EGFR inhibitors for treating disease

Abstract

The present disclosure relates to compounds targeting kinases such as EGFR, pharmaceutical compositions containing the compounds, and methods of using such compounds to treat disease, such as cancer.

Description

EGFR INHIBITORS FOR TREATING DISEASE RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 463,498, filed May 2, 2023, U.S. Provisional Application No. 63 / 627,624, filed January 31, 2024, and U.S. Provisional Application No.63 / 636,734, filed April 20, 2024, the entire disclosures of all of which are incorporated herein by reference. TECHNICAL FIELD

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

[0003] Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G, et al., The protein kinase complement of the human genome. Science.2002, 298:1912–34). Dysregulation of kinase activity is associated with many diseases, including cancers, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A., Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36:462–469). The molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al., New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res. 2018, 78:15-29). The critical role of kinases in cancer and other diseases makes them attractive targets for drug inventions with 62 small molecule kinase inhibitors have been approved and 55 of them for cancer targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2021 Update. Pharmacol Res 2021, 165:105463). Although kinase inhibitors have achieved dramatic success in cancer targeted therapies, the development of treatment resistance has remained as a challenge for small molecule kinase inhibitors. Acquired secondary mutations within kinase domain during the treatment often lead to treatment resistance to kinase inhibitors (Pottier C, et al., Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers (Basel), 2020, 12:731). Resistance can also arise from subpopulations of tolerant / persister cells that survive in the presence of thetreatment. Different processes contribute to the emergence of tolerant persister cells, including pathway rebound through the release of negative feedback loops, transcriptional rewiring mediated by chromatin remodeling and autocrine / paracrine communication among tumor cells and within the tumor microenvironment (Swayden M, et al., Tolerant / Persister Cancer Cells and the Path to Resistance to Targeted Therapy. Cells 2020, 9, 2601). Therefore, it is necessary to invent kinase inhibitors that can target not only the kinase oncogenic drivers, overcome most frequent resistance mutations, but also tolerant persister cancer cells for overcoming resistance, achieving better efficacy and longer disease control.

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

[0005] The first-generation reversible EGFR inhibitors, erlotinib and gefitinib are superior to chemotherapy in patients with advanced EGFR mutation-positive (Del19 or L858R) NSCLC and have been used as first-line standard of care in this setting. However, most patients will develop resistance to gefitinib or erlotinib with 50% to 70% of tumors developing EGFR T790M gatekeeper mutation with time of treatment (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 of 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] Although afatinib and dacomitinib are more potent EGFR inhibitors approved as first- line therapy for advanced EGFR mutation-positive (Del19 or L858R) NSCLC with longer progression free survival time (PFS) in comparison with gefitinib and erlotinib, EGFR T790M has been developed with time of treatment with afatinib (Tanaka K, et al., Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Onco-target 2017;8:68123-30). EGFR T790M confers resistance to dacomitinib 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 targeting both EGFR activating mutations (Del19 and L858R) and T790M resistant double mutations, with selectivity over the wild-type EGFR (Finlay MR, et al., Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014; 57:8249-67). Osimertinib was first approved for patients with metastatic EGFR T790M mutation-positive NSCLC after failure of first-line EGFR inhibitors, and later approved in the first-line setting for patients with EGFR mutation-positive NSCLC following the phase III FLAURA trial with head-to-head trials comparing with erlotinib or gefitinib (Soria JC, et al., Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378:113-25). The mutation C797S at the EGFR covalent binding residue with irreversible EGFR inhibitor Osimertinib has been detected in Osimertinib-resistant patients (Ramalingam SS, et al., Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Presented at the ESMO 2018). EGFR mutations (L858R or exon 19 deletions (Ex19del)) are classified as EGFR classic mutations, or common mutations, which showed marked efficacy with currently approved EGFR inhibitors.

[0007] Therefore, there is an urgent medical need to develop holistic EGFR inhibitors that are potent against classical EGFR mutations, including L858R, Δ746-750, Δ746-750 / C979S, L858R / T790M, L858R / T790M / C979S, and D770_N771insNPG, while maintaining good selectivity over wild-type EGFR. SUMMARY

[0008] In one aspect, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof,I

[0009] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, B, m, n, p, and q are as described herein.

[0010] In another aspect, the disclosure relates to a compound of the formula II, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof,

[0011] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, B, m, n, p, and q are as described herein.

[0012] In another aspect, the disclosure relates to a compound of the formula III, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof,

[0013] wherein X1, X2, X3, Y1, Y2, Y3, R3, R4, R5, R6, R7, R8, R9, A, B, p, and q are asdescribed herein.

[0014] In another aspect, the disclosure relates to a compound of the formula IV, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof,

[0015] wherein X1, X2, X3, Y1, Y2, Y3, R3, R4, R5, R6, R7, R8, R9, A, and B are as described herein.

[0016] In certain embodiments of the above aspects, the compound of Formula (I)-(IV) is a compound selected from those species described or exemplified in the detailed description below.

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

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

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

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

[0021] In further aspects, the disclosure relates to a method of inhibiting a tyrosine kinase, such as EGFR, including the certain mutations as described herein, comprising contacting a cell comprising one or more of kinase with an effective amount of at least one compound ofFormula (I)-(IV), or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, and / or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.

