, 2.5 equivalents), and Pd(OAc)2 (468 mg, 2.09 mmol, 0.2 equivalents) were added. The mixture was degassed three times, purged with N2, and then stirred at 140°C for 1 hour under an N2 atmosphere. After completion, the mixture was quenched with water (890 mL) and extracted with ethyl acetate (450 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 1:0 to 1:1) to obtain (10R,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-6,8,10-trimethyl-2-(oxan-2-yl)-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (3.30 g, 4.59 mmol, 44% yield) as a yellow solid. LCMS: (M+1: 719.8).

[0211] Step 15. TFA (38.4 g, 337 mmol, 73.3 equivalents) was added to a solution of (10R,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-6,8,10-trimethyl-2-(oxan-2-yl)-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (3.30 g, 4.59 mmol, 1 equivalent) in DCM (25 mL). The mixture was stirred at 25 °C for 12 hours. After completion, the mixture was concentrated to obtain a brown solid (2.83 g, crude). This brown solid (2.83 g, 4.59 mmol, 1 equivalent) was dissolved in MeOH (29 mL), and K2CO3 (6.34 g, 45.9 mmol, 10 equivalents) was added. The mixture was stirred at 25°C for 0.5 hours. After completion, the mixture was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / THF = 1:0~1:3) to obtain 2-[(10R,17E)-16-ethoxy-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (1.15 g, 2.21 mmol, 48.13% yield) as a white solid. LCMS: (M+1: 521.3). Example 1 1 The 1H NMR spectrum can be seen in the NMR table below. The final structure was confirmed by X-ray crystallography.

[0212] Preparation of 2-[(10S,17E)-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 5) [ka]

[0213] Step 1. To a solution of MeNH2 (41.1 g, 397 mmol, 30% purity, 20 equivalents) in acetone (800 mL), K2CO3 (8.24 g, 59.6 mmol, 3 equivalents) was added at 0°C. Then, a solution of 2-[5-(bromomethyl)-4-iodo-3-isopropoxypyrazole-1-yl]ethoxy-tert-butyl-dimethyl-silane (prepared according to the method described in Example 3 / Example 4) (10 g, 19.8 mmol, 1 equivalent) in acetone (200 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 12 hours. After completion, the mixture was quenched with water (1000 mL) and extracted with ethyl acetate (1000 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 20:1 to 15:1) to obtain 1-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-isopropoxypyrazole-3-yl]-N-methylmethanamine (7.00 g, 15.4 mmol, 77.7% yield) as a yellow oil. LCMS: (M+1: 454.1).

[0214] Step 2. A solution of commercially available (2R)-2-methyloxirane (1.92 g, 33.0 mmol, 2.32 mL, 3 equivalents) and 1-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-isopropoxypyrazole-3-yl]-N-methylmethanamine (5.00 g, 11.0 mmol, 1 equivalent) in EtOH (125 mL) was stirred at 80°C for 12 hours. After completion, the mixture was concentrated to obtain (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-isopropoxypyrazole-3-yl]methyl-methylamino]propan-2-ol (5.5 g, 10.7 mmol, 97.5% yield) as a yellow oil. LCMS: (M+1: 512.2).

[0215] Step 3. To a solution of commercially available 2-methylpyrazole-3-ol (3.06 g, 31.1 mmol, 1.2 equivalents) and 5-bromo-1-tetrahydropyran-2-yl-3-vinylpyrazolo[3,4-c]pyridine (which was prepared according to the method described in Example 1) (8.00 g, 25.9 mmol, 1 equivalent) in dioxane (80 mL), K2CO3 (10.7 g, 77.8 mmol, 3 equivalents) and [2-(2-aminophenyl)phenyl]methylsulfonyloxypalladium; ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphan (tBuBrettPhos Pd G3) (1.77 g, 2.08 mmol, 0.08 equivalents) were added. The mixture was stirred at 100°C for 2 hours. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 20:1~15:1) to obtain 2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (4.30 g, 13.2 mmol, 51% yield) as a red solid. LCMS: (M+1: 326.0).

[0216] Step 4. PPh3 (1.13 g, 4.30 mmol, 2.2 equivalents) and DBAD (990 mg, 4.30 mmol, 2.2 equivalents) were added to a THF (15 mL) solution of 2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (699 mg, 2.15 mmol, 1.1 equivalents) and (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-isopropoxy-pyrazole-3-yl]methyl-methyl-amino]propan-2-ol (1.00 g, 1.95 mmol, 1 equivalent) from Step 2. The mixture was stirred at 25°C for 2 hours. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / THF = 2:1 to 1:1) to obtain (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-isopropoxy-pyrazole-3-yl]methyl]-N-methyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-propan-1-amine (1.50 g, 1.83 mmol, 94% yield) as a white solid. LCMS: (M+1: 819.1).

[0217] Step 5. (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-isopropoxypyrazole-3-yl]methyl]-N-methyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-propan-1-amine (1.3 g, 1.59 mmol, 1 equivalent) and TBAC (441 mg, 1.59 mmol, 1 equivalent) were dissolved in DMF (130 mL), to which NaHCO3 (333 mg, 3.97 mmol, 2.5 equivalents) and Pd(OAc)2 (71.2 mg, 317 μmol, 0.2 equivalents) were added. The mixture was stirred at 130 °C for 2 hours under an N2 atmosphere. After completion, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (250 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 1:1~1:1) to obtain (10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-8,10,12-trimethyl-2-(oxan-2-yl)-16-[(propan-2-yl)oxy]-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (250 mg, 362 μmol, 23% yield) as a yellow solid. LCMS: (M+1: 691.2).

[0218] Step 6. TFA (153 g, 1.35 mol, 4650 equivalents) was added to a solution of (10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-8,10,12-trimethyl-2-(oxan-2-yl)-16-[(propan-2-yl)oxy]-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (200 mg, 289 μmol, 1 equivalent) in DCM (5.00 mL). The mixture was stirred at 25°C for 2 hours. After completion, the mixture was concentrated to obtain Example 5 (58.7 mg, 119 μmol, 41% yield) as a yellow solid. LCMS: (M+1: 493.1). Example 5 1 The 1H NMR spectrum can be seen in the NMR table below.

[0219] 2-[(10R,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 6) and Preparation of 2-[(11S,17E)-16-ethoxy-12-ethyl-8,11-dimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 7) [ka]

[0220] Step 1. Commercially available (2R)-2-methyloxirane (5 g, 86.1 mmol, 1 equivalent) was dissolved in MeOH (50 mL) and commercially available ethanamine (2 M, 129 mL, 3 equivalents) was added. The mixture was stirred at 25°C for 12 hours. After completion, the mixture was concentrated to obtain (2R)-1-(ethylamino)propan-2-ol (7.55 g, 73.2 mmol, 85% yield) as a brown solid.1 H NMR (400 MHz, CDCl3) δ = 3.85 - 3.68 (m, 1H), 2.73 - 2.56 (m, 3H), 2.44 - 2.34 (m, 2H), 1.18 - 1.05 (m, 6H).

[0221] Step 2. To a solution of 5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazole (which was prepared according to the method described in Example 1) (1.00 g, 2.04 mmol, 1.00 equivalent) and (2R)-1-(ethylamino)propan-2-ol (316 mg, 3.07 mmol, 1.50 equivalent) in DMF (10 mL), K2CO3 (847 mg, 6.13 mmol, 3.00 equivalent) was added. The mixture was stirred at 80°C for 2 hours. After completion, the reaction mixture was diluted with H2O (15 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with H2O (8 mL), 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 = 1:0 to 4:1) to obtain (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-ethyl-amino]propan-2-ol (1.04 g, 1.95 mmol, 96% yield, 96% purity) as a white liquid. 1H NMR (400 MHz, DMSO-d6) δ = 4.28 (d, J = 4.4 Hz, 1H), 4.23 - 4.18 (m, 2H), 4.16 - 4.10 (m, 2H), 3.81 (t, J = 5.2 Hz, 2H), 3.62 (d, J = 13.6 Hz, 2H), 3.53 - 3.45 (m, 1H), 3.32 (s, 3H), 2.88 (s, 1H), 2.73 (s, 1H), 2.35 - 2.27 (m, 1H), 2.23 (d, J = 6.4, 11.6 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H), 0.97 (s, 3H), 0.77 (s, 9H), -0.09 - -0.12 (m, 6H).

[0222] Step 3. (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-ethyl-amino]propan-2-ol (1.00 g, 1.95 mmol, 1.00 equivalent) and DIEA (758 mg, 5.86 mmol, 3.00 equivalent) were mixed in a 10 mL DCM solution to which methylsulfonyl methanesulfonate (511 mg, 2.93 mmol, 1.50 equivalent) was added at 0°C. The mixture was stirred at 25°C for 1 hour. After completion, the reaction mixture was diluted with H2O (15 mL) and extracted with DCM (12 mL x 3). The combined organic layers were washed with H2O (8 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain [(1R)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-ethyl-amino]-1-methyl-ethyl]methanesulfonate (1.10 g, crude) as an orange oil. LCMS: (M+1: 590.3).

[0223] Step 4. To a 20 mL NMP solution of [(1R)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-ethyl-amino]-1-methyl-ethyl]methanesulfonate (1.00 g, 1.70 mmol, 1.00 equivalent), 2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (which was prepared according to the method described in Example 5) (552 mg, 1.70 mmol, 1.00 equivalent) and K2CO3 (703 mg, 5.09 mmol, 3.00 equivalent) were added. The mixture was stirred at 80°C for 2 hours. After completion, the reaction mixture was diluted with H2O (150 mL) and extracted with EA (120 mL x 3). The combined organic layers were washed with H2O (80 mL), 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 = 1:0 to 1:1) to obtain (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-N-ethyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-propan-1-amine (934 mg, 1.06 mmol, 63% yield, 93% purity) as an orange liquid. 1H NMR (400 MHz, DMSO-d6) δ = 9.17 (s, 1H), 8.09 - 8.00 (m, 1H), 7.93 - 7.84 (m, 1H), 7.08 - 6.93 (m, 1H), 6.20 - 6.09 (m, 1H), 6.02 - 5.92 (m, 1H), 5.60 (d, J = 12.0 Hz, 1H), 4.57 - 4.46 (m, 1H), 4.13 - 4.05 (m, 3H), 3.34 - 3.27 (m, 15H), 1.60 (s, 2H), 1.30 - 1.23 (m, 3H), 1.14 - 1.08 (m, 3H), 0.99 - 0.89 (m, 3H), 0.74 - 0.65 (m, 9H), -0.20 (d, J = 1.6 Hz, 6H).

[0224] Step 5. To a solution of (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-N-ethyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-propan-1-amine (830 mg, 1.01 mmol, 1.00 equivalent) in DMF (8 mL), Pd(OAc)2 (34.1 mg, 152 μmol, 0.15 equivalent), TBAC (563 mg, 2.03 mmol, 2.00 equivalent), and KOAc (497 mg, 5.07 mmol, 5.00 equivalent) were added. The mixture was stirred under N2 at 80°C for 16 hours. After completion, the reaction mixture was diluted with H2O (150 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with H2O (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1:0~10:1) to obtain 2-[(10R,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2-(oxan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol (100 mg, 139 μmol, 14% yield, 80% purity) as a red oil. LCMS: (M+1-114: 577.3).

[0225] Step 6. TFA (1.54 g, 13.5 mmol, 1.00 mL, 86.3 equivalents) was added to a solution of 2-[(10R,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2-(oxan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (90.0 mg, 156 μmol, 1.00 equivalent) in DCM (2 mL). The mixture was stirred at 25°C for 3 hours. After completion, the reaction mixture was concentrated under vacuum to obtain 1-[(10R,17E)-16-ethoxy-12-ethyl-14-(2-hydroxyethyl)-8,10-dimethyl-11,12,13,14-tetrahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-2(10H)-yl]-2,2,2-trifluoroethane-1-one (90.0 mg, crude) as an orange oily substance. LCMS: (M+1: 589.2).

[0226] Step 7. 1-[(10R,17E)-16-ethoxy-12-ethyl-14-(2-hydroxyethyl)-8,10-dimethyl-11,12,13,14-tetrahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-2(10H)-yl]-2,2,2-trifluoroethane-1-one (90.0 mg, 153 μmol, 1.00 equivalent) was dissolved in MeOH (1 mL) and K2CO3 (106 mg, 765 μmol, 5.00 equivalent) was added. The mixture was stirred at 25°C for 0.5 hours. After completion, the reaction product was concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; gradient: 10%~40%B over 8 minutes) to obtain Example 6 (19.18 mg, 37.26 μmol, 24% yield, 95.69% purity) as a yellow solid. LCMS: (M+1: 493.2). 1The 1H NMR spectrum can be seen in the NMR table below.

[0227] The by-product was also obtained as Example 7 (2.75 mg, 5.25 μmol, 15% yield, 94.02% purity) as a white solid. LCMS: (M+1: 493.1). 1 The 1H NMR spectrum can be seen in the NMR table below.

[0228] Preparation of 2-[(10S,17E)-16-ethoxy-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 8) [ka]

[0229] Step 1. Commercially available (2S)-2-methyloxirane (5.00 g, 86.1 mmol, 1 equivalent) was added to a solution of commercially available propan-2-amine (15.3 g, 258 mmol, 3 equivalents) in MeOH (80 mL). The mixture was stirred at 25°C for 24 hours. After completion, the mixture was concentrated to obtain (2S)-1-(isopropylamino)propan-2-ol (7.14 g, 60.9 mmol, 71% yield) as a white liquid. 1 H NMR (400 MHz, CDCl3) δ = 3.78 - 3.65 (m, 1H), 2.83 - 2.65 (m, 2H), 2.39 - 2.28 (m, 1H), 1.17 - 1.09 (m, 3H), 1.08 - 0.99 (m, 6H).

[0230] Step 2. To a solution of (2S)-1-(isopropylamino)propan-2-ol (848 mg, 7.24 mmol, 1.5 equivalents) in ACN (33 mL), K2CO3 (1.33 g, 9.65 mmol, 2 equivalents) and 5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazole (which was prepared according to the method described in Example 1) (2.36 g, 4.82 mmol, 1 equivalent) were added. The mixture was stirred at 50°C for 12 hours. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / THE = 1:0-5:1) to obtain (2S)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-isopropylamino]propan-2-ol (2.26 g, 4.30 mmol, 89% yield) as a colorless oil. LCMS: (M+1: 526.6).

[0231] Step 3. The mixture of (2S)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-isopropyl-amino]propan-2-ol (650 mg, 1.24 mmol, 1 equivalent), 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (which was prepared according to the method described in Example 1) (420 mg, 1.24 mmol, 1 equivalent), PPh3 (649 mg, 2.47 mmol, 2 equivalents), and DBAD (427 mg, 1.86 mmol, 1.5 equivalents) was degassed three times, purged with N2, and then THF (10 mL) was added. 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 = 1:1~1:1) to obtain (2R)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-isopropyl-propane-1-amine (781 mg, 922 μmol, 74% yield) as a brown solid. LCMS: (M+1: 847.3).