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

[0023] 1. A compound of the formula II

[0024] wherein

[0025] ring A and ring B are each independently a 5-membered heteroarylene;

[0026] each R1and R2, when present, is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd,-NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2;

[0027] each R3, R4, R5, and R6is independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or two of R3, R4, R5, and R6, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C3-C6cycloalkyl and 3- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0028] R7is H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -C(O)Rc, or -C(O)NRcRd, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc,-P(O)2ORc, -CN, or -NO2; or R7and one of R3, R4, R5, or R6, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, - SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0029] R8is H, -S(O)2Rc, -S(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, or -P(O)2ORc;

[0030] R9is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2;

[0031] each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, and C1-C6alkylene-5- to 10-membered heteroaryl; or Raand Rbor Rcand Rdor Reand Rf, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, and C1-C6alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OC1-C6alkyl, -OC(O)-(H or C1-C6alkyl), -OC(O)N(H or C1-C6alkyl)2, -OC(O)N(C2-C6alkylene), -OS(O)-(H or C1-C6alkyl), -OS(O)2-(H or C1-C6alkyl), -OS(O)N(H or C1-C6alkyl)2, -OS(O)N(C2-C6alkylene), -OS(O)2N(H or C1-C6alkyl)2, -OS(O)2N(C2-C6alkylene), -S(H or C1-C6alkyl), -S(O)(H or C1-C6alkyl), -S(O)2(H or C1-C6alkyl), -S(O)N(H or C1-C6alkyl)2, -S(O)N(C2-C6alkylene), -S(O)2N(H or C1-C6alkyl)2, -S(O)2N(C2-C6alkylene), -N(H or C1-C6alkyl)2, -N(C2-C6alkylene), -N(H or C1-C6alkyl)C(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)O(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)C(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)2(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)2N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)2N(C2-C6alkylene), -C(O)-(H or C1-C6alkyl), -C(O)O(H or C1-C6alkyl), -C(O)N(C2-C6alkylene), -P(H or C1-C6alkyl)2, -P(C2-C6alkylene), -P(O)(H or C1-C6alkyl)2, -P(O)(C2-C6alkylene), -P(O)2(H or C1-C6alkyl)2, -P(O)2(C2-C6alkylene), -P(O)N(H or C1-C6alkyl)2, -P(O)N(C2-C6alkylene), -P(O)2N(H or C1-C6alkyl)2, -P(O)2N(C2-C6alkylene), -P(O)O(H or C1-C6alkyl), -P(O)2O(H or C1-C6alkyl), -CN, or -NO2;

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

[0033] n is 0, 1, 2, or 3;

[0034] p is 1, 2, 3, or 4; and

[0035] q is 1, 2, or 3;

[0036] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0037] 2. The compound of clause 1, having the formula IIII

[0038] wherein each “ ” is independently a carbon-carbon single bond or a carbon- carbon double bond;

[0039] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0040] 3. The compound of clause 1 or 2, having the formula IIIIII

[0041] wherein

[0042] each “ ” is independently a carbon-carbon single bond or a carbon-carbon double bond;

[0043] X1, X2, and X3are each independently -O-, -S-, =C(H)-, =C(R1)-, -N(H)-, -N(R1)- or =N-, provided that at least one of X1, X2, and X3is not =C(H)-, or =C(R1)-; and / or

[0044] Y1, Y2, and Y3are each independently -O-, -S-, =C(H)-, =C(R2)-, -N(H)-, -N(R2)- or =N-, provided that at least one of Y1, Y2, and Y3is not =C(H)-, or =C(R2)-;

[0045] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0046] 4. The compound of clause 3, having the formula IVIV

[0047] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0048] 5. The compound of clause 3 or 4, wherein

[0049] X2is =N- or -N(R1)-, X1and X3are each independently -O-, -S-, =C(H)-, =C(R1)-, -N(H)-, or -N(R1)-; and / or

[0050] Y2is =N-, Y1and Y3are each independently -O-, -S-, =C(H)-, =C(R2)-, -N(H)-, or -N(R2)-;

[0051] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0052] 6. The compound of any one of clauses 1 to 4, wherein:

[0053] ring A is selected from the group consisting of

[0054] wherein each “ ” represents a point of covalent attachment;

[0055] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0056] 7. The compound of any one of the preceding clauses, wherein ring A is selected from the group consisting of

[0057]

[0058] wherein each “ ” represents a point of covalent attachment;

[0059] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0060] 8. The compound of any one of the preceding clauses, wherein ring A is selected from the group consisting of

[0061] wherein each “” represents a point of covalent attachment;

[0062] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0063] 9. The compound of any one of clauses 1 to 4 or 6, wherein ring B is selected from the group consisting of,

[0064] wherein each “” represents a point of covalent attachment;

[0065] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0066] 10. The compound of any one of the preceding clauses, wherein ring B is selected from the group consisting of

[0067] wherein each “” represents a point of covalent attachment;

[0068] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0069] 11. The compound of any one of the preceding clauses, wherein p is 2 or 3, and the portion

[0070] is an ethylene or propylene, wherein each R3and R4is independently H, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra,-OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or at least one instance of R3and R4, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C3-C6cycloalkyl or 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or R7and one instance of R3or R4, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 7-membered heterocycloalkyl formed is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and each “ ” represents a point of covalent attachment;