[0232] Step 4. (2R)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-isopropyl-propan-1-amine (710 mg, 838 μmol, 1 equivalent) was dissolved in DMF (35 mL) and NaHCO3 (176 mg, 2.10 mmol, 2.5 equivalents), TBAC (233 mg, 838 μmol, 1 equivalent), and Pd(OAc)2 (37.6 mg, 167 μmol, 0.2 equivalents) were added. The mixture was degassed three times, purged with N2, and then stirred at 130°C for 1 hour under an N2 atmosphere. After completion, the reaction mixture was partitioned into EA (10 mL x 3) and water (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:1 to 1:1) to obtain (17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-6,8,10-trimethyl-2-(oxan-2-yl)-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadesine (396 mg, 551 μmol, 66% yield) as a yellow solid. LCMS: (M+1: 719.6).

[0233] Step 5. To a solution of (17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-6,8,10-trimethyl-2-(oxan-2-yl)-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (366 mg, 509 μmol, 1 equivalent) in DCM (3.5 mL), TFA (1.87 g, 16.42 mmol, 32.3 equivalents) was added, and the mixture was stirred at 25°C for 2 hours. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 15:1~15:1) to obtain 2-[(17E)-16-ethoxy-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol (40 mg, 76.83 μmol, 15% yield) as a brown solid. LCMS: (M+1: 521.3).

[0234] Step 6. SFC Separation: The above products were separated by SFC (column: DAISEL Chiralpak IC (250 mm × 30 mm, 10 μm); mobile phase: [CO2-ACN / MeOH (0.1% NH3H2O)]; B%: 40%, constant composition elution mode) to obtain Example 8 (4.4 mg, 8.45 μmol, 11% yield) as a white solid and Example 1 (4.7 mg, 9.03 μmol, 11.75% yield) as a white solid. LCMS: (M+1: 521.3). Example 8 1 The 1H NMR spectrum can be seen in the NMR table below.

[0235] 2-[(10S,17E)-16-ethoxy-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 11) and Preparation of 2-[(10R,17E)-16-ethoxy-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 12) [ka]

[0236] Step 1. To a 10 mL solution of (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-isopropyl-amino]propan-2-ol (prepared according to the method described in Example 1) (600 mg, 1.14 mmol, 1 equivalent) and 2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (prepared according to the method described in Example 5) (371 mg, 1.14 mmol, 1 equivalent) in THF (10 mL), PPh3 (598 mg, 2.28 mmol, 2 equivalents) and DBAD (394 mg, 1.71 mmol, 1.5 equivalents) were added. The mixture was stirred at 25°C for 2 hours. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / THF = 1:1 to 1:1) to obtain (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-N-isopropyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-propan-1-amine (662 mg, 794 μmol, 70% yield) as a white solid. LCMS: (M+1: 833.2).

[0237] Step 2. (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-N-isopropyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-propan-1-amine (640 mg, 768 μmol, 1 equivalent) and TBAC (213 mg, 768 μmol, 1 equivalent) were dissolved in DMF (20 mL), to which NaHCO3 (161 mg, 1.92 mmol, 2.5 equivalents) and Pd(OAc)2 (17.2 mg, 76.8 μmol, 0.1 equivalent) were added. The mixture was stirred at 130 °C for 2 hours. After completion, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (250 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA = 1:1 to 0:1) to obtain (10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-8,10-dimethyl-2-(oxan-2-yl)-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (230 mg, 326 μmol, 42% yield) as a yellow solid. LCMS: (M+1: 705.4).

[0238] Step 3. To a solution of (10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-8,10-dimethyl-2-(oxan-2-yl)-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (200 mg, 283 μmol, 1 equivalent) in DCM (0.3 mL), TFA (4.60 g, 40.3 mmol, 3.00 mL, 142 equivalents) was added. The mixture was stirred at 25°C for 2 hours. After completion, the crude product was ground in ACN (5 mL) at 25°C for 5 minutes to obtain 2-[(10S,17E)-16-ethoxy-8,10-dimethyl-12-(propan-2-yl)-10,11,12,13-tetrahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14(2H)-yl]ethane-1-ol (65 mg, 128 μmol, 45.2% yield) as a white solid. LCMS: (M+1: 507.2).

[0239] Step 4. SFC Separation: The above product was purified by SFC (column: DAISEL Chiralcel OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-MeOH]; B%: 40%, constant composition elution mode) to obtain Example 11 (32.97 mg, 65.08 μmol, 54.95% yield) as a white solid and Example 12 (8.41 mg, 16.60 μmol, 14.02% yield) as a white solid.

[0240] Example 11: LCMS: (M+1: 507.1). Example 11 1 The 1H NMR spectrum can be seen in the NMR table below.

[0241] Example 12: LCMS: (M+1: 507.2). Example 12 1 The 1H NMR spectrum can be seen in the NMR table below.

[0242] 2-[(10S,17E)-12-ethyl-6,8,10,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 13) and Preparation of 2-[(10R,17E)-12-ethyl-6,8,10,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 14) [ka]

[0243] Step 1. A mixture of commercially available methyl 3-methyl-1H-pyrazole-5-carboxylate (20.0 g, 143 mmol, 1 equivalent), commercially available 2-[tert-butyl(dimethyl)silyl]oxyethanol (50.3 g, 285 mmol, 2 equivalents), and PPh3 (82.4 g, 314 mmol, 2.2 equivalents) in THF (120 mL) was degassed with N2, stirred under N2 at 25°C for 30 minutes, and then DIAD (63.5 g, 314 mmol, 61 mL, 2.2 equivalents) was added dropwise at 0°C. The resulting mixture was stirred under N2 at 25°C for a further 5 hours. After completion, the mixture was ground with petroleum ether (400 mL), filtered, and TPPO was removed. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / tetrahydrofuran = 1 / 0 to 10 / 1) to obtain methyl 2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methylpyrazole-3-carboxylate (40.0 g, 134 mmol, 94% yield) as a colorless oil. LCMS: (M+1 = 299.0).

[0244] Step 2. To a solution of methyl 2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methylpyrazole-3-carboxylate (50.0 g, 168 mmol, 1 equivalent) in THF (400 mL), LiAlH4 (2.5 M, 67.0 mL, 1 equivalent) was added at 0°C. The mixture was stirred at 25°C for 2.5 hours. After completion, the reaction mixture was quenched with water (6 mL) and adjusted with 15% NaOH (6 mL). Then, water (18 mL) was added to the mixture and it was filtered. The filtrate was concentrated under reduced pressure to obtain [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methylpyrazole-3-yl]methanol (45.0 g, 153 mmol, 91% yield, 92% purity) as a colorless oil. LCMS: (M+1 = 271.1).

[0245] Step 3. To a solution of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrazole-3-yl]methanol (45.0 g, 166 mmol, 1 equivalent) in ACN (300 mL), NIS (37.4 g, 166 mmol, 1 equivalent) was added at 0°C. The mixture was stirred at 25°C for 8 hours. After completion, the mixture was quenched with a saturated Na2SO3 solution (12 mL) and partitioned into water (300 mL) and ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 1 / 2) to obtain [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methyl-pyrazole-3-yl]methanol (10.0 g, 25.2 mmol, 15% yield) as an amber solid. 1 H NMR (400 MHz, DMSO-d6) δ = 5.26 (br s, 1H), 4.46 (s, 2H), 4.24 - 4.18 (m, 2H), 3.84 (t, J = 5.6 Hz, 2H), 2.14 - 2.04 (m, 3H), 0.80 - 0.74 (m, 9H), -0.07 - -0.16 (m, 6H). LCMS: (M+1 = 397.4).

[0246] Step 4. To a 48 mL solution of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methylpyrazole-3-yl]methanol (4.80 g, 12.1 mmol, 1 equivalent) and PPh3 (3.81 g, 14.5 mmol, 1.2 equivalents) in DCM, CBr4 (4.82 g, 14.5 mmol, 1.2 equivalents) was added at 0°C. The mixture was stirred at 0°C for 1 hour. After completion, the mixture was diluted with water (150 mL), extracted with DCM (40 mL x 3), dried over Na2SO4, and filtered. The filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / tetrahydrofuran = 1 / 0~85 / 155) to obtain 2-[5-(bromomethyl)-4-iodo-3-methylpyrazole-1-yl]ethoxy-tert-butyl-dimethyl-silane (4.30 g, 9.36 mmol, 77% yield) as a white solid. LCMS: (M+1 = 460.9).

[0247] Step 5. K2CO3 (602 mg, 4.36 mmol, 2 equivalents) was added to a solution of 2-[5-(bromomethyl)-4-iodo-3-methylpyrazole-1-yl]ethoxy-tert-butyldimethylsilane (1.00 g, 2.18 mmol, 1 equivalent) and commercially available (2R)-1-(ethylamino)propan-2-ol (449 mg, 4.36 mmol, 2 equivalents) in DMF (6 mL). The mixture was stirred at 80°C for 50 minutes. After completion, the reaction mixture was partitioned into ethyl acetate (10 mL x 3) and water (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / tetrahydrofuran = 4 / 1 to 3 / 1) to obtain (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methyl-pyrazole-3-yl]methyl-ethyl-amino]propan-2-ol (1.00 g, 2.08 mmol, 95% yield) as a colorless oil. 1H NMR (400 MHz, MeOD-d) δ = 4.39 - 4.30 (m, 1H), 4.27 - 4.19 (m, 1H), 3.89 (br s, 2H), 3.45 (s, 2H), 3.08 (br s,1H), 2.64 - 2.59 (m, 1H), 2.37 (br s, 2H), 2.33 - 2.27 (m, 1H), 2.21 (s, 3H), 1.10 - 1.03 (m, 6H), 0.78 (s, 9H), -0.11 (d, J = 6.4 Hz, 6H). LCMS: (M+1 = 481.9).

[0248] Step 6. The mixture of (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methylpyrazole-3-yl]methyl-ethyl-amino]propan-2-ol (875 mg, 1.62 mmol, 1 equivalent), 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (which was prepared according to the method described in Example 1) (878 mg, 2.59 mmol, 1.6 equivalents), PPh3 (933 mg, 3.56 mmol, 2.2 equivalents), and DBAD (819 mg, 3.56 mmol, 2.2 equivalents) was degassed three times, purged with N2, and then 2-MeTHF (9 mL) was added to the mixture and stirred under an N2 atmosphere at 25°C for 1.5 hours. After completion, the mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / tetrahydrofuran = 2 / 1 to 1 / 1) to obtain (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methyl-pyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-ethyl-propane-1-amine (650 mg, 810 μmol, 5% yield) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.23 (s, 1H), 7.93 (d, J = 0.8 Hz, 1H), 7.03 (dd, J = 12.0, 17.6 Hz, 1H), 6.10 (d, J = 18.0 Hz, 1H), 5.97 (dd, J = 2.2, 9.6 Hz, 1H), 5.63 - 5.50 (m, 1H), 4.13 - 4.07 (m, 2H), 3.94 - 3.86 (m, 1H), 3.77 - 3.73 (m, 2H), 3.56 (s, 2H), 3.51 (s, 2H), 3.32 (s, 3H), 2.59 (br d, J = 5.2 Hz, 2H), 2.42 (br s, 2H), 2.35 - 2.31 (m, 2H), 2.26 (s, 3H), 2.06 (s, 3H), 2.02 (br d, J = 5.6 Hz, 1H), 1.78 - 1.70 (m, 1H), 1.61 (br s, 2H), 0.96 (br d, J = 6.0 Hz, 3H), 0.83 (br t, J = 7.2 Hz, 3H), 0.70 (s, 9H), -0.19 (d, J = 1.6 Hz, 6H). LCMS: (M+1 = 803.6).

[0249] Step 7. The mixture in DMF (7 mL) of (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methylpyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-ethyl-propan-1-amine (650 mg, 810 μmol, 1 equivalent), TBAC (225 mg, 810 μmol, 1 equivalent), NaHCO3 (170 mg, 2.02 mmol, 2.5 equivalents), and Pd(OAc)2 (36.4 mg, 162 μmol, 0.2 equivalents) was degassed three times, purged with N2, and then stirred at 140°C for 1.5 hours under an N2 atmosphere. After completion, the reaction mixture was partitioned into ethyl acetate (30 mL x 3) and water (90 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / tetrahydrofuran = 1 / 1 to 1 / 2) to obtain (10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-12-ethyl-6,8,10,16-tetramethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (210 mg, 311 μmol, 38% yield) as a brown solid. LCMS: (M+1 = 675.4).

[0250] Step 8. To a solution of (10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-12-ethyl-6,8,10,16-tetramethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (200 mg, 296 μmol, 1 equivalent), DCM (2.5 mL) and TFA (0.5 mL) were added. The mixture was stirred at 25°C for 1 hour. After completion, the mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (TFA)-ACN]; gradient: 10%~40%B over 10 minutes) to obtain 2-[(10S,17E)-12-ethyl-6,8,10,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol (50.0 mg, 105 μmol, 35% yield) as a yellow solid. 1 H NMR (400 MHz, MeOD-d4) δ = 9.11 (d, J = 0.8 Hz, 1H), 8.62 (s, 1H), 7.66 (br d, J = 17.2 Hz, 1H), 7.20 (d, J = 16.8 Hz, 1H), 5.37 - 5.26 (m, 1H), 4.93 (br s, 1H), 4.71 - 4.63 (m, 1H), 4.39 - 4.26 (m, 2H), 3.99 (br d, J = 4.0 Hz, 1H), 3.94 - 3.83 (m, 2H), 3.74 (s, 3H), 3.47 (br d, J = 14.4 Hz, 2H), 3.39 - 3.33 (m, 1H), 2.56 (d, J = 12.4 Hz, 6H), 1.46 (br t, J = 6.4 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H). LCMS: (M+1 = 477.3).

[0251] Step 9. SFC separation: The residue was separated using SFC (column: DAISEL Chiralcel OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 40%, constant composition elution mode) to obtain Example 13 (5.93 mg, 12.4 μmol, 12% yield, 100% purity) as a white solid and Example 14 (5.93 mg, 12.44 μmol, 11.86% yield, 100% purity) as a white solid.

[0252] Example 13: LCMS: (M+1 = 477.1). Example 13 1 The 1H NMR spectrum can be seen in the NMR table below.

[0253] Example 14: LCMS: (M+1 = 477.1). Example 14 1 The 1H NMR spectrum can be seen in the NMR table below.

[0254] Preparation of 2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 15) [ka]

[0255] Step 1. 2-[5-(bromomethyl)-3-ethoxy-4-iodopyrazole-1-yl]ethoxy-tert-butyldimethylsilane (prepared according to the method described in Example 1) (539 mg, 1.10 mmol, 1 equivalent) and K2CO3 (304 mg, 2.20 mmol, 2 equivalents) were dissolved in DMF (5 mL) to which commercially available (2R)-1-(ethylamino)propan-2-ol (170 mg, 1.65 mmol, 1.5 equivalents) was added. The mixture was stirred at 80°C for 1 hour. After completion, the resulting mixture was diluted with H2O (20 mL) and extracted with siRNA (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / EA = 1 / 0 to 1 / 1) to obtain (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-ethyl-amino]propan-2-ol (500 mg, 918 μmol, 83% yield, 94% purity) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 4.26 (q, J = 7.2 Hz, 3H), 4.15 (d, J = 13.6 Hz, 1H), 3.91 - 3.74 (m, 4H), 3.50 (d, J = 13.6 Hz, 1H), 3.09 (s, 1H), 2.73 - 2.58 (m, 1H), 2.55 - 2.40 (m, 2H), 2.38 - 2.24 (m, 1H), 1.47 - 1.36 (m, 4H), 1.13 - 1.06 (m, 4H), 0.81 (s, 9H), -0.07 (d, J = 6.0 Hz, 6H). LCMS: (M+1: 512.1).

[0256] Step 2. The mixture of (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-ethyl-amino]propan-2-ol (457 mg, 893 μmol, 1 equivalent), 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (which was prepared according to the method described in Example 1) (606 mg, 1.79 mmol, 2 equivalents), DBAD (452 ​​mg, 1.97 mmol, 2.2 equivalents), and PPh3 (515 mg, 1.97 mmol, 2.2 equivalents) in THF (10 mL) was stirred at 25°C for 1 hour. After completion, the mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 1 / 0 to 5 / 1) to obtain (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-ethyl-propane-1-amine (426 mg, 347 μmol, 39% yield, 68% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.93 (s, 1H), 6.10 (d, J = 17.2 Hz, 1H), 5.97 (dd, J = 2.0, 9.6 Hz, 1H), 5.58 (d, J = 11.2 Hz, 1H), 4.11 - 4.02 (m, 4H), 3.95 - 3.85 (m, 2H), 3.83 - 3.68 (m, 4H), 3.57 (s, 3H), 3.48 (s, 2H), 2.69 - 2.59 (m, 3H), 2.33 (s, 3H), 2.08 - 2.00 (m, 3H), 1.61 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.2 Hz, 2H), 0.96 (d, J = 6.0 Hz, 2H), 0.83 (t, J = 7.2 Hz, 3H), 0.71 (s, 9H), -0.18 (d, J = 1.6 Hz, 6H). LCMS: (M+1: 833.1).

[0257] Step 3. To a solution of (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-ethyl-propan-1-amine (400 mg, 480 μmol, 1 equivalent), NaHCO3 (100 mg, 1.20 mmol, 2.5 equivalents), and Pd(OAc)2 (21.5 mg, 96.1 μmol, 0.2 equivalents) in DMF (35 mL), TBAC (133 mg, 480 μmol, 1 equivalent) was added at 25 °C. The mixture was stirred at 140 °C for 1 hour under a nitrogen atmosphere. After completion, brine (100 mL) was added to the mixture and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2). The organic layers were concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to obtain (10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadesine (180 mg, 209 μmol, 44% yield, 82% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.47 (s, 1H), 8.08 (d, J = 17.8 Hz, 1H), 7.10 (d, J = 16.8 Hz, 1H), 5.91 (d, J = 9.6 Hz, 1H), 4.35 - 4.25 (m, 2H), 4.10 (s, 2H), 3.96 - 3.82 (m, 6H), 3.63 (s, 3H), 2.62 - 2.58 (m, 2H), 2.33 (s, 4H), 2.09 - 1.95 (m, 3H), 1.80 - 1.70 (m, 1H), 1.60 (d, J = 2.4 Hz, 3H), 1.42 (t, J = 7.2 Hz, 4H), 1.10 - 1.03 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H), 0.79 (s, 9H), -0.07 (s, 6H). LCMS: (M+1: 705.3).

[0258] Step 4. To a solution of (10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (150 mg, 144 μmol, 1 equivalent) in DCM (2 mL), TFA (3.54 g, 31.0 mmol, 2.31 mL, 214 equivalents) was added at 25°C. The mixture was stirred at 25°C for 1.5 hours. After completion, the mixture was concentrated to obtain a yellow oily substance (103 mg, 105 μmol, 73% yield, 73% purity, TFA salt). LCMS: (M+1: 603.2). This yellow oily substance (103 mg, 144 μmol, 1 equivalent, TFA) was dissolved in MeOH (2 mL), and K2CO3 (199 mg, 1.45 mmol, 10 equivalents) was added. The mixture was stirred at 25°C for 1 hour. After completion, the mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (4g silica gel column, 0% to 20% DCM solution of MeOH) to obtain 2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol (50.0 mg, 98.7 μmol, 68% yield) as a white solid, which was further separated by preparative SFC (column: DAISEL Chiralcel). Purification was performed using OD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 30%, constant composition elution mode) to obtain Example 15 (25.01 mg, 47.39 μmol, 48.02% yield, 96% purity) as a grayish-white solid. LCMS: (M+1: 507.2). 1 The 1H NMR spectrum can be seen in the NMR table below.

[0259] 2-[(11S,17E)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 16) and Preparation of 2-[(10R,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 17) [ka]

[0260] Step 1. K2CO3 (1.02 g, 7.36 mmol, 3 equivalents) was added to a 15 mL solution of commercially available (2S)-2-aminopropan-1-ol (553 mg, 7.36 mmol, 3 equivalents) and 5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazole (which was prepared according to the method described in Example 1) (1.20 g, 2.45 mmol, 1 equivalent) in DMF (15 mL). The mixture was stirred at 70°C for 2 hours. After completion, the crude mixture was used in the next step. (2S)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methylamino]propan-1-ol (1.19 g, 2.46 mmol, 100% yield) was obtained as a colorless oil. LCMS: (M+1 = 484.3).

[0261] Step 2. K2CO3 (1.02 g, 7.38 mmol, 3 equivalents) was added to a mixture of (2S)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methylamino]propan-1-ol (1.19 g, 2.46 mmol, 1 equivalent) and EtI (1.15 g, 7.38 mmol, 3 equivalents) in DMF (15 mL). The mixture was stirred at 70°C for 2 hours. After completion, the mixture was diluted with water (50 mL) and extracted with siRNA (30 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by CombiFlash chromatography (20 g silica gel column, 0% to 100% siRNA PE solution). (2S)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-ethyl-amino]propan-1-ol (940 mg, 1.84 mmol, 74% yield) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ = 4.43 - 4.31 (m, 1H), 4.29 - 4.20 (m, 2H), 4.15 - 4.03 (m, 1H), 3.97 - 3.80 (m, 3H), 3.56 - 3.45 (m, 1H), 3.43 - 3.29 (m, 2H), 3.01 - 2.79 (m, 2H), 2.69 - 2.55 (m, 1H), 2.41 - 2.24 (m, 1H), 1.46 - 1.38 (m, 3H), 1.12 (t, J = 6.8 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H), 0.87 - 0.75 (m, 9H), -0.01 - -0.15 (m, 6H).

[0262] Step 3. A solution of (2S)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-ethyl-amino]propan-1-ol (900 mg, 1.76 mmol, 1 equivalent), 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (this was prepared according to the method described in Example 1) (744 mg, 2.29 mmol, 1.3 equivalents), PPh3 (1.02 g, 3.87 mmol, 2.2 equivalents), and DBAD (891 mg, 3.87 mmol, 2.2 equivalents) in 2-MeTHF (10 mL) was stirred at 25°C for 2 hours. After completion, the mixture was concentrated under vacuum to obtain the crude product. The residue was purified by CombiFlash chromatography (20g silica gel, 0%-100% PE solution of siRNA). (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-1-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-ethyl-propan-2-amine (1.00g, 1.20 mmol, 68% yield) was obtained as a yellow solid. LCMS: (M+1 = 833.7).

[0263] Step 4. A solution of (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-1-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-ethyl-propan-2-amine (980 mg, 1.18 mmol, 1 equivalent), TBAC (327 mg, 1.18 mmol, 1 equivalent), NaHCO3 (247 mg, 2.94 mmol, 2.5 equivalents), and Pd(OAc)2 (52.8 mg, 235 μmol, 0.2 equivalents) in DMF (10 mL) was stirred at 140 °C for 1 hour. After completion, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by CombiFlash chromatography (20 g silica gel column, 0% to 100% ethyl acetate solution). (11S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (540 mg, 766 μmol, 65% yield) was obtained as a brown oil. LCMS: (M+1 = 705.4).

[0264] Step 5. TFA (1.84 g, 16.2 mmol, 1.2 mL, 22.3 equivalents) was added to a solution of (11S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (510 mg, 723 μmol, 1 equivalent) in DCM (6 mL). The mixture was stirred at 25°C for 2 hours. After completion, the mixture was concentrated under vacuum to obtain a yellow oily substance (380 mg, 614 μmol, 85% yield). LCMS: (M+1 = 603.3). This yellow oily substance (380 mg, 614 μmol, 1 equivalent) was dissolved in MeOH (6 mL), and K2CO3 (424 mg, 3.07 mmol, 5 equivalents) was added. The mixture was stirred at 25°C for 2 hours. After completion, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (TFA)-ACN]; gradient: 13%~43% B). Example 16 (19.78 mg, 36.92 μmol, 6.01% yield, 94.55% purity) was obtained as an orange solid and Example 17 (3.03 mg, 5.61 μmol, 9.13 e-1% yield, 93.79% purity) as a white solid as byproducts.

[0265] Example 16: LCMS: (M+1 = 507.3). Example 16 1 The 1H NMR spectrum can be seen in the NMR table below.

[0266] Example 17: LCMS: (M+1 = 507.3). Example 17 1 The 1H NMR spectrum can be seen in the NMR table below.

[0267] Preparation of 2-[(11R,17E)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 18) [ka]

[0268] Step 1. K2CO3 (1.02 g, 7.36 mmol, 3.00 equivalent) was added to a 12 mL solution of 2-[5-(bromomethyl)-3-ethoxy-4-iodopyrazole-1-yl]ethoxy-tert-butyldimethylsilane (prepared according to the method described in Example 1) (1.20 g, 2.45 mmol, 1.00 equivalent) and commercially available (2R)-2-aminopropan-1-ol (552 mg, 7.36 mmol, 573 μL, 3.00 equivalent) in DMF (12 mL). The mixture was stirred at 70°C for 2 hours. After completion, the compound (2R)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methylamino]propan-1-ol (1.00 g in DMF) was obtained as a colorless liquid.

[0269] Step 2. (2R)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methylamino]propan-1-ol (1.00 g in DMF) and iodoethane (1.29 g, 8.27 mmol, 4.00 equivalents) were dissolved in DMF (12 mL) and K2CO3 (572 mg, 4.14 mmol, 2.00 equivalents) was added. The mixture was stirred at 70°C for 2 hours. After completion, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3:1 to 1:1) to obtain (2R)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-ethyl-amino]propan-1-ol (800 mg, 1.49 mmol, 72% yield, 95% purity) as a colorless oil. LCMS: (M+1 = 512.4).

[0270] Step 3. The mixture of (2R)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-ethyl-amino]propan-1-ol (750 mg, 1.47 mmol, 1.00 equivalent), 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (which was prepared according to the method described in Example 1) (647 mg, 1.91 mmol, 1.30 equivalent), PPh3 (846 mg, 3.23 mmol, 2.20 equivalent), and DBAD (743 mg, 3.23 mmol, 2.20 equivalent) was degassed three times and purged with N2. Next, 2-MeTHF (7.5 mL) was added, and the mixture was stirred under an N2 atmosphere at 25°C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 1:0 to 0:1) to obtain (2R)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-1-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-ethyl-propane-2-amine (840 mg, 917 μmol, 63% yield, 91% purity) as a colorless oil. LCMS: (M+1 = 833.3).

[0271] Step 4. The mixture of (2R)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-1-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-ethyl-propan-2-amine (790 mg, 949 μmol, 1.00 equivalent), diacetoxypalladium (42.6 mg, 189 μmol, 0.20 equivalent), TBAC (264 mg, 949 μmol, 1.00 equivalent), and NaHCO3 (199 mg, 2.37 mmol, 2.50 equivalent) in DMF (1 mL) was degassed three times, purged with N2, and then stirred at 120°C for 1 hour under an N2 atmosphere. After completion, the mixture was quenched with water (40 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:1~1:1) to obtain (11R,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (530 mg, 752 μmol, 79% yield) as a brown oil. LCMS: (M+1 = 705.6).

[0272] Step 5. TFA (1.54 g, 13.5 mmol, 73.0 equivalents) was added to a solution of (11R,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (130 mg, 184 μmol, 1.00 equivalent) in DCM (1 mL). The mixture was stirred at 25°C for 2 hours. After completion, the mixture was concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10μm; mobile phase: [water (FA)-ACN]; gradient: 12%~42%B over 15 minutes) to obtain Example 18 (15.49 mg, 27.75 μmol, 15.05% yield, 99% purity, FA) as a white solid. LCMS: (M+1 = 507.2). 1 The 1H NMR spectrum can be seen in the NMR table below.

[0273] Preparation of (2S)-2-[(10S,17E)-16-ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol (Example 19) [ka]

[0274] Step 1. To a solution of commercially available (2R)-propane-1,2-diol (50.0 g, 657 mmol, 48.0 mL, 1 equivalent) in DCM (500 mL), TBSCl (99.0 g, 657 mmol, 1 equivalent) and imidazole (44.7 g, 657 mmol, 1 equivalent) were added. The mixture was stirred at 0°C for 2 hours, then at 25°C for 10 hours. After completion, the mixture was filtered and concentrated to obtain (2R)-1-[tert-butyl(dimethyl)silyl]oxypropan-2-ol (120 g, 630 mmol, 95% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ = 4.75 - 4.22 (m, 1H), 3.64 - 3.53 (m, 1H), 3.47 (dd, J = 5.6, 9.6 Hz, 1H), 3.31 - 3.23 (m, 1H), 1.06 - 0.97 (m, 3H), 0.92 - 0.84 (m, 9H), 0.02 (s, 6H).

[0275] Step 2. The mixture of methyl 3-ethoxy-1H-pyrazole-5-carboxylate (which was prepared according to the method described in Example 1) (22.0 g, 129 mmol, 1 equivalent), (2R)-1-[tert-butyl(dimethyl)silyl]oxypropan-2-ol (49.2 g, 258 mmol, 2 equivalents), and PPh3 (74.6 g, 284 mmol, 2.2 equivalents) in THF (250 mL) was degassed three times, purged with N2, and then stirred at 25°C for 0.5 hours. Then DIAD (57.5 g, 284 mmol, 55.1 mL, 2.2 equivalents) was added at 0°C, and then the mixture was stirred at 25°C for 2 hours. After completion, the mixture was concentrated under vacuum to obtain the residue, then petroleum ether / ethyl acetate = 5:1 (200 mL) was added, and stirred at 25°C for 10 minutes. The mixture was then filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 5:1) to obtain methyl 2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxypyrazole-3-carboxylate (36.0 g, 105 mmol, 81% yield) as a clear oil. 1H NMR (400 MHz, CDCl3-d) δ = 6.15 (s, 1H), 5.47 - 5.33 (m, 1H), 4.15 (dq, J = 1.2, 7.2 Hz, 2H), 3.87 - 3.71 (m, 5H), 1.44 - 1.36 (m, 6H), 0.80 (s, 9H), -0.03 - -0.12 (m, 6H).