[0071] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0072] 12. The compound of any one of the preceding clauses, wherein one R3is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and / or two R3and R4, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C3-C6cycloalkyl and 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf,-NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and / or R7and one instance of R3or R4and, taken together with the atoms to which they are attached, combine to form a 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and any remaining R3and R4are H or deuterium;

[0073] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0074] 13. The compound of any one of the preceding clauses, wherein one R3is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and / or R7and one instance of R3or R4taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and any remaining R3and R4are H or deuterium;

[0075] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0076] 14. The compound of any one of the preceding clauses, wherein one instance of R3is C1-C6alkyl; and any remaining R3and R4are H or deuterium;

[0077] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0078] 15. The compound of any one of the preceding clauses, wherein one instance of R3is C1-C6alkyl; R7and one instance of R4, taken together with the atoms to which they are attached, combine to form a 4- to 7-membered heterocycloalkyl; and any remaining R3and R4are H or deuterium;

[0079] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0080] 16. The compound of any one of the preceding clauses, wherein one instance of R3is methyl, and any remaining R3and R4are H or deuterium;

[0081] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0082] 17. The compound of any one of the preceding clauses, wherein R7is H, C1-C6alkyl, C3-C6cycloalkyl, or -C(O)Rc; or R7and one instance of R3or R4, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6alkyl, C3-C6cycloalkyl, and 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2;

[0083] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0084] 18. The compound of any one of the preceding clauses, wherein the portion

[0085] is of the formulawherein each “ ” represents a point of covalent attachment, and each hydrogen is independently optionally substituted with deuterium;

[0086] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0087] 19. The compound of any one of the preceding clauses, wherein R5and R6are each H;

[0088] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0089] 20. The compound of any one of the preceding clauses, wherein the portion

[0090] is of the formula, wherein each “ ” represents a point of covalent attachment, and each hydrogen is independently optionally substituted with deuterium;

[0091] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0092] 21. The compound of any one of the preceding clauses, wherein R8is H or C1-C6alkyl;

[0093] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0094] 22. The compound of any one of the preceding clauses, wherein R9is H, deuterium, halogen, C1-C6alkyl, or -ORa, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted with deuterium;

[0095] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0096] 23. The compound of any one of the preceding clauses, wherein R9is H, deuterium, halogen, -OCH3, -CH3, or -CD3;

[0097] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0098] 24. The compound of clause 1, selected from the group consisting of,

[0099] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0100] 25. The compound of clause 1, selected from the group consisting of,, ,,

[0101] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0102] 26. A pharmaceutical composition comprising a compound of any one of the preceding clauses, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, and optionally one or more excipients.

[0103] 27. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of clauses 1 to 25, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a pharmaceutical composition of clause 26.

[0104] 28. A compound according to any one of clauses 1 to 25, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, for use in a method of treating disease in a subject.

[0105] 29. Use of a compound according to any one of clauses 1 to 25, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, in the manufacture of a medicament for the treatment of disease in a subject. DETAILED DESCRIPTION

[0106] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0107] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0108] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0109] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0110] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and / or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.

[0111] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0112] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp.360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0113] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0114] As used herein and in connection with chemical structures depicting the various embodiments described herein, “*”, “**”, and “ ”, each represent a point of covalent attachment of the chemical group or chemical structure in which the identifier is shown to an adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure A-B, where A and B are joined by a covalent bond, in some embodiments, the portionof A-B defined by the group or chemical structure A can be represented by ,” represents a bond to A and the point of covalent bond attachment to B. Alternatively, in some embodiments, the portion of A-B defined by the group or chemical structure B can be represented by,represents a bond to B and the point of covalent bond attachment to A.

[0115] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. CHEMICAL DEFINITIONS

[0116] The term “alkyl” refers to a straight- or branched-chain monovalent hydrocarbon group. The term “alkylene” refers to a straight- or branched-chain divalent hydrocarbon group. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C1-C20 alkyl or C1-C20 alkylene, C1-C12 alkyl or C1-C12 alkylene, or C1-C6alkyl or C1-C6alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n-propylene ((-CH2-)3), iso-propylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substitutedas described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0117] The term “alkenyl” refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” to a specific range of atoms, such as C2-C20alkenyl, C2-C12alkenyl, or C2-C6alkenyl. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl can be unsubstituted or substituted as described herein. An alkenyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0118] The term “alkynyl” refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” to a specific range of atoms, such as C2-C20 alkynyl, C2-C12alkynyl, or C2-C6alkynyl. Examples of alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), and the like. It will be appreciated that an alkynyl group can be unsubstituted or substituted as described herein. An alkynyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0119] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” to a specific range of atoms, such as having 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include monovalent radicals of the following entities:In particular, a cyclopropyl moiety can be depicted by the structural formulabe appreciated that a cycloalkyl group can be unsubstituted or substituted as described herein.A cycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0120] The term “oxo” represents a carbonyl oxygen.

[0121] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.