[0276] Step 3. To a solution of methyl 2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxypyrazole-3-carboxylate (36.0 g, 105 mmol, 1 equivalent) in THF (300 mL), LAH (2.5 M, 63.0 mL, 1.5 equivalents) was added at 0°C. The mixture was stirred at 25°C for 2 hours. After completion, the reaction mixture was quenched with H2O (6 mL) and adjusted with 15% NaOH (6 mL). The combined organic layer was dried over Na2SO4 with stirring at 25°C for 10 minutes, filtered, and concentrated under reduced pressure to obtain [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxypyrazole-3-yl]methanol (30.0 g, crude) as a clear oil. LCMS: (M+1: 315.3).

[0277] Step 4. To a solution of [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxypyrazole-3-yl]methanol (29.5 g, 93.8 mmol, 1 equivalent) in ACN (400 mL), NIS (21.1 g, 93.8 mmol, 1 equivalent) was added. The mixture was stirred at 0°C for 2 hours. After completion, the reaction mixture was quenched by the dropwise addition of sodium sulfite aqueous solution (300 mL), and then extracted with EA (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5:1~3:1) to obtain [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy-4-iodopyrazole-3-yl]methanol (25.6 g, 58.1 mmol, 61.9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 5.28 (dd, J = 4.4, 6.0 Hz, 1H), 4.56 - 4.43 (m, 2H), 4.34 (dd, J = 4.4, 13.2 Hz, 1H), 4.20 - 4.09 (m, 2H), 3.67 (d, J = 6.8 Hz, 2H), 1.33 - 1.25 (m, 6H), 0.75 (s, 9H), -0.07 (s, 3H), -0.17 (s, 3H).

[0278] Step 5. To a 20 mL solution of [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy-4-iodopyrazole-3-yl]methanol (2.00 g, 4.54 mmol, 1 equivalent) in DCM (20 mL), PPh3 (1.43 g, 5.45 mmol, 1.2 equivalents) and then CBr4 (1.81 g, 5.45 mmol, 1.2 equivalents) were added under N2 conditions at 0°C. 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 = 1:0-5:1) to obtain [(2S)-2-[5-(bromomethyl)-3-ethoxy-4-iodopyrazole-1-yl]propoxy]-tert-butyl-dimethyl-silane (1.7 g, 3.38 mmol, 74% yield) as a yellow oil. LCMS: (M+1: 504.7).

[0279] Step 6. K2CO3 (2.06 g, 14.9 mmol, 3 equivalents) was added to a solution of MeNH2 (10.2 g, 99.3 mmol, 30% purity, 20 equivalents) in acetone (150 mL). Then, [(2S)-2-[5-(bromomethyl)-3-ethoxy-4-iodopyrazole-1-yl]propoxy]-tert-butyldimethylsilane (2.50 g, 4.97 mmol, 1 equivalent) in acetone (150 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 2 hours. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / THF = 1:1 to 1:1) to obtain 1-[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy-4-iodopyrazole-3-yl]-N-methyl-methanamine (1.83 g, 4.04 mmol, 81% yield) as a yellow oil. LCMS: (M+1: 454.0).

[0280] Step 7. A mixture of 1-[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy-4-iodopyrazole-3-yl]-N-methylmethanamine (1.70 g, 3.75 mmol, 1 equivalent) and commercially available (2R)-2-methyloxirane (1.09 g, 18.7 mmol, 5 equivalents) in EtOH (20 mL) was stirred at 80°C for 2 hours. After completion, the mixture was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 2:1 to 1:1) to obtain (2R)-1-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-methyl-amino]propan-2-ol (1.90 g, 3.71 mmol, 99% yield) as a yellow oil. LCMS: (M+1: 512.5).

[0281] Step 8. (2R)-1-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-methyl-amino]propan-2-ol (600 mg, 1.17 mmol, 1 equivalent) and 2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (this was prepared according to the method described in Example 5) (382 mg, 1.17 mmol, 1 equivalent) were dissolved in THF (15 mL) to which PPh3 (615 mg, 2.35 mmol, 2 equivalents) and DBAD (405 mg, 1.76 mmol, 1.5 equivalents) were added. The mixture was stirred under N2 at 25°C for 2 hours. After completion, the mixture was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / THF) to obtain (2S)-N-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-N-methyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-propan-1-amine (700 mg, 854 μmol, 73% yield) as a white solid. LCMS: (M+1: 819.3).

[0282] Step 9. (2S)-N-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-N-methyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-propan-1-amine (680 mg, 830 μmol, 1 equivalent) and TBAC (230 mg, 830 μmol, 1 equivalent) were dissolved in DMF (70 mL), to which Pd(OAc)2 (18.6 mg, 83.0 μmol, 0.1 equivalent) and NaHCO3 (174 mg, 2.08 mmol, 2.5 equivalent) were added. The mixture was stirred at 100 °C for 2 hours under an N2 atmosphere. After completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA = 1:1 to 1:1) to obtain (10S,17E)-14-[(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]-16-ethoxy-8,10,12-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (280 mg, 405 μmol, 49% yield) as a white solid. LCMS: (M+1: 691.3).

[0283] Step 10. (10S,17E)-14-[(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]-16-ethoxy-8,10,12-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (200 mg, 289 μmol, 1 equivalent) was dissolved in DCM (1 mL) and TFA (30.7 g, 269 mmol, 930 equivalents) was added. The mixture was stirred at 25°C for 2 hours. After completion, the mixture was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 30:1~15:1) to obtain Example 19 (33.5 mg, 68.1 μmol, 23% yield) as a white solid. LCMS: (M+1: 493.1). 1 The 1H NMR spectrum can be seen in the NMR table below.

[0284] 2-[(10R,17E)-6,8,10,16-tetramethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol (Example 20) and Preparation of 2-[(10S,17E)-6,8,10,16-tetramethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 21) [ka]

[0285] Step 1. K2CO3 (1.38 g, 10.0 mmol, 2.00 equivalent) was added to a solution of 2-[5-(bromomethyl)-4-iodo-3-methylpyrazole-1-yl]ethoxy-tert-butyldimethylsilane (which was prepared according to the method described in Examples 13 and 14) (2.30 g, 5.01 mmol, 1.00 equivalent) and commercially available (2R)-1-(isopropylamino)propan-2-ol (1.17 g, 10.0 mmol, 2.00 equivalent) in DMF (23 mL). The mixture was stirred at 80°C for 1 hour. After completion, the reaction mixture was partitioned into ethyl acetate (40 mL x 3) and water (150 mL). The combined organic phase was washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~60 / 40) to obtain (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methyl-pyrazole-3-yl]methyl-isopropylamino]propan-2-ol (1.90 g, 3.83 mmol, 77% yield) as a yellow oil. LCMS: (M+1 = 496.1).

[0286] Step 2. (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methylpyrazole-3-yl]methyl-isopropyl-amino]propan-2-ol (964 mg, 1.94 mmol, 1.00 equivalent), 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole A mixture of ru-3-ol (prepared according to the method described in Example 1) (858 mg, 2.53 mmol, 1.30 equivalents), PPh3 (1.12 g, 4.28 mmol, 2.20 equivalents), and DBAD (985 mg, 4.28 mmol, 2.20 equivalents) was degassed three times, purged with N2, and then 2-MeTHF (30 mL) was added to the mixture and stirred under an N2 atmosphere at 25°C for 2 hours. After completion, the mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / tetrahydrofuran = 2 / 1 to 1 / 1) to obtain (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methyl-pyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-isopropyl-propane-1-amine (670 mg, 820 μmol, 42% yield) as a colorless solid. LCMS: (M+1 = 817.5).

[0287] Step 3. (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methylpyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-isopropyl-propane-1-amine(330m A mixture of (g, 404 μmol, 1.00 equivalent), TBAC (112 mg, 404 μmol, 1.00 equivalent), NaHCO3 (84.8 mg, 1.01 mmol, 2.50 equivalents), and Pd(OAc)2 (18.1 mg, 80.8 μmol, 0.20 equivalents) in DMF (3 mL) was degassed three times, purged with N2, and then the mixture was stirred at 130°C for 2 hours under an N2 atmosphere. After completion, the reaction mixture was partitioned into ethyl acetate (30 mL x 3) and water (100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / tetrahydrofuran = 2 / 1 to 1 / 1) to obtain (10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6,8,10,16-tetramethyl-2-(oxan-2-yl)-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (120 mg, 174 μmol, 43% yield) as a brown solid. LCMS: (M+1 = 689.6).

[0288] Step 4. (10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6,8,10,16-tetramethyl-2-(oxan-2-yl)-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadesine (110 mg, 160 μmol, 1.00 equivalent) was dissolved in DCM (0.5 mL) and TFA (0.5 mL) was added. The mixture was stirred at 25°C for 3 hours. After completion, the mixture was concentrated under reduced pressure to obtain the residue. The residue was separated and purified by HPLC (column: Xtimate C18). 150×40mm×10μm; Mobile phase: [Water (TFA)-ACN]; Gradient: Purified over 10 minutes from 0% to 28% (B), then 2-[(10S,17E)-6,8,10,16-tetramethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl ]ethane-1-ol and 2-[(10R,17E)-6,8,10,16-tetramethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol (50.0 mg, 102 μmol, 64% yield) were obtained as a yellow solid.

[0289] Step 5. SFC purification: The products obtained above were separated by SFC (conditions: column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 40%, constant composition elution mode) to obtain Example 20 (7.38 mg, 14.53 μmol, 13.85% yield, 96.6% purity) as an orange solid and Example 21 (28.43 mg, 57.60 μmol, 54.90% yield, 99.4% purity) as an orange solid.

[0290] Example 20: LCMS: (M+1 = 491.1). Example 20 1 The 1H NMR spectrum can be seen in the NMR table below.

[0291] Example 21: LCMS: (M+1 = 491.2). Example 21 1 The 1H NMR spectrum can be seen in the NMR table below.

[0292] (2S)-2-[(10R,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Example 24) and Preparation of (2S)-2-[(11S,17E)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol (Example 25) [ka]

[0293] Step 1. To a 10 mL solution of [(2S)-2-[5-(bromomethyl)-3-ethoxy-4-iodopyrazole-1-yl]propoxy]-tert-butyldimethylsilane (which was prepared according to the method described in Example 19) (960 mg, 1.91 mmol, 1 equivalent) in DMF (791 mg, 5.72 mmol, 3 equivalents) and commercially available (2S)-2-aminopropan-1-ol (430 mg, 5.72 mmol, 3 equivalents) were added. The mixture was stirred at 80°C for 2 hours. After completion, the yellow solution of (S)-2-(((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazole-5-yl)methyl)amino)propan-1-ol (theoretical amount: 948 mg in DMF) was used directly in the next step. LCMS: (M+1 = 498.1).

[0294] Step 2. EtI (2.65 g, 17.0 mmol, 9 equivalents) was added to a DMF solution of the above (S)-2-(((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazole-5-yl)methyl)amino)propan-1-ol (theoretical amount from Step 1, 948 mg). The mixture was stirred at 80°C for 2 hours. After completion, the reaction mixture was diluted with H2O (100 mL) and extracted with EA (50 mL x 3). The combined organic layer was 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 = 1 / 0 to 0 / 1) to obtain (S)-2-(((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazole-5-yl)methyl)(ethyl)amino)propan-1-ol (600 mg, 60% yield) as a yellow oily substance. LCMS: (M+1 = 526.1).

[0295] Step 3. (S)-2-(((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazole-5-yl)methyl)(ethyl)amino)propan-1-ol (550 mg, 1.05 mmol, 1 equivalent), 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine- A mixture of 5-yl)pyrazole-3-ol (prepared according to the method described in Example 1) (462 mg, 1.36 mmol, 1.3 equivalents), PPh3 (604 mg, 2.30 mmol, 2.2 equivalents), and DBAD (530 mg, 2.30 mmol, 2.2 equivalents) in 2-MeTHF (6 mL) was degassed three times, purged with N2, and then stirred under an N2 atmosphere at 25°C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain (2S)-N-((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazole-5-yl)methyl)-1-((1,3-dimethyl-4-(1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridine-5-yl)-1H-pyrazole-5-yl)oxy)-N-ethylpropan-2-amine (510 mg, 58% yield) as a yellow oil. LCMS: (M+1 = 847.4).

[0296] Step 4. The mixture of the product from Step 3 (460 mg, 0.543 mmol, 1 equivalent), diacetoxypalladium (24.4 mg, 0.109 mmol, 0.2 equivalents), tetrabutylammonium chloride (151 mg, 0.543 mmol, 1 equivalent), and NaHCO3 (114 mg, 1.36 mmol, 2.5 equivalents) in DMF (5 mL) was degassed three times, purged with N2, and then stirred under an N2 atmosphere at 140 °C for 1 hour. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EA (15 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain (11S,17E)-14-[(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]-16-ethoxy-12-ethyl-6,8,11-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (294 mg, 75% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 9.08 (d, J = 4.4 Hz, 1H), 8.48 - 8.42 (m, 1H), 7.42 - 7.35 (m, 2H), 5.79 - 5.72 (m, 1H), 4.65 - 4.51 (m, 1H), 4.50 - 4.42 (m, 1H), 4.39 - 4.31 (m, 2H), 4.11 - 4.04 (m, 1H), 3.83 - 3.78 (m, 2H), 3.75 - 3.72 (m, 3H), 3.71 - 3.67 (m, 1H), 3.38 - 3.26 (m, 1H), 2.96 (s, 1H), 2.90 - 2.88 (m, 1H), 2.86 - 2.75 (m, 1H), 2.71 - 2.66 (m, 3H), 2.61 - 2.49 (m, 1H), 2.45 - 2.36 (m, 1H), 2.19 - 2.10 (m, 2H), 1.83 - 1.73 (m, 2H), 1.70 - 1.59 (m, 2H), 1.50 - 1.45 (m, 3H), 1.41 - 1.37 (m, 3H), 1.35 - 1.31 (m, 3H), 1.16 - 1.10 (m, 3H), 0.79 - 0.76 (m, 9H), -0.04 - -0.06 (m, 3H), -0.15 - -0.18 (m, 3H). LCMS: (M+1 = 719.4).

[0297] Step 5. To a solution of the product from Step 4 (260 mg, 0.362 mmol, 1 equivalent) in DCM (1 mL), TFA (3.22 g, 28.2 mmol, 2.10 mL, 78.1 equivalents) was added. The mixture was stirred at 25°C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water(FA)-ACN]; gradient: 17%~47%B) and preparative HPLC (column: Phenomenex luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; gradient: 10%~40%B over 8 minutes) to obtain Example 25 (34.36 mg, 17.34% yield) as a yellow solid and by-product Example 24 (41.0 mg, 21.56% yield) as a yellow solid. 1 The 1H NMR spectrum can be seen in the NMR table below.

[0298] 2-[(8aR,9S,19E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethane-1-ol (Example 32) and Preparation of 2-[(8aR,9R,19E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethane-1-ol (Example 33) [ka]

[0299] Step 1. A mixture of commercially available (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (20.0 g, 92.9 mmol, 1 equivalent), commercially available N-methoxymethaneamine (6.24 g, 102 mmol, 1.10 equivalents), DIEA (24.0 g, 185 mmol, 2.00 equivalents), and HATU (38.8 g, 102 mmol, 1.10 equivalents) was stirred in 200 mL of DCM at 25°C for 1 hour. After completion, the mixture was diluted with water (300 mL) and extracted with DCM (60 mL x 3). The combined organic phase was washed with water (200 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1:0 to 90:10) to obtain tert-butyl(R)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (11.0 g, 42.5 mmol, 46% yield) as a yellow oil. LCMS: (M+1-100: 159.1).

[0300] Step 2. To a solution of tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (10.0 g, 38.7 mmol, 1.00 equivalent) in THF (100 mL), bromo(methyl)magnesium (3 M, 38.7 mL, 3.00 equivalent) was added under atmosphere at -78°C. The mixture was stirred at -78°C for 2 hours. After completion, the reaction mixture was quenched with saturated NH4Cl (200 mL) at 0°C, then diluted with H2O (150 mL), and extracted with EA (60 mL x 3). The combined organic layer was 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 = 1:0 to 1:1) to obtain tert-butyl(R)-2-acetylpyrrolidine-1-carboxylate (7.00 g, 32.8 mmol, 85% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 4.37 - 4.13 (m, 1H), 3.60 - 3.38 (m, 2H), 2.31 - 2.00 (m, 4H), 1.92 - 1.76 (m, 3H), 1.52 - 1.37 (m, 9H).

[0301] Step 3. To a solution of tert-butyl (2R)-2-acetylpyrrolidine-1-carboxylate (6.50 g, 30.4 mmol, 1.00 equivalent) in MeOH (65 mL), NaBH4 (3.46 g, 91.4 mmol, 3.00 equivalent) was added at 0°C. 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, petroleum ether / ethyl acetate = 1:0 to 1:1) to obtain tert-butyl (2R)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (5.60 g, 26.0 mmol, 85% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 4.01 - 3.81 (m, 1H), 3.77 - 3.45 (m, 2H), 3.31 - 3.20 (m, 1H), 2.05 - 1.64 (m, 4H), 1.46 (s, 9H), 1.16 - 1.03 (m, 3H). LCMS: (M+1-100: 116.2).

[0302] Step 4. To a solution of tert-butyl (2R)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (1.00 g, 4.64 mmol, 1.00 equivalent) in DCM (10 mL), HCl / dioxane (4 M, 2.00 mL, 1.72 equivalents) was added. The mixture was stirred at 25°C for 2 hours. After completion, the mixture was concentrated to obtain 1-((R)-pyrrolidine-2-yl)ethane-1-ol (700 mg, crude) as a white oil.

[0303] Step 5. K2CO3 (777 mg, 5.62 mmol, 3 equivalents) was added to a 10 mL solution of 1-((R)-pyrrolidine-2-yl)ethane-1-ol (284 mg, 1.87 mmol, 1 equivalent, HCl) and 2-[5-(bromomethyl)-3-ethoxy-4-iodopyrazole-1-yl]ethoxy-tert-butyldimethylsilane (prepared according to the method described in Example 1) (1.01 g, 2.06 mmol, 1.1 equivalents) in DMF (10 mL). The mixture was stirred at 80°C for 1 hour. After completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0-10:1) to obtain 1-[(2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]pyrrolidine-2-yl]ethanol (1.07 g, 1.84 mmol, 98% yield, 90% purity) as a grayish-white oily substance. LCMS: (M+1 = 524.0).

[0304] Process 6. The mixture of 1-[(2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]pyrrolidine-2-yl]ethanol (970 mg, 1.85 mmol, 1 equivalent), 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (which was prepared according to the method described in Example 1) (1.01 g, 2.96 mmol, 1.6 equivalents), DBAD (939 mg, 4.08 mmol, 2.2 equivalents), and PPh3 (1.07 g, 4.08 mmol, 2.2 equivalents) in 2-MeTHF (10 mL) was degassed three times, purged with N2, and then stirred at 25°C for 2 hours under an N2 atmosphere. After completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain the compound tert-butyl-[2-[5-[[(2R)-2-[1-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxyethyl]pyrrolidine-1-yl]methyl]-3-ethoxy-4-iodopyrazole-1-yl]ethoxy]-dimethyl-silane (1.00 g, 1.18 mmol, 64% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3-d) δ = 9.13 (s, 1H), 7.97 - 7.81 (m, 1H), 7.10 - 6.93 (m, 1H), 6.18 - 6.03 (m, 1H), 5.87 - 5.71 (m, 1H), 5.63 - 5.49 (m, 1H), 4.27 - 4.19 (m, 2H), 4.06 (br s, 1H), 3.79 - 3.73 (m, 2H), 3.68 (br d, J = 17.2 Hz, 4H), 3.54 - 3.44 (m, 1H), 2.84 - 2.72 (m, 1H), 2.58 - 2.47 (m, 1H), 2.43 - 2.33 (m, 4H), 2.21 - 2.06 (m, 2H), 1.89 - 1.62 (m, 8H), 1.46 - 1.34 (m, 5H), 1.12 - 1.00 (m, 3H), 0.91 - 0.83 (m, 2H), 0.81 - 0.71 (m, 9H), -0.07 - -0.20 (m, 6H). LCMS: (M+1 = 845.5).

[0305] Step 7. The mixture of tert-butyl-[2-[5-[[(2R)-2-[1-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxyethyl]pyrrolidine-1-yl]methyl]-3-ethoxy-4-iodopyrazole-1-yl]ethoxy]-dimethyl-silane (420 mg, 497 μmol, 1 equivalent), diacetoxypalladium (22.3 mg, 99.4 μmol, 0.2 equivalents), TBAC (138 mg, 497 μmol, 1 equivalent), and NaHCO3 (104 mg, 1.24 mmol, 2.5 equivalents) in DMF (10 mL) was degassed three times, purged with N2, and then stirred at 120 °C for 1 hour under an N2 atmosphere. After completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 1:0~0:1) to obtain (8aR,19E)-3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-ethoxy-9,11,13-trimethyl-17-(oxan-2-yl)-3,4,7,8,8a,9,11,17-octahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin (327 mg, 456 μmol, 92% yield) as a yellow solid. LCMS: (M+1 = 717.2).

[0306] Step 8. TFA (40.4 mmol, 3 mL, 92.5 equivalents) was added to a solution of (8aR,19E)-3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-ethoxy-9,11,13-trimethyl-17-(oxan-2-yl)-3,4,7,8,8a,9,11,17-octahydro-6H-14,16-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin (313 mg, 437 μmol, 1 equivalent) in DCM (3 mL). The mixture was stirred at 25°C for 1 hour. After completion, the mixture was filtered. The filtrate was separated and purified by preparative HPLC (column: Phenomenex luna C18 150×30mm×5μm; mobile phase: [water (FA)-ACN]; gradient: 10%~40% B over 10 minutes) to obtain Example 32 (31.73 mg, 55.76 μmol, 12.77% yield, 99.22% purity, FA) as a yellow solid and Example 33 (34.49 mg, 66.50 μmol, 15.23% yield) as a yellow solid.

[0307] Example 32: LCMS: (M+1 = 519.3). Example 32 1 The 1H NMR spectrum is shown in the NMR table below.

[0308] Example 33: LCMS: (M+1 = 519.2). Example 33 1 The 1H NMR spectrum is shown in the NMR table below.

[0309] Preparation of 2-[(17E)-16-ethoxy-6,8,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 68) [ka]

[0310] Step 1. Potassium carbonate (430.51 mg, 3.11 mmol), followed by commercially available 2-(methylamino)ethanol (93.58 mg, 1.25 mmol, 99.66 μL), was added to a solution of 2-[5-(bromomethyl)-3-ethoxy-4-iodopyrazole-1-yl]ethoxy-tert-butyldimethylsilane (prepared according to the method described in Example 1) (508 mg, 1.04 mmol) in acetonitrile (5.09 mL). The reaction mixture was stirred at 22 °C for 18 hours. The solution was diluted with DCM (5 mL) and cooled in an ice bath. The solid was filtered through a Celite pad and thoroughly washed with DCM. The filtrate was concentrated by rotary evaporation, and the residue was purified by flash column chromatography (automated system, 12 g silica, 0-10% methanol DCM solution) to obtain 2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-methyl-amino]ethanol (404 mg, 835.65 μmol, 80.48% yield) as a colorless oil.

[0311] Step 2. DBAD (81.41 mg, 353.57 μmol) was added at 0°C to a mixture of 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (which was prepared according to the method described in Example 1) (75 mg, 220.98 μmol), 2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-methyl-amino]ethanol (106.84 mg, 220.98 μmol), and triphenylphosphine (86.94 mg, 331.48 μmol) in dry methyl THF (441.97 μL). The mixture was stirred at 22°C for 18 hours. The reaction was diluted with DCM and water (4 mL), and the layers were separated. The aqueous layer was extracted again with DCM (2 × 3 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Flash column chromatography (automated system, 12 g silica, hexane solution of 0-100% EA) yielded N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-methyl-ethanamine (114 mg, 141.64 μmol, 64.10% yield).

[0312] Step 3. To a 1.40 mL solution of N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-methyl-ethanamine (114 mg, 141.64 μmol) in DMF (1.40 mL), sodium bicarbonate (36 mg, 424.9 μmol) and TBAC (43.3 mg, 155.8 μmol) were added. The mixture was stirred while bubbling with argon, and then palladium acetate (6.4 mg, 28.3 μmol) was added. The container was sealed and heated at 140 °C for 1.5 hours. The reaction product was then converted to DCM The mixture was diluted with pre-treatment water (4 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2 × 4 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Crude (17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-6,8,12-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (40 mg, 59.09 μmol, 41.72% yield) was obtained as a brown oil by flash column chromatography (automated system, 12 g silica, 0-100% EA hexane solution).

[0313] Step 4. Crude (17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-6,8,12-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadesine (40 mg, 59.09 μmol) was added to a mixture in DCM (2 mL) with TFA (2.61 mmol, 0.2 mL). The mixture was stirred at 22°C for 18 hours. After completion, the reaction mixture was concentrated under reduced pressure, the residue was diluted in DCM (1 mL), and 0.1 mL of TEA was added. Flash column chromatography (automated system, 12g silica, 0-10% MeOH DCM solution) was used to obtain Example 68 (2.60 mg, 5.38 μmol, 9.11% yield, 99.03% purity). LC / MS: (M+1: 479.3). 1 The 1H NMR spectrum is shown in the NMR table below.

[0314] Preparation of 2-[(17E)-16-ethoxy-6,8,12-trimethyl-2,6,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:3'',4''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 69) [ka]

[0315] Step 1. To a solution of 5-bromo-1-tetrahydropyran-2-yl-3-vinylpyrazolo[3,4-c]pyridine (prepared according to the method described in Example 1) (250 mg, 811.23 μmol) in 1,4-dioxane (4 mL), commercially available 1,3-dimethylpyrazole-4-ol (109.2 mg, 973.5 μmol) and potassium carbonate (336 mg, 2.43 mmol) were added. The mixture was bubbling with argon and tBuBrettPhos Pd G3 (69 mg, 81.12 μmol) was added. The mixture was stirred at 130 °C for 1.5 hours. The reaction product was diluted with DCM and water (10 mL) 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. Flash column chromatography (automated system, 12g silica, hexane solution of 20-80% EA) yielded 1,3-dimethyl-5-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-4-ol.

[0316] Step 2. DBAD (12 mg, 50.4 μmol) was added at 0°C to a dry Me-THF (0.2 mL) solution of 1,3-dimethyl-5-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-4-ol (10.7 mg, 31.53 μmol), 2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-methyl-amino]ethanol (which was prepared according to the method described in Example 68) (23 mg, 47.3 μmol), and triphenylphosphine (12.4 mg, 47.3 μmol). The mixture was stirred at 22°C for 18 hours. Flash column chromatography (automated system, 12 g silica, hexane solution of 0-100% EA) yielded N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-2-[1,3-dimethyl-5-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-4-yl]oxy-N-methyl-ethanamine (7.85 mg, 9.75 μmol, 30.94% yield).

[0317] Step 3. To a solution of N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-2-[1,3-dimethyl-5-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-4-yl]oxy-N-methyl-ethanamine (7.85 mg, 9.75 μmol) in anhydrous DMF (0.5 mL), sodium bicarbonate (2.46 mg, 29.26 μmol, 1.14 μL) and TBAC (2.98 mg, 10.73 μmol) were added. The reaction mixture was stirred while bubbling with argon, and palladium acetate (2.19 mg, 9.75 μmol, 1 μL) was added. The mixture was bubbling with argon for a further 5 minutes. The container was sealed and the reaction mixture was heated at 140°C for 1.5 hours. The reaction mixture was diluted with DCM and water (5 mL), and the layers were separated. The aqueous layer was extracted again with DCM (2 × 3 mL). The combined organic layers were washed with brine and dried over sodium sulfate. (17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-6,8,12-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-6H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:3'',4''-n][1,4]oxazacyclopentadecin (2.29 mg, 3.38 μmol, 34.68% yield) was obtained by flash column chromatography (automated system, 12 g silica, 30-100% EA hexane solution, injected with 0.5 mL of TEA).

[0318] Step 4. TFA (1.31 mmol, 0.1 mL) was added to a solution of (17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-16-ethoxy-6,8,12-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-6H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:3'',4''-n][1,4]oxazacyclopentadesine (2.29 mg, 3.38 μmol) in DCM (0.5 mL). The mixture was stirred at 22°C for 18 hours. Volatile substances were removed under reduced pressure. Next, 0.2 mL of TEA was added, and the residue was purified by flash column chromatography (automated system, 12 g silica, 0-40% MeOH DCM solution) to obtain Example 69 (0.8 mg, 1.67 μmol, 49.42% yield, LC / MS: (M+H: 479.3)). 1 The 1H NMR spectrum is shown in the NMR table below.