[0122] The term “haloalkyl” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include –CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F. The term “aryl” refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. In some embodiments, it can be advantageous to limit the number of atoms in an “aryl” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6-C14 aryl), or monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-C10aryl).Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. It will be appreciated that an aryl group can be unsubstituted or substituted as described herein. An aryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0123] The term “heterocycloalkyl” refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. In some embodiments, it can be advantageous to limit the number of atoms in a “heterocycloalkyl” to a specific range of ring atoms, such as from 3 to 12 ring atoms (3- to 12- membered), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6-membered), or 4 to 6 ring atoms (4- to 6-membered), 5 to 7 ring atoms (5- to 7-membered), or 4 to 10 ring atoms (4- to 10-membered). In some embodiments, it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Examples, without limitations, of mono-cyclic heterocycloalkyl groups include tetrahydrofuran, pyrrolidine, and morpholine. Polycyclic ring systems include fused, bridged, and spiro systems. In some embodiments, it can be advantageous to limit the number of atoms in a bicyclic “heterocycloalkyl” to a specific range of ring atoms, such as from 5 to 10 ring atoms (5- to 10-membered), or 6 to 10 ring atoms (6- to 10-membered). The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Examples, without limitations, of fused bicyclic, bridged bicyclic, and spiro bicyclic heterocycloalkyl groups include pyrrolizine, 2,5- diazabicyclo[2.2.2]octane, and 1-oxaspiro[4.5]decane. Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities:

[0124] A three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of three- membered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane. A five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-1H- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2- one, and oxazolidin-2-one. A six-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocycle groups include mono- valent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4- tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring.

[0125] As described herein, certain embodiments can include a heteroatom-C2-C6alkylene moiety (e.g., -N(C2-C6alkylene) or -P(O)2(C2-C6alkylene)). Illustratively,-heteroatom-(C2-C6alkylene) represents a cyclic group wherein the heteroatom atom (e.g., nitrogen, phosphorus, etc.) forms two covalent bonds with the C2-C6alkylene group (e.g., example, -OC(O)N(C2-C6alkylene) can be depicted by the structural formula.

[0126] It will be appreciated that a heterocycloalkyl group can be unsubstituted or substituted as described herein. A heterocycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0127] The term “heteroaryl” refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle. The term “heteroarylene” refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. In some embodiments, it can be advantageous to limit the number of ring atoms in a “heteroaryl” or “heteroarylene” to a specific range of atom members, such as 5- to 10-membered heteroaryl or 5- to 10-membered heteroarylene. In some instances, a 5- to 10- membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. In some instances, a 5- to 10-membered heteroarylene can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities, while examples of 5- to 10-membered heteroarylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:

[0128] In some embodiments, a “monocyclic” heteroaryl can be an aromatic five- or six- membered heterocycle. A five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include mono-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-limiting examples of five-membered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of six-membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H- benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole. Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of azaindazole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin- 3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.

[0129] In particular, a pyrazolyl moiety can be depicted by the structural formulaparticular, an example of a pyrazolylene moiety can be depicted by the structural formula.

[0130] In particular, an azaindazolylene or pyrazolopyridylene moiety such as 1H- pyrazolo[3,4-c]pyridylene moiety can be depicted by the structural formula.

[0131] It will be appreciated that a heteroaryl group can be unsubstituted or substituted as described herein. A heteroaryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0132] It will be appreciated that a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. A heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0133] As used herein, the phrase “taken together with the atoms to which each is attached” means that two substituents (e.g., R7and one of R3, R4, R5, or R6) attached to two separate atoms combine to form a 4- to 7-membered heterocycloalkyl that are defined by the claim, such as. In particular, the phrase “taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl” means R7and one of R3, R4, R5, or R6, for example, on different ring atoms, form a 4- to 7-membered ring with those ring atoms.

[0134] For example, the phrase “taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl” used in connection with the embodiments described herein includes the compound represented as follows:.

[0135] The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments, “substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent.

[0136] As used herein, “independently” means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances. For example, in a circumstance where several equivalent hydrogen groups are optionally substituted by another group described in the circumstance, the use of “independently optionally” means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different. Or for example, where multiple groups exist all of which can be selected from a set of possibilities, the use of “independently” means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.

[0137] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.

[0138] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,15N,18O,17O,31P,32P,35S,18F,36Cl, and125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0139]

[0140] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(IV), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

[0141] A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0142] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2- sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ- hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0143] For a compound of Formula (I)-(IV) that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0144] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(IV), and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(IV). A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985.

[0145] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(IV), and uses of such metabolites in the methods of the disclosure. A “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(IV) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem.1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

[0146] As used herein, the term “EGFR inhibitor” includes, but is not limited to, a compound that is capable of inhibiting the protein encoded by the EGFR gene. EGFR inhibitors include, but are not limited to compounds that are capable of inhibiting the protein that is encoded by the classical EGFR mutations, uncommon 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, other emerging and established resistance mutations, and the like. It will be understood by a person having ordinary skill in the art that reference to a inhibiting of EGFR mutations, such as EGFR L858R refers to inhibiting the protein encoded by a single missense mutation in exon 21 of the EGFR gene. REPRESENTATIVE EMBODIMENTS

[0147] In some embodiments, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereofI

[0148] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, B, m, n, p, and q are as described herein.

[0149] In some embodiments, the disclosure relates to a compound of the formula II, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof,II

[0150] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, B, m, n, p, and q are as described herein.

[0151] In some embodiments, the disclosure relates to a compound of the formula III, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof,III

[0152] wherein X1, X2, X3, Y1, Y2, Y3, R3, R4, R5, R6, R7, R8, R9, A, B, p, and q are as described herein.

[0153] In some embodiments, the disclosure relates to a compound of the formula IV, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof,IV

[0154] wherein X1, X2, X3, Y1, Y2, Y3, R3, R4, R5, R6, R7, R8, R9, A, and B are as described herein.

[0155] In some embodiments, X1, X2, and X3are each independently -O-, -S-, =C(H)-, =C(R1)- , -N(H)-, -N(R1)- or =N- and ring A is a 5-membered heteroarylene, provided that at least one of X1, X2, and X3is not =C(H)-, or =C(R1)-. In some embodiments, X2is =N- or -N(R1)-, X1and X3are each independently -O-, -S-, =C(H)-, =C(R1)-, -N(H)-, or -N(R1)-, and ring A is a 5-membered heteroarylene. In some embodiments, X2is =N- or -N(R1)-, X1and X3are each independently =C(H)-, =C(R1)-, and ring A is a 5-membered heteroarylene. In some embodiments, X1, X2, and X3are each independently -N(R1)-, =N-, =C(R1)-, and ring A is a 5-membered heteroarylene, provided that at least one of X1, X2, and X3is not =C(R1)-.

[0156] In some embodiments, Y1, Y2, and Y3are each independently -O-, -S-, =C(H)-, =C(R2)- , -N(H)-, -N(R2)- or =N- and ring B is a 5-membered heteroarylene, provided that at least one of Y1, Y2, and Y3is not =C(H)-, or =C(R2)-. In some embodiments, Y1, Y2, and Y3are each independently =C(H)-, =C(R2)-, -N(R2)- or =N- and ring B is a 5-membered heteroarylene, provided that at least one of Y1, Y2, and Y3is not =C(H)-, or =C(R2)-. In some embodiments, Y2is =N-, Y1and Y3are each independently -O-, -S-, =C(H)-, =C(R2)-, -N(H)-, or -N(R2)-, and ring B is a 5-membered heteroarylene.In some embodiments, ring A and ring B are each independently a 5-membered heteroarylene.

[0157] In some embodiments, ring A is selected from the group consisting ofrepresents a point of covalent attachment. In some embodiments, ring A is a pyrazolylene. In some embodiments, ring A is selected from the group consisting of, wherein each “ ” represents a point of covalent attachment. In some embodiments, ring A is selected from the group consisting ofwherein each “ ” represents a point of covalent attachment. In some embodiments, ringwherein each “ ” represents a point of covalent attachment. In some embodiments, ringwherein each “ ” represents a point of covalent attachment. In some embodiments, ring A is selected from the group consisting ofwherein each “ ” represents a point of covalent attachment. In some embodiments, ring A is selected from the group consisting ofwherein each“ ” represents a point of covalent attachment. In some embodiments, ring A is selected from the group consisting ofwherein each “ ” represents a point of covalent attachment.

[0158] In some embodiments, ring B is selected from the group consisting of, wherein each “ ” represents a point of covalent attachment. In some embodiments, ring B is a pyrazolylene. In some embodiments, ring B is selected from the group consisting of, wherein each“ ” represents a point of covalent attachment. In some embodiments, ring“ ” represents a point of covalent attachment. In some embodiments, ringerein each “ ” represents a point of covalent attachment. In some embodiments, ringwherein each “ ” represents a point of covalentattachment. In some embodiments, ring B is, wherein each “” represents a point of covalent attachment. In some embodiments, In some embodiments, ring B is selected from the group consisting of, wherein each “ ” represents a point of covalent attachment. In some embodiments, ring B is selected from the group consisting ofwherein each “ ” represents a point of covalent attachment. In some embodiments,wherein each “ ” represents a point of covalent attachment.

[0159] In some embodiments, ring A and ring B are each a pyrazolylene.

[0160] In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0161] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0162] In some embodiments, each R1and R2, when present, is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0163] In some embodiments, each R1and R2, when present, is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0164] In some embodiments, each R1and R2, when present, is independently halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6- C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra,-OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0165] In some embodiments, each R1and R2, when present, is independently halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, -ORa, -OC(O)Ra, -OC(O)NRaRb, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -CN, or -NO2. In some embodiments, each R1and R2, when present, is independently halogen, C1-C6alkyl, C2-C6alkynyl, -ORa, or –CN, wherein each hydrogen atom in C1-C6alkyl and C2-C6alkynyl is independently optionally substituted by halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, or -CN. In some embodiments, each R1and R2, when present, is independently halogen, C1-C6alkyl, C2-C6alkynyl, -ORa, or –CN, wherein each hydrogen atom in C1-C6alkyl or C2-C6alkynyl is independently optionally substituted by -ORcor -CN.

[0166] In some embodiments, each R1, when present, is independently C1-C6alkyl, -ORa, or -CN, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by -ORcor -CN. In some embodiments, each R1, when present, is independently C1-C6alkyl, -ORa, or –CN, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by -OH or -CN.