[0319] (10S,17E)-6,8,10,14,16,20-Hexamethyl-12-(propan-2-yl)-2,10,11,12,13,14-Hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (Example 106) and Preparation of (11R,17E)-6,8,11,14,16,20-Hexamethyl-12-(propan-2-yl)-2,10,11,12,13,14-Hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (Example 108) [ka]

[0320] Step 1. Commercially available (2S)-1-(isopropylamino)propan-2-ol (600 mg, 5.12 mmol, 1.5 equivalents) was dissolved in ACN (6 mL) and commercially available 5-(bromomethyl)-4-iodo-1,3-dimethylpyrazole (1.08 g, 3.41 mmol, 1 equivalent) and K2CO3 (1.42 g, 10.2 mmol, 3 equivalents) were added. The mixture was stirred at 80°C for 2 hours. After completion, the reaction mixture was filtered to remove K2CO3 and then concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 1:1) to obtain (2S)-1-[(4-iodo-2,5-dimethylpyrazole-3-yl)methylisopropylamino]propan-2-ol (1.15 g, 3.21 mmol, 94% yield) as an orange oily substance. 1 H NMR (400 MHz, DMSO-d6) δ = 4.20 (d, J = 4.0 Hz, 1H), 3.81 (s, 3H), 3.67 - 3.61 (m, 1H), 3.55 (d, J = 13.6 Hz, 1H), 2.77 - 2.61 (m, 2H), 2.30 - 2.24 (m, 1H), 2.20 - 2.14 (m, 1H), 2.07 (s, 3H), 0.97 (d, J = 3.6 Hz, 3H), 0.96 (d, J = 3.2 Hz, 3H), 0.93 (d, J = 6.0 Hz, 3H). LCMS: (M+1: 351.9).

[0321] Step 2. To a 10 mL solution of (2S)-1-[(4-iodo-2,5-dimethylpyrazole-3-yl)methylisopropylamino]propan-2-ol (1.05 g, 2.99 mmol, 1 equivalent) and DIEA (1.16 g, 8.97 mmol, 1.56 mL, 3 equivalents) in DCM, methylsulfonyl methanesulfonate (1.04 g, 5.98 mmol, 2 equivalents) was added at 0°C. The mixture was stirred at 25°C for 0.5 hours. After completion, the reaction mixture was diluted with H2O (50 mL) and extracted with DCM (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain [(1S)-2-[(4-iodo-2,5-dimethylpyrazole-3-yl)methylisopropyl-amino]-1-methylethyl]methanesulfonate (1.37 g, crude) as an orange oily substance. LCMS: (M+1: 429.9).

[0322] Step 3. To a solution of [(1S)-2-[(4-iodo-2,5-dimethylpyrazole-3-yl)methyl-isopropyl-amino]-1-methyl-ethyl]methanesulfonate (1.37 g, 3.19 mmol, 1 equivalent) in DMF (14 mL), 2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (which was prepared according to the method described in Example 47) (1.13 g, 3.19 mmol, 1 equivalent) and K2CO3 (1.32 g, 9.57 mmol, 3 equivalents) were added. The mixture was stirred at 80°C for 0.5 hours. After completion, the reaction mixture was diluted with H2O (150 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with H2O (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0~2:1) to obtain (2S)-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-[(4-iodo-2,5-dimethylpyrazole-3-yl)methyl]-N-isopropyl-propan-1-amine (1.78 g, 2.51 mmol, 78% yield, 97% purity) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.58 (s, 1H), 7.22 (d, J = 11.6, 17.6 Hz, 1H), 6.06 - 5.90 (m, 2H), 5.68 - 5.59 (m, 1H), 4.03 (q, J = 7.2 Hz, 2H), 3.93 - 3.73 (m, 2H), 3.62 - 3.49 (m, 6H), 2.76 - 2.70 (m, 3H), 2.27 - 2.16 (m, 3H), 2.04 - 1.96 (m, 6H), 1.61 (s, 2H), 1.35 (s, 2H), 1.17 (t, J = 7.2 Hz, 3H), 1.07 (d, J = 6.4 Hz, 1H), 1.00 - 0.91 (m, 3H), 0.85 (d, J = 6.4, 13.6 Hz, 5H). LCMS: (M+1: 687.1).

[0323] Step 4. To a solution of the product from Step 3 (1.20 g, 1.75 mmol, 1 equivalent) in DMF (12 mL), NaHCO3 (734 mg, 8.74 mmol, 5 equivalents), TBAC (971 mg, 3.50 mmol, 2 equivalents), and Pd(OAc)2 (58.9 mg, 262 μmol, 0.15 equivalents) were added after degassing three times and purging with N2. The mixture was stirred at 130°C for 1 hour under an N2 atmosphere. After completion, the reaction mixture was diluted with H2O (100 mL) and extracted with EA (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (10S,17E)-6,8,10,14,16,20-hexamethyl-2-(oxan-2-yl)-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (750 mg, crude) as a dark brown oily substance. LCMS: (M+1: 559.4).

[0324] Step 5. To a solution of the product from Step 4 (600 mg, 1.07 mmol, 1 equivalent) in DCM (6 mL), HCl / siRNA (4.00 M, 3 mL, 11.2 equivalents) was added. The mixture was stirred at 25°C for 1 hour. After completion, the reaction product was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 12% to 42% B over 11 minutes) to obtain Example 106 (94.81 mg, 17.63% yield) as a yellow solid and by-product Example 108 (15.22 mg, 2.87% yield) as a grayish-white solid. 1 The 1H NMR spectrum is shown in the NMR table below.

[0325] Preparation of (2S)-1-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol (Example 107) [ka]

[0326] Step 1. K2CO3 (335 mg, 2.43 mmol, 3 equivalents) was added to a solution of commercially available (2S)-1-(cyclopropylamino)propan-2-ol (140 mg, 1.22 mmol, 1.5 equivalents) and [(1S)-2-[5-(bromomethyl)-3-ethoxy-4-iodopyrazole-1-yl]-1-methylethoxy]-tert-butyldimethylsilane (407 mg, 810 μmol, 1 equivalent) (which was prepared according to the method described in Example 86) in DMF (5 mL). The mixture was stirred at 80°C for 0.5 hours. After completion, the reaction mixture was partitioned into ethyl acetate (10 mL x 3) and water (15 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain (2S)-1-[[2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-cyclopropyl-amino]propan-2-ol (400 mg, 744 μmol, 91% yield) as a yellow oil. LCMS: (M+1: 538.1).

[0327] Step 2. To a solution of the product from Step 1 (400 mg, 744 μmol, 1 equivalent) in DCM (4 mL), TEA (225 mg, 2.23 mmol, 3 equivalents) and methylsulfonyl methanesulfonate (324 mg, 1.86 mmol, 2.5 equivalents) were added. The mixture was stirred at 25°C for 2 hours. After completion, the reaction mixture was partitioned into dichloromethane (5 mL x 3) and water (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain [(1S)-2-[[2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl-cyclopropyl-amino]-1-methyl-ethyl]methanesulfonate (400 mg, 87% yield) as a yellow solid. LCMS: (M+1: 616.2).

[0328] Step 3. To a solution of mesylate (240 mg, 389 μmol, 1 equivalent) from Step 2 and 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinylpyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (which was prepared according to the method described in Example 1) (132 mg, 389 μmol, 1 equivalent) in DMF (4 mL), K2CO3 (161 mg, 1.17 mmol, 3 equivalents) was added. The mixture was stirred at 80°C for 0.5 hours. After completion, the reaction mixture was partitioned into ethyl acetate (10 mL x 3) and water (12 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain N-[[2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-ethoxy-4-iodopyrazole-3-yl]methyl]-N-[(2S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxypropyl]cyclopropanamine (140 mg, 41% yield) as a yellow oil. LCMS: (M+1: 859.3).

[0329] Step 4. The mixture of the product from Step 3 (60.0 mg, 69.8 μmol, 1 equivalent), Cs2CO3 (68.2 mg, 209 μmol, 3 equivalents), ditert-butyl(cyclopentyl)phosphine, and dichloropalladium;iron(Pd(dtbpf)Cl2) (22.7 mg, 34.9 μmol, 0.5 equivalents) in dioxane (1 mL) was degassed three times and purged with N2. The mixture was then stirred at 80°C for 10 minutes under an N2 atmosphere. After completion, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain (10S,17E)-14-[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}propyl]-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (10.0 mg, 19% yield) as a yellow oil. LCMS: (M+1: 731.3).

[0330] Step 5. To a solution of the product from Step 4 (5.00 mg, 6.84 μmol, 1 equivalent) in DCM (1 mL), HCl / Â (4 M, 0.5 mL, 3 equivalents) was added. The mixture was stirred at 25°C for 0.5 hours. After completion, the mixture was filtered, and the filtrate was concentrated to obtain the residue. The crude product was purified by reverse-phase HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 26% to 56% B over 10 minutes) to obtain Example 107 (0.98 mg, 23% yield) as a yellow solid. 1 The 1H NMR spectrum is shown in the NMR table below.

[0331] Preparation of 2-[(10S,17E)-6,8,10,16,20-pentamethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 109) [ka]

[0332] Step 1. Two starting materials were prepared as in Examples 8 and 14. The chemistry was carried out in the same manner as in Example 8.

[0333] Steps 2, 3, and 4 were carried out in the same manner as in Example 108, except that in step 3, 2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (which was prepared according to the method described in Example 47) was used.

[0334] Step 5. (10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6,8,10,16,20-pentamethyl-2-(oxan-2-yl)-12-(propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (85.0 mg, 0.121 mmol, 1 equivalent) was dissolved in DCM (8 mL) and HCl / siRNA (2 M, 4 mL, 66 equivalents) was added. The mixture was stirred at 25°C for 1 hour. After completion, the mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Welch Ultimate C18 150×25mm×5μm; mobile phase: [water(FA)-ACN]; gradient: 0%~30%B over 10 minutes) to obtain Example 109 (19.97 mg, 31.09% yield) as a yellow solid. 1 The 1H NMR spectrum is shown in the NMR table below.

[0335] (2S)-2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Example 110) and Preparation of (2S)-2-[(11R,17E)-12-cyclopropyl-16-ethoxy-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Example 111) [ka]

[0336] Steps 1 to 4 were carried out in the same manner as in Example 107, using [(2S)-2-[5-(bromomethyl)-3-ethoxy-4-iodopyrazole-1-yl]propoxy]-tert-butyl-dimethyl-silane (which was prepared according to the method described in Example 19) and commercially available (2S)-1-(cyclopropylamino)propan-2-ol in step 1, DIEA in step 2, and 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (which was prepared according to the method described in Example 1) in step 3. Step 5 was carried out in the same manner as in Example 109 to obtain Example 110 and by-product Example 111. 1 The 1H NMR spectrum is shown in the NMR table below.

[0337] 2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol (Example 113) and Preparation of 2-[(11R,17E)-12-cyclopropyl-16-ethoxy-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol (Example 114) [ka]

[0338] 2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethane-1-ol (Example 113) and 2-[(11R,17E)-12-cyclopropyl-16-ethoxy-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4 '',3''-n][1,4]oxazacyclopentadecine-14-yl]ethane-1-ol (Example 114) was prepared using 2-[5-(bromomethyl)-3-ethoxy-4-iodopyrazole-1-yl]ethoxy-tert-butyl-dimethyl-silane and 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol, which were prepared according to the method described in Example 1, by replacing the base and solvent with Na2CO3 and DMF, respectively, in step 4, according to the method described in Example 1. 1The 1H NMR spectrum is shown in the NMR table below.

[0339] (2S)-2-[(10S,17E)-12-cyclopropyl-6,8,10,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Example 127) and Preparation of (2S)-2-[(11R,17E)-12-cyclopropyl-6,8,11,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Example 128) [ka]

[0340] Step 1. A mixture of commercially available methyl 1H-pyrazole-5-carboxylate (10.0 g, 79.3 mmol, 1 equivalent), (2R)-1-[tert-butyl(dimethyl)silyl]oxypropan-2-ol (which was prepared according to the method described in Example 19) (22.6 g, 119 mmol, 1.5 equivalents), PPh3 (41.6 g, 158 mmol, 2 equivalents), and DIAD (40.1 g, 198 mmol, 2.5 equivalents) was mixed with 300 mL of THF at 0°C, and the resulting mixture was stirred under N2 at 25°C for a further 2 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column silica gel chromatography (120 g silica gel, EA petroleum ether solution, 0% to 100%) to obtain methyl 2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrazole-3-carboxylate (22.4 g, 92% yield) as a yellow oily substance. 1H NMR (400 MHz, DMSO-d6) δ = 7.64 - 7.55 (m, 1H), 6.84 - 6.81 (m, 1H), 5.45 (qd, J = 6.8, 13.2 Hz, 1H), 3.82 - 3.70 (m, 5H), 1.39 (d, J = 6.8 Hz, 3H), 0.72 (s, 9H), -0.07 - -0.24 (m, 6H). LCMS: (M+1: 299.1).

[0341] Step 2. 21.0 g, 70.3 mmol, 1 equivalent of methyl 2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrazole-3-carboxylate (21.0 g, 70.3 mmol, 1 equivalent) was dissolved in 200 mL of THF, to which LAH (2.5 M, 30.9 mL, 1.1 equivalents) was added at 0°C. The mixture was stirred at 25°C for 1 hour. After completion, the mixture was slowly added to 3 mL of water at 0°C, and quenched by adding 3 mL of 15% sodium hydroxide solution and 9 mL of water at 0°C. The reaction mixture was filtered and concentrated under reduced pressure to obtain [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrazole-3-yl]methanol (17.0 g, 89% yield) as a colorless oil. LCMS: (M+1: 271.1).

[0342] Step 3. To a solution of [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrazole-3-yl]methanol (16.0 g, 59.1 mmol, 1 equivalent) in ACN (160 mL), NIS (14.6 g, 65.1 mmol, 1.1 equivalents) was added over 0.5 hours at 0°C. The mixture was stirred at 25°C for 1.5 hours. After completion, the reaction mixture was quenched by adding saturated sodium sulfite solution (100 mL) at 0°C, then diluted with H2O (300 mL), and extracted with EA (150 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column silica gel chromatography (220 g silica gel, EA petroleum ether solution, 0% to 100%) to obtain [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodopyrazole-3-yl]methanol (17.0 g, 72% yield) as a colorless oil. LCMS: (M+1: 397.0).

[0343] Step 4. To a solution of [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodopyrazole-3-yl]methanol (17.0 g, 42.9 mmol, 1 equivalent) in DCM (170 mL), CBr4 (17.1 g, 51.5 mmol, 1.2 equivalents) was added under N2 conditions at 0°C, followed by PPh3 (13.5 g, 51.5 mmol, 1.2 equivalents) at 0°C. The mixture was stirred at 25°C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column silica gel chromatography (80g silica gel, EA petroleum ether solution, 0% to 100%) to obtain [(2S)-2-[5-(bromomethyl)-4-iodopyrazole-1-yl]propoxy]-tert-butyl-dimethyl-silane (16.0g, 81% yield) as a yellow oily substance. LCMS: (M+1: 460.9).

[0344] Step 5. To a solution of [(2S)-2-[5-(bromomethyl)-4-iodopyrazole-1-yl]propoxy]-tert-butyldimethylsilane (1.50 g, 3.27 mmol, 1 equivalent) in DMF (15 mL), K2CO3 (677 mg, 4.90 mmol, 1.5 equivalents) and commercially available (2S)-1-(cyclopropylamino)propan-2-ol (432 mg, 3.76 mmol, 1.15 equivalents) were added. The mixture was stirred at 80°C for 1 hour. After completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (15 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column silica gel chromatography (4g silica gel, EA petroleum ether solution, 0% to 100%) to obtain (2S)-1-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodopyrazole-3-yl]methyl-cyclopropyl-amino]propan-2-ol (1.58g, 3.00 mmol, 91% yield, 93% purity) as a yellow oily substance. LCMS: (M+1: 494.1).