[0167] In some embodiments, each R2, when present, is independently halogen, C1-C6alkyl, or C2-C6alkynyl. In some embodiments, each R2, when present, is independently halogen, methyl, ethyl, or ethyne.

[0168] In some embodiments, each Rais C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium or –CN. In some embodiments, eachRais methyl, ethyl, or propyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium or –CN.

[0169] In some embodiments, each Rcis H.

[0170] In some embodiments, each R3, R4, R5, and R6is independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or two of R3, R4, R5, and R6, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 3- to 7- membered heterocycloalkyl, wherein each hydrogen atom in C3-C6cycloalkyl or 3- to 7- membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, each R3, R4, R5, and R6is independently H or C1-C6alkyl. In some embodiments, each R3, R4, R5, and R6is independently H, methyl, or ethyl. In some embodiments, each R3, R4, R5, and R6is independently H or methyl.

[0171] In some embodiments, each R3and R4is independently H, methyl, or ethyl. In some embodiments, each R3and R4is independently H or methyl. In some embodiments, one instance of R3is methyl, and any remaining R3and R4are H or deuterium. In some embodiments, one instance of R3is C1-C6alkyl; R7and one instance of R4, taken together with the atoms to which they are attached, combine to form a 4- to 7-membered heterocycloalkyl; and any remaining R3and R4are H or deuterium.

[0172] In some embodiments, R5and R6are each H.

[0173] In some embodiments, R7is H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -C(O)Rc, or -C(O)NRcRd, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; or R7and one of R3, R4, R5, or R6, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0174] In some embodiments, R7is H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; or R7and one of R3, R4, R5, or R6, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0175] In some embodiments, R7is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; or R7and one of R3, R4, R5, or R6, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0176] In some embodiments, R7is H, C1-C6alkyl, C3-C6cycloalkyl, or -C(O)Rc; or R7and one instance of R3or R4, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl. In some embodiments, R7is H, C1-C6alkyl, C3-C6cycloalkyl. In some embodiments, R7and one of R3, R4, R5, or R6, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl. In some embodiments, R7is H, methyl, ethyl, propyl, or cyclopropyl. In some embodiments, R7is H, C1-C6alkyl, or C3-C6cycloalkyl. In some embodiments, R7and one instance of R3or R4, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl. In some embodiments, R7and one instance of R3or R4, taken together with the atoms to which they are attached, combine to form 5-membered heterocycloalkyl.

[0177] In some embodiments, R7is H, C1-C6alkyl, C3-C6cycloalkyl, or -C(O)Rc; or R7and one instance of R3or R4, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6alkyl, C3-C6cycloalkyl, and 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd,-C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0178] In some embodiments, p is 2 or 3 and the portionis an ethylene or propylene, wherein each R3and R4is independently H, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or at least one instance of R3and R4, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C3-C6cycloalkyl and 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or R7and one instance of R3or R4, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 7- membered heterocycloalkyl formed is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and each “ ” represents a point of covalent attachment.

[0179] In some embodiments, the portionethylene, wherein each R3and R4is independently H or C1-C6alkyl; and / or R7and one instance of R3or R4, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl.

[0180] In some embodiments, the portion iattachment, and each hydrogen is independently optionally substituted with deuterium.

[0181] In some embodiments, the portion irepresents a point of covalent attachment, and each hydrogen is independently optionally substituted with deuterium. In some embodiments, the portion i” represents a point of covalent attachment, and each hydrogen is independently optionally substituted with deuterium.

[0182] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 2, 3, or 4. In some embodiments, p is 1 or 2. In some embodiments, p is 2 or 3. In some embodiments, p is 3 or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0183] In some embodiments, the portion i ,attachment and each hydrogen is independently optionally substituted with deuterium.

[0184] In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 2 or 3. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0185] In some embodiments, R8is H, -S(O)2Rc, -S(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, or -P(O)2ORc.

[0186] In some embodiments, R8is H, deuterium, -S(O)2Rc, -S(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, -P(O)2ORc. In some embodiments, R8is H or C1-C6alkyl. In some embodiments, R8is H, -S(O)2Rc, -S(O)2NRcRd,-C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, -P(O)2ORc. In some embodiments, R8is H or C1-C6alkyl. In some embodiments, R8is H.

[0187] In some embodiments, R9is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0188] In some embodiments, R9is H, deuterium, halogen, C1-C6alkyl, or -ORa, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted with deuterium. In some embodiments, R9is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C-(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or-NO2. In some embodiments, R9is H, deuterium, halogen, C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted with deuterium. In some embodiments, R9is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl, is independently optionally substituted by deuterium. In some embodiments, R9is H, deuterium, halogen, -CH3, or -CD3. In some embodiments, R9is H, deuterium, halogen, -OCH3, -CH3, or -CD3.

[0189] In some embodiments, each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, C1-C6alkylene-C6-C10aryl, 5- to 10-membered heteroaryl, and C1-C6alkylene-5- to 10-membered heteroaryl; or Raand Rbor Rcand Rdor Reand Rf, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, C1-C6alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, and C1-C6alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OC1-C6alkyl, -OC(O)-(H or C1-C6alkyl), -OC(O)N(H or C1-C6alkyl)2, -OC(O)N(C2-C6alkylene), -OS(O)-(H or C1-C6alkyl), -OS(O)2-(H or C1-C6alkyl), -OS(O)N(H or C1-C6alkyl)2, -OS(O)N(C2-C6alkylene), -OS(O)2N(H or C1-C6alkyl)2, -OS(O)2N(C2-C6alkylene), -S(H or C1-C6alkyl), -S(O)(H or C1-C6alkyl), -S(O)2(H or C1-C6alkyl), -S(O)N(H or C1-C6alkyl)2, -S(O)N(C2-C6alkylene), -S(O)2N(H or C1-C6alkyl)2, -S(O)2N(C2-C6alkylene), -N(H or C1-C6alkyl)2, -N(C2-C6alkylene), -N(H or C1-C6alkyl)C(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)O(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)C(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)2(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)2N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)2N(C2-C6alkylene), -C(O)-(H or C1-C6alkyl), -C(O)O(H or C1-C6alkyl), -C(O)N(C2-C6alkylene), -P(H or C1-C6alkyl)2, -P(C2-C6alkylene), -P(O)(H or C1-C6alkyl)2, -P(O)(C2-C6alkylene), -P(O)2(H or C1-C6alkyl)2, -P(O)2(C2-C6alkylene), -P(O)N(H or C1-C6alkyl)2, -P(O)N(C2-C6alkylene), -P(O)2N(H or C1-C6alkyl)2, -P(O)2N(C2-C6alkylene), -P(O)O(H or C1-C6alkyl), -P(O)2O(H or C1-C6alkyl), -CN, or -NO2.

[0190] In certain embodiments, R9is deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb,-NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0191] In certain embodiments, R9is halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0192] In certain embodiments, R9is halogen, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2.

[0193] In certain embodiments, R9is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In certain embodiments, R9is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0194] In certain embodiments, each of R8and R9is H. In other embodiments, R8is H and R9is not H. For example, in some embodiments, R8is H and R9is as described herein and may be deuterium, optionally substituted C1-C6alkyl (e.g., methyl or -CD3) or optionally substituted alkoxy (i.e., -O-C1-C6alkyl) (e.g., methoxy).

[0195] In some embodiments, R8is H, R9is as described herein and may be deuterium, optionally substituted C1-C6alkyl (e.g., methyl or -CD3) or optionally substituted alkoxy (e.g., -O-C1-C6alkyl such as methoxy), m is 2, and one R1is optionally substituted C1-C6alkyl (e.g., unsubstituted such as methyl, hydoxy substituted such as -CH(CH3)(CH2OH) or ethanol, or heterocyloalkyl substituted such as -ethylene-pyrrolidinyl), and the other R1is either optionally substituted C1-C6alkyl (e.g., ethyl, optionally substituted -N(H or C1-C6alkyl)-C1-C6alkyl) or optionally substituted -O-C1-C6alkyl (e.g., ethoxy or -O-CH2CN).

[0196] In some embodiments, R8is H, R9is optionally substituted C1-C6alkyl (e.g., methyl or -CD3) or optionally substituted alkoxy (e.g., -O-C1-C6alkyl such as methoxy), m is 2, and one R1is optionally substituted C1-C6alkyl (e.g., unsubstituted such as methyl, hydoxy substituted such as -CH(CH3)(CH2OH) or ethanol, or heterocyloalkyl substituted such as -ethylene- pyrrolidinyl), and the other R1is either optionally substituted C1-C6alkyl (e.g., ethyl, optionally substituted -N(H or C1-C6alkyl)-C1-C6alkyl) or optionally substituted -O-C1-C6alkyl (e.g., ethoxy or -O-CH2CN), n is 2, and each R2is optionally substituted C1-C6alkyl (e.g., unsubstituted such as methyl, hydoxy substituted such as -CH(CH3)(CH2OH), or ethanol).

[0197] In some embodiments, each of ring A and ring B are a pyrazole, and both of 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 some embodiments, each of ring A and ring B are a pyrazole, m is 1 or 2, and n is 2. In some embodiments, each of ring A and ring B are a pyrazole, m is 1, and n is 2. In some embodiments, each of ring A and ring B are a pyrazole, m is 2 and n is 2.

[0198] In some embodiments, p is 2 or 3, q is 1 or 2, and R7is as described herein except is not H. For example, in some embodiments, p is 2 or 3, q is 1 or 2, and R7is C1-C6alkyl (e.g., methyl, ethyl, or isopropyl) or C3-C6cycloalkyl (e.g., cyclopropyl).

[0199] In some embodiments, each of ring A and ring B are a pyrazole, each of m and n are independently 1, 2, or 3; R8is H; and R9is halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; p is 2 or 3, q is 1 or 2, and R7is C1-C6alkyl (e.g., methyl, ethyl, or isopropyl) or C3-C6cycloalkyl (e.g., cyclopropyl).

[0200] In some embodiments, each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, and C1-C6alkyl.