[0345] Step 6. To a 14 mL solution of the product from Step 5 (1.40 g, 2.84 mmol, 1 equivalent) in DCM, DIEA (1.10 g, 8.51 mmol, 1.48 mL, 3 equivalents) and methylsulfonyl methanesulfonate (988 mg, 5.67 mmol, 2 equivalents) were added at 0°C. The mixture was stirred at 25°C for 1 hour. After completion, the mixture was diluted with water (40 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain [(1S)-2-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodopyrazole-3-yl]methyl-cyclopropyl-amino]-1-methyl-ethyl]methanesulfonate (1.76 g, crude) as a colorless oil. LCMS: (M+1: 572.1).

[0346] Step 7. The mixture of mesylate (1.50 g, 2.62 mmol, 1 equivalent) from Step 6, 2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinylpyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (881 mg, 2.49 mmol, 0.95 equivalents) (which was prepared according to the method described in Example 47), and K2CO3 (1.09 g, 7.87 mmol, 3 equivalents) in ACN (15 mL) was stirred at 60°C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column silica gel chromatography (12g silica gel, EA petroleum ether solution, 0% to 100%) to obtain N-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodopyrazole-3-yl]methy...

Claims

1. Equation I 【Chemistry 1】 [During the ceremony, Rings A and B are independently five-membered heteroarylenes; Each R １ and R ２ when present, are independently deuterium, halogen, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -C １０ aryl, 5- to 10-membered heteroaryl, -OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -OS(O)R ａ , -OS(O) ２ R ａ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ａ R ｂ , -S(O) ２ NR ａ R ｂ , -OS(O)NR ａ R ｂ , -OS(O) ２ NR ａ R ｂ , -NR ａ R ｂ , -NR ａ C(O)R ｂ , -NR ａ C(O)OR ｂ , -NR ａ C(O)NR ａ R ｂ , -NR ａ S(O)R ｂ , -NR ａ S(O) ２ R ｂ , -NR ａ S(O)NR ａ R ｂ , -NR ａ S(O) ２ NR ａ R ｂ , -C(O)R ａ , -C(O)OR ａ 、 -C(O)NR ａ R ｂ 、 -PR ａ R ｂ 、 -P(O)R ａ R ｂ 、 -P(O) ２ R ａ R ｂ 、 -P(O)NR ａ R ｂ 、 -P(O) ２ NR ａ R ｂ 、 -P(O)OR ａ 、 -P(O) ２ OR ａ 、 -CN, or -NO ２ where C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, 3-7 member heterocycloalkyl, C ６ -C １０ aryl, and each hydrogen atom in 5-10 member heteroaryl may independently be deuterium, halogen, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -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) ２ R ｃ 、 -OS(O)NR ｃ R ｄ 、 -OS(O) ２ NR ｃ R ｄ 、 -SR ｃ 、 -S(O)R ｃ 、 -S(O) ２ R ｃ 、 -S(O)NR ｃ R ｄ , -S(O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｃ C(O)R ｄ , -N(C(O)R ｃ )(C(O)R ｄ ), -NR ｃ C(O)OR ｄ , -NR ｃ C(O)NR ｃ R ｄ , -NR ｃ C(=NR ｄ )NR ｃ R ｄ , -NR ｃ S(O)R ｄ , -NR ｃ S(O) ２ R ｄ , -NR ｃ S(O)NR ｃ R ｄ , -NR ｃ S(O) ２ NR ｃ R ｄ , -C(O)R ｃ , -C(O)OR ｃ , -C(O)NR ｃ R ｄ , -C(=NR ｄ )NR ｃ R ｄ ,-PR ｃ R ｄ ,-P(O)R ｃ R ｄ , -P(O) ２ R ｃ R ｄ , -P(O)NR ｃ R ｄ , -P(O) ２ NR ｃ R ｄ , -P(O)OR ｃ , -P(O) ２ OR ｃ -CN, or -NO ２ It has been replaced with; Each R ３ , R ４ , R ５ , and R ６ These are independently H, deuterium, halogen, and C. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 3-7 member heterocycloalkyl, C ６ -C １０ Aryl, 5-10 member heteroaryl, -OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -OS(O)R ａ , -OS(O) ２ R ａ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ａ R ｂ , -S(O) ２ NR ａ R ｂ , -OS(O)NR ａ R ｂ , -OS(O) ２ NR ａ R ｂ , -NR ａ R ｂ , -NR ａ C(O)R ｂ , -NR ａ C(O)OR ｂ , -NR ａ C(O)NR ａ R ｂ , -NR ａ S(O)R ｂ , -NR ａ S(O) ２ R ｂ , -NR ａ S(O)NR ａ R ｂ , -NR ａ S(O) ２ NR ａ R ｂ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ａ R ｂ ,-PR ａ R ｂ ,-P(O)R ａ R ｂ , -P(O) ２ R ａ R ｂ , -P(O)NR ａ R ｂ , -P(O) ２ NR ａ R ｂ , -P(O)OR ａ , -P(O) ２ OR ａ -CN, or -NO ２ And here, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 3-7 member heterocycloalkyl, C ６ -C １０ Each hydrogen atom in aryls and 5- to 10-membered heteroaryls can be independently and optionally replaced with deuterium, halogen, or C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -NR ｅ R ｆ , -NR ｅ C(O)R ｆ , -NR ｅ C(O)OR ｆ , -NR ｅ C(O)NR ｅ R ｆ , -NR ｅ S(O)R ｆ , -NR ｅ S(O) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR ｅ R ｆ , -C(O)R ｅ , -C(O)OR ｅ , -C(O)NR ｅ R ｆ ,-PR ｅ R ｆ ,-P(O)R ｅ R ｆ , -P(O) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ -CN, or -NO ２ It is replaced by; or R ３ , R ４ , R ５ , and R ６ These two atoms, together with one or more carbon atoms to which they are bonded, become C ３ -C ６ Forms a cycloalkyl or 3- to 7-membered heterocycloalkyl, where C ３ -C ６ Each hydrogen atom in cycloalkyl and 3- to 7-membered heterocycloalkyl groups can be independently and optionally -OR ｅ , -OC(O)R ｅ 、-OC(O)NR ｅ R ｆ 、-OS(O)R ｅ 、-OS(O) ２ R ｅ 、-OS(O)NR ｅ R ｆ 、-OS(O) ２ NR ｅ R ｆ 、-SR ｅ 、-S(O)R ｅ 、-S(O) ２ R ｅ 、-S(O)NR ｅ R ｆ 、-S(O) ２ NR ｅ R ｆ 、-NR ｅ R ｆ 、-NR ｅ C(O)R ｆ 、-NR ｅ C(O)OR ｆ 、-NR ｅ C(O)NR ｅ R ｆ 、-NR ｅ S(O)R ｆ 、-NR ｅ S(O) ２ R ｆ 、-NR ｅ S(O)NR ｅ R ｆ 、-NR ｅ S(O) ２ NR ｅ R ｆ 、-C(O)R ｅ 、-C(O)OR ｅ 、-C(O)NR ｅ R ｆ 、-PR ｅ R ｆ 、-P(O)R ｅ R ｆ 、-P(O) ２ R ｅ R ｆ 、-P(O)NR ｅ R ｆ 、-P(O) ２ NR ｅ R ｆ 、-P(O)OR ｅ 、-P(O) ２ OR ｅ -CN, or -NO ２ It has been replaced with; R ７ H, deuterium, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 4-7 member heterocycloalkyl, C ６ -C １０ Aryl, 5-10 member heteroaryl, -C(O)R ｃ , or -C(O)NR ｃ R ｄ And here, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 4-7 member heterocycloalkyl, C ６ -C １０ Each hydrogen atom in aryls and 5- to 10-membered heteroaryls can be 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) ２ R ｃ , -OS(O)NR ｃ R ｄ , -OS(O) ２ NR ｃ R ｄ , -SR ｃ , -S(O)R ｃ , -S(O) ２ R ｃ , -S(O)NR ｃ R ｄ , -S(O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｃ C(O)R ｄ , -N(C(O)R ｃ )(C(O)R ｄ ), -NR ｃ C(O)OR ｄ , -NR ｃ C(O)NR ｃ R ｄ , -NR ｃ C(=NR ｄ )NR ｃ R ｄ , -NR ｃ S(O)R ｄ , -NR ｃ S(O) ２ R ｄ , -NR ｃ S(O)NR ｃ R ｄ , -NR ｃ S(O) ２ NR ｃ R ｄ , -C(O)R ｃ , -C(O)OR ｃ , -C(O)NR ｃ R ｄ , -C(=NR ｄ )NR ｃ R ｄ ,-PR ｃ R ｄ ,-P(O)R ｃ R ｄ , -P(O) ２ R ｃ R ｄ , -P(O)NR ｃ R ｄ , -P(O) ２ NR ｃ R ｄ , -P(O)OR ｃ , -P(O) ２ OR ｃ -CN, or -NO ２ It is replaced by; or R ７ and R ３ , R ４ , R ５ , or R ６ One of these atoms, together with the atom to which each of them is bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the 4- to 7-membered heterocycloalkyl group can be independently and optionally -OR ｅ , -OC(O)R ｅ 、-OC(O)NR ｅ R ｆ 、-OS(O)R ｅ 、-OS(O) ２ R ｅ 、-OS(O)NR ｅ R ｆ 、-OS(O) ２ NR ｅ R ｆ 、0173SR ｅ 、-S(O)R ｅ 、-S(O) ２ R ｅ 、-S(O)NR ｅ R ｆ 、-S(O) ２ NR ｅ R ｆ 、-NR ｅ R ｆ 、-NR ｅ C(O)R ｆ 、-NR ｅ C(O)OR ｆ 、-NR ｅ C(O)NR ｅ R ｆ 、-NR ｅ S(O)R ｆ 、-NR ｅ S(O) ２ R ｆ 、-NR ｅ S(O)NR ｅ R ｆ 、-NR ｅ S(O) ２ NR ｅ R ｆ 、-C(O)R ｅ 、-C(O)OR ｅ 、-C(O)NR ｅ R ｆ 、-PR ｅ R ｆ 、-P(O)R ｅ R ｆ 、-P(O) ２ R ｅ R ｆ 、-P(O)NR ｅ R ｆ 、-P(O) ２ NR ｅ R ｆ 、-P(O)OR ｅ 、-P(O) ２ OR ｅ -CN, or -NO ２ It has been replaced with; R ８ H, -S(O) ２ R ｃ , -S(O) ２ NR ｃ R ｄ , -C(O)R ｃ , -C(O)OR ｃ , -C(O)NR ｃ R ｄ , -C(=NR ｄ )NR ｃ R ｄ , -P(O) ２ R ｃ R ｄ , -P(O) ２ NR ｃ R ｄ , or -P(O) ２ OR ｃ And; R ９ H, deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 3-7 member heterocycloalkyl, C ６ -C １０ Aryl, 5-10 member heteroaryl, -OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -OS(O)R ａ , -OS(O) ２ R ａ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ａ R ｂ , -S(O) ２ NR ａ R ｂ , -OS(O)NR ａ R ｂ , -OS(O) ２ NR ａ R ｂ , -NR ａ R ｂ , -NR ａ C(O)R ｂ , -NR ａ C(O)OR ｂ , -NR ａ C(O)NR ａ R ｂ , -NR ａ S(O)R ｂ , -NR ａ S(O) ２ R ｂ , -NR ａ S(O)NR ａ R ｂ , -NR ａ S(O) ２ NR ａ R ｂ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ａ R ｂ ,-PR ａ R ｂ ,-P(O)R ａ R ｂ , -P(O) ２ R ａ R ｂ , -P(O)NR ａ R ｂ , -P(O) ２ NR ａ R ｂ , -P(O)OR ａ , -P(O) ２ OR ａ -CN, or -NO ２ And here, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 3-7 member heterocycloalkyl, C ６ -C １０ Each hydrogen atom in aryls and 5- to 10-membered heteroaryls can be independently and optionally replaced with deuterium, halogen, or C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -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) ２ R ｃ , -OS(O)NR ｃ R ｄ , -OS(O) ２ NR ｃ R ｄ , -SR ｃ , -S(O)R ｃ , -S(O) ２ R ｃ , -S(O)NR ｃ R ｄ , -S(O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｃ C(O)R ｄ , -N(C(O)R ｃ )(C(O)R ｄ ), -NR ｃ C(O)OR ｄ , -NR ｃ C(O)NR ｃ R ｄ , -NR ｃ C(=NR ｄ )NR ｃ R ｄ , -NR ｃ S(O)R ｄ , -NR ｃ S(O) ２ R ｄ , -NR ｃ S(O)NR ｃ R ｄ , -NR ｃ S(O) ２ NR ｃ R ｄ , -C(O)R ｃ , -C(O)OR ｃ , -C(O)NR ｃ R ｄ , -C(=NR ｄ )NR ｃ R ｄ ,-PR ｃ R ｄ ,-P(O)R ｃ R ｄ , -P(O) ２ R ｃ R ｄ , -P(O)NR ｃ R ｄ , -P(O) ２ NR ｃ R ｄ , -P(O)OR ｃ , -P(O) ２ OR ｃ -CN, or -NO ２ It has been replaced with; Each R ａ , R ｂ , R ｃ , R ｄ , R ｅ , and R ｆ These are independently H, deuterium, and C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 3-7 member heterocycloalkyl, C ６ -C １０ Ariel, C １ -C ６ Alkylene-C ６ -C １０ Aryl, 5-10 member heteroaryl, and C １ -C ６ Selected from the group consisting of alkylene-5 to 10-membered heteroaryls; or R ａ and R ｂ or R ｃ and R ｄ or R ｅ and R ｆ These, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycloalkyl group, where C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C ６ Cycloalkyl, 3-7 member heterocycloalkyl, C ６ -C １０ Ariel, C １ -C ６ Alkylene-C ６ -C １０ Aryl, 5-10 member heteroaryl, and C １ -C ６ In alkylene-5 to 10-membered heteroaryls, each hydrogen atom can be independently replaced with deuterium, halogen, or C as desired. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, -OC １ -C ６ Alkyl, -OC(O)-(H or C １ -C ６ Alkyl), -OC(O)N(H or C １ -C ６ Alkyl) ２ , -OC(O)N(C ２ -C ６ Alkylene), -OS(O)-(H or C １ -C ６ Alkyl), -OS(O) ２ -(H or C １ -C ６ Alkyl), -OS(O)N(H or C １ -C ６ Alkyl) ２ , -OS(O)N(C ２ -C ６ Alkylene), -OS(O) ２ N(H or C １ -C ６ Alkyl) ２ , -OS(O) ２ N(C) ２ -C ６ Alkylene), -S (H or C) １ -C ６ Alkyl), -S(O)(H or C １ -C ６ Alkyl), -S(O) ２ (H or C １ -C ６ Alkyl), -S(O)N(H or C １ -C ６ Alkyl) ２ , -S(O)N(C ２ -C ６ Alkylene), -S(O) ２ N(H or C １ -C ６ Alkyl) ２ , -S(O) ２ N(C) ２ -C ６ Alkylene), -N(H or C) １ -C ６ Alkyl) ２ , -N(C ２ -C ６ Alkylene), -N(H or C) １ -C ６ Alkyl)C(O)-(H or C １ -C ６ Alkyl), -N(H or C) １ -C ６ Alkyl)C(O)O(H or C １ -C ６ Alkyl), -N(H or C) １ -C ６ Alkyl)C(O)N(H or C １ -C ６ Alkyl) ２ , -N(H or C １ -C ６ Alkyl)C(O)N(C ２ -C ６ Alkylene), -N(H or C) １ -C ６ Alkyl)S(O)-(H or C １ -C ６ Alkyl), -N(H or C) １ -C ６ Alkyl)S(O) ２ (H or C １ -C ６ Alkyl), -N(H or C) １ -C ６ Alkyl)S(O)N(H or C １ -C ６ Alkyl) ２ , -N(H or C １ -C ６ Alkyl)S(O)N(C) ２ -C ６ Alkylene), -N(H or C) １ -C ６ Alkyl)S(O) ２ N(H or C １ -C ６ Alkyl) ２ , -N(H or C １ -C ６ Alkyl)S(O) ２ N(C) ２ -C ６ Alkylene), -C(O)-(H or C １ -C ６ Alkyl), -C(O)O(H or C １ -C ６ (alkyl), -C(O)N(C ２ -C ６ (alkylene), -P(H or C １ -C ６ (alkyl) ２ , -P(C ２ -C ６ (alkylene), -P(O)(H or C １ -C ６ (alkyl) ２ , -P(O)(C ２ -C ６ (alkylene), -P(O) ２ (H or C １ -C ６ (alkyl) ２ , -P(O) ２ (C ２ -C ６ (alkylene), -P(O)N(H or C １ -C ６ (alkyl) ２ , -P(O)N(C ２ -C ６ (alkylene), -P(O) ２ N(H or C １ -C ６ (alkyl) ２ , -P(O) ２ N(C ２ -C ６ (alkylene), -P(O)O(H or C １ -C ６ (alkyl), -P(O) ２ O(H or C １ -C ６ (alkyl), -CN, or -NO ２ is substituted with; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 1, 2, 3, or 4; and q is 1, 2, or 3. Compounds thereof or their pharmaceutically acceptable salts, solvates, hydrates, or cocrystals.

2. Formula II 【Chemistry 2】 [During the ceremony, each 【Transformation 3】 These are independently carbon-carbon single bonds or carbon-carbon double bonds. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal having the above.

3. Formula III 【Chemistry 4】 [During the ceremony, each 【Transformation 5】 These are independently carbon-carbon single bonds or carbon-carbon double bonds; X １ , X ２ , and X ３ -O-, -S-, =C(H)-, =C(R) １ )-, -N(H)-, -N(R １ ) - or = N -, however X １ , X ２ , and X ３ At least one of them is =C(H)- or =C(R １ ) - not; and / or Y １ , Y ２ , and Y ３ -O-, -S-, =C(H)-, =C(R) ２ )-, -N(H)-, -N(R ２ ) - or = N -, however, Y １ , Y ２ , and Y ３ At least one of them is =C(H)- or =C(R ２ ) - but not; A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, having the above.

4. Formula IV 【Transformation 6】 A compound according to claim 3 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal having the above.

5. X ２ ga = N - or -N(R １ ) - and X １ and X ３ -O-, -S-, =C(H)-, =C(R) １ )-, -N(H)-, or -N(R １ ) - and / or Y ２ ga = N-, Y １ and Y ３ -O-, -S-, =C(H)-, =C(R) ２ )-, -N(H)-, or -N(R ２ ) - and; The compound of claim 3 or 4 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

6. Ring A 【Transformation 7】 A group consisting of is selected, where each 【Transformation 8】 represents a covalent bond point; Any compound according to claims 1 to 4 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

7. Ring A 【Chemistry 9】 A group consisting of is selected, where each 【Chemistry 10】 represents a covalent bond point; A compound according to any of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

8. Ring A 【Chemistry 11】 A group consisting of is selected, where each 【Chemistry 12】 represents a covalent bond point; A compound according to any of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

9. Ring B 【Chemistry 13】 A group consisting of is selected, where each 【Chemistry 14】 represents a covalent bond point; A compound according to any of claims 1 to 4 or 6, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

10. Ring B 【Chemistry 15】 A group consisting of is selected, where each 【Chemistry 16】 represents a covalent bond point; Any compound according to claims 1 to 9 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

11. p is 2 or 3, part 【Chemistry 17】 is ethylene or propylene, where each R ３ and R ４ are independently H, halogen, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, 3-7 member heterocycloalkyl, C ６ -C １０ aryl, 5-10 member heteroaryl, -OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -OS(O)R ａ , -OS(O) ２ R ａ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ａ R ｂ , -S(O) ２ NR ａ R ｂ , -OS(O)NR ａ R ｂ , -OS(O) ２ NR ａ R ｂ , -NR ａ R ｂ , -NR ａ C(O)R ｂ , -NR ａ C(O)OR ｂ , -NR ａ C(O)NR ａ R ｂ , -NR ａ S(O)R ｂ , -NR ａ S(O) ２ R ｂ , -NR ａ S(O)NR ａ R ｂ , -NR ａ S(O) ２ NR ａ R ｂ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ａ R ｂ ,-PR ａ R ｂ ,-P(O)R ａ R ｂ , -P(O) ２ R ａ R ｂ , -P(O)NR ａ R ｂ , -P(O) ２ NR ａ R ｂ , -P(O)OR ａ , -P(O) ２ OR ａ -CN, or -NO ２ is; or R ３ and R ４ At least one of them becomes one with one or more carbon atoms to which they are bonded, C ３ -C ６ It forms a cycloalkyl or a 4- to 7-membered heterocycloalkyl, where C ３ -C ６ Each hydrogen atom in cycloalkyl and 4- to 7-membered heterocycloalkyl groups can be independently and optionally -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -NR ｅ R ｆ , -NR ｅ C(O)R ｆ , -NR ｅ C(O)OR ｆ , -NR ｅ C(O)NR ｅ R ｆ , -NR ｅ S(O)R ｆ , -NR ｅ S(O) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR ｅ R ｆ , -C(O)R ｅ , -C(O)OR ｅ , -C(O)NR ｅ R ｆ ,-PR ｅ R ｆ ,-P(O)R ｅ R ｆ , -P(O) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ -CN, or -NO ２ It is replaced by; or R ７ and R ３ or R ４ At least one of these atoms, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the formed 4- to 7-membered heterocycloalkyl group is independently and optionally -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -NR ｅ R ｆ , -NR ｅ C(O)R ｆ , -NR ｅ C(O)OR ｆ , -NR ｅ C(O)NR ｅ R ｆ , -NR ｅ S(O)R ｆ , -NR ｅ S(O) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR ｅ R ｆ , -C(O)R ｅ , -C(O)OR ｅ , -C(O)NR ｅ R ｆ ,-PR ｅ R ｆ ,-P(O)R ｅ R ｆ , -P(O) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ -CN, or -NO ２ It is replaced by; and each [Chemistry 18] represents a covalent bond point; Any compound according to claims 1 to 10 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

12. One R ３ C １ -C ６ It is alkyl, and here, C １ -C ６ Each hydrogen atom in the alkyl group can be independently replaced with deuterium, halogen, or C as desired. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -NR ｅ R ｆ , -NR ｅ C(O)R ｆ , -NR ｅ C(O)OR ｆ , -NR ｅ C(O)NR ｅ R ｆ , -NR ｅ S(O)R ｆ , -NR ｅ S(O) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR ｅ R ｆ , -C(O)R ｅ , -C(O)OR ｅ , -C(O)NR ｅ R ｆ ,-PR ｅ R ｆ ,-P(O)R ｅ R ｆ , -P(O) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ -CN, or -NO ２ It is replaced by; and / or two R ３ and R ４ These then become one with one or more carbon atoms to which they are bonded, C ３ -C ６ It forms a cycloalkyl or a 4- to 7-membered heterocycloalkyl, where C ３ -C ６ Each hydrogen atom in cycloalkyl and 4- to 7-membered heterocycloalkyl groups can be independently and optionally -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -NR ｅ R ｆ , -NR ｅ C(O)R ｆ , -NR ｅ C(O)OR ｆ , -NR ｅ C(O)NR ｅ R ｆ , -NR ｅ S(O)R ｆ , -NR ｅ S(O) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR ｅ R ｆ , -C(O)R ｅ , -C(O)OR ｅ , -C(O)NR ｅ R ｆ ,-PR ｅ R ｆ ,-P(O)R ｅ R ｆ , -P(O) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ -CN, or -NO ２ It is replaced by; and / or R ７ and R ３ or R ４ At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the 4- to 7-membered heterocycloalkyl group is independently and optionally -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -NR ｅ R ｆ , -NR ｅ C(O)R ｆ , -NR ｅ C(O)OR ｆ , -NR ｅ C(O)NR ｅ R ｆ , -NR ｅ S(O)R ｆ , -NR ｅ S(O) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR ｅ R ｆ , -C(O)R ｅ , -C(O)OR ｅ , -C(O)NR ｅ R ｆ ,-PR ｅ R ｆ ,-P(O)R ｅ R ｆ , -P(O) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ -CN, or -NO ２ It is replaced by; and any remaining R ３ and R ４ is either H or deuterium; Any compound according to claims 1 to 11 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

13. One R ３ C １ -C ６ It is alkyl, and here, C １ -C ６ Each hydrogen atom in the alkyl group can be independently replaced with deuterium, halogen, or C as desired. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -NR ｅ R ｆ , -NR ｅ C(O)R ｆ , -NR ｅ C(O)OR ｆ , -NR ｅ C(O)NR ｅ R ｆ , -NR ｅ S(O)R ｆ , -NR ｅ S(O) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR ｅ R ｆ , -C(O)R ｅ , -C(O)OR ｅ , -C(O)NR ｅ R ｆ ,-PR ｅ R ｆ ,-P(O)R ｅ R ｆ , -P(O) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ -CN, or -NO ２ It is replaced by; and / or R ７ and R ３ or R ４ At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group, where each hydrogen atom in the 4- to 7-membered heterocycloalkyl group is independently and optionally -OR ｅ , -OC(O)R ｅ , -OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -NR ｅ R ｆ , -NR ｅ C(O)R ｆ , -NR ｅ C(O)OR ｆ , -NR ｅ C(O)NR ｅ R ｆ , -NR ｅ S(O)R ｆ , -NR ｅ S(O) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S(O) ２ NR ｅ R ｆ , -C(O)R ｅ , -C(O)OR ｅ , -C(O)NR ｅ R ｆ ,-PR ｅ R ｆ ,-P(O)R ｅ R ｆ , -P(O) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ -CN, or -NO ２ It is replaced by; and any remaining R ３ and R ４ is either H or deuterium; A compound according to any of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

14. R ３ One of them is C １ -C ６ Alkyl; and any residual R ３ and R ４ is either H or deuterium; Any compound according to claims 1 to 13 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

15. R ３ One of them is C １ -C ６ It is alkyl; R ７ and R ４ One of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group; and any remaining R ３ and R ４ is either H or deuterium; Any compound according to claims 1 to 14 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

16. R ３ One of them is methyl, and any remaining R ３ and R ４ is either H or deuterium; Any compound according to claims 1 to 15 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

17. R ７ H, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or -C(O)R ｃ is; or R ７ and R ３ or R ４ At least one of them, together with the atom to which they are bonded, forms a 4- to 7-membered heterocycloalkyl group; where C １ -C ６ Alkyl, C ３ -C ６ Each hydrogen atom in cycloalkyls and 4- to 7-membered heterocycloalkyls can be 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) ２ R ｃ , -OS(O)NR ｃ R ｄ , -OS(O) ２ NR ｃ R ｄ , -SR ｃ , -S(O)R ｃ , -S(O) ２ R ｃ , -S(O)NR ｃ R ｄ , -S(O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｃ C(O)R ｄ , -N(C(O)R ｃ )(C(O)R ｄ ), -NR ｃ C(O)OR ｄ , -NR ｃ C(O)NR ｃ R ｄ , -NR ｃ C(=NR ｄ )NR ｃ R ｄ , -NR ｃ S(O)R ｄ , -NR ｃ S(O) ２ R ｄ , -NR ｃ S(O)NR ｃ R ｄ , -NR ｃ S(O) ２ NR ｃ R ｄ , -C(O)R ｃ , -C(O)OR ｃ , -C(O)NR ｃ R ｄ , -C(=NR ｄ )NR ｃ R ｄ ,-PR ｃ R ｄ ,-P(O)R ｃ R ｄ , -P(O) ２ R ｃ R ｄ , -P(O)NR ｃ R ｄ , -P(O) ２ NR ｃ R ｄ , -P(O)OR ｃ , -P(O) ２ OR ｃ -CN, or -NO ２ It has been replaced with; Any compound according to claims 1 to 15 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

18. portion 【Chemistry 19】 is the formula 【Chemistry 20】 These are, and here, each 【Chemistry 21】 The ∫ represents a covalent bond, where each hydrogen is independently substituted with deuterium as desired; Any compound according to claims 1 to 17 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

19. R ５ and R ６ Each of these is H; Any compound according to claims 1 to 18 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

20. portion 【Chemistry 22】 is the formula 【Chemistry 23】 These are, and here, each 【Chemistry 24】 The ∫ represents a covalent bond, where each hydrogen is independently substituted with deuterium as desired; Any compound according to claims 1 to 19 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

21. R ８ is H or C １ -C ６ It is alkyl; A compound according to any of claims 1 to 20 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

22. R ９ H, deuterium, halogen, C １ -C ６ Alkyl, or -OR ａ And here, C １ -C ６ Each hydrogen atom in the alkyl group is independently substituted with deuterium as desired; Any compound according to claims 1 to 21 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

23. R ９ H, deuterium, halogen, -OCH ３ ien-CH ３ , or -CD ３ And; Any compound according to claims 1 to 22 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof. [Request Item 24] [Chemistry 25] 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, selected from the group consisting of the above. 【Request Item 25】 【Chemistry 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, selected from the group consisting of the above.

26. A pharmaceutical composition comprising any compound of claims 1 to 25 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, and optionally one or more additives.

27. A method for treating a target disease, comprising administering a therapeutically effective amount of any compound from claims 1 to 25 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or the pharmaceutical composition of claim 26.

28. A compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, for use in a method of treating a disease in a subject.

29. Use of any compound according to claims 1 to 25 or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof in the manufacture of a pharmaceutical for the treatment of a disease in a subject.

Images