[0201] In some embodiments, the disclosure provides a compound of the formula (I)-(IV) selected from the group consisting of 2-[(10R,17E)-16-ethoxy-6,8,10-trimethyl-12-(propan-2- yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0202] 2-[(11S,17E)-16-ethoxy-6,8,11-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0203] 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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0204] 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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0205] 2-[(10S,17E)-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0206] 2-[(10R,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0207] 2-[(11S,17E)-16-ethoxy-12-ethyl-8,11-dimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0208] 2-[(10S,17E)-16-ethoxy-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0209] 2-[(10S,17E)-12-ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0210] 2-[(10R,17E)-12-ethyl-8,10-dimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0211] 2-[(10S,17E)-16-ethoxy-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0212] 2-[(10R,17E)-16-ethoxy-8,10-dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0213] 2-[(10S,17E)-12-ethyl-6,8,10,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0214] 2-[(10R,17E)-12-ethyl-6,8,10,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0215] 2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol;

[0216] 2-[(11S,17E)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol;

[0217] 2-[(10R,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol;

[0218] 2-[(11R,17E)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol;

[0219] (2S)-2-[(10S,17E)-16-ethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0220] 2-[(10R,17E)-6,8,10,16-tetramethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0221] 2-[(10S,17E)-6,8,10,16-tetramethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0222] {[(10S,17E)-14-(2-hydroxyethyl)-6,8,10,12-tetramethyl-2,10,11,12,13,14-hexahydro- 8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16- yl]oxy}acetonitrile;

[0223] {[(10S,17E)-12-ethyl-14-(2-hydroxyethyl)-6,8,10-trimethyl-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0224] (2S)-2-[(10R,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0225] (2S)-2-[(11S,17E)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0226] (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0227] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan- 1-ol;

[0228] 2-[(10S,17E)-12-cyclopropyl-16-ethoxy-8,10-dimethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0229] {[(11S,17E)-14-(2-hydroxyethyl)-6,8,11,12-tetramethyl-2,10,11,12,13,14-hexahydro- 8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16- yl]oxy}acetonitrile;

[0230] 2-[(8aR,9S,19E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin- 3(4H)-yl]ethan-1-ol;

[0231] 2-[(8aR,9R,19E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin- 3(4H)-yl]ethan-1-ol;

[0232] 2-[(10S,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0233] (2S)-2-[(10R,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan- 1-ol;

[0234] {[(10R,17E)-12-ethyl-14-(2-hydroxyethyl)-6,8,10-trimethyl-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0235] 2-[(8aR,19E)-1-ethoxy-11,13-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin- 3(4H)-yl]ethan-1-ol;

[0236] 2-[(10S,17E)-6,8,10,12,16-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0237] {[(10R,17E)-14-(2-hydroxyethyl)-6,8,10,12-tetramethyl-2,10,11,12,13,14-hexahydro- 8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16- yl]oxy}acetonitrile;

[0238] {[(8aR,19E)-3-(2-hydroxyethyl)-11,13-dimethyl-3,4,7,8,8a,9,11,17-octahydro-6H- 14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1- c][1,4]oxazacyclopentadecin-1-yl]oxy}acetonitrile;

[0239] 2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0240] (2S)-2-[(10S,17E)-6,8,10,12,16-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0241] (10S,17E)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,12-tetramethyl-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine-16-carbonitrile;

[0242] {[(11R,17E)-14-(2-hydroxyethyl)-6,8,11,12-tetramethyl-2,10,11,12,13,14-hexahydro- 8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16- yl]oxy}acetonitrile;

[0243] {[(8aR,19E)-3-(2-hydroxyethyl)-9,11,13-trimethyl-3,4,7,8,8a,9,11,17-octahydro-6H- 14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1- c][1,4]oxazacyclopentadecin-1-yl]oxy}acetonitrile;

[0244] {[(10S,17E)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,12-tetramethyl-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0245] 2-[(10R,17E)-12,16-diethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0246] (2S)-2-[(8aR,9S,19E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9,11,17-hexahydro-6H- 14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1- c][1,4]oxazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0247] {[(10R,17E)-12-ethyl-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10-trimethyl- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0248] (2S)-2-[(17E)-16-ethoxy-6,8,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0249] 2-[(10S,17E)-16-ethyl-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0250] (2S)-2-[(10S,17E)-16-ethyl-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan- 1-ol;

[0251] 2-[(10S,17E)-12,16-diethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0252] {[(8aR,19E)-3-[(2S)-1-hydroxypropan-2-yl]-11,13-dimethyl-3,4,7,8,8a,9,11,17- octahydro-6H-14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1- c][1,4]oxazacyclopentadecin-1-yl]oxy}acetonitrile;

[0253] (2S)-2-[(8aR,19E)-1-ethoxy-11,13-dimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin- 3(4H)-yl]propan-1-ol;

[0254] {[(17E)-12-ethyl-14-[(2S)-1-hydroxypropan-2-yl]-6,8-dimethyl-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0255] {[(10S,17E)-12-ethyl-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10-trimethyl- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0256] 2-[(17E)-16-ethoxy-6,8,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

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

[0258] {[(17E)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,12-trimethyl-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0259] (17E)-8,15,16-trimethyl-2,10,11,12,13,15-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine;

[0260] (17E)-8,12,15,16-tetramethyl-2,10,11,12,13,15-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine;

[0261] 2-[(10S,17E)-16-ethoxy-6,12-diethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol;

[0262] (2S)-2-[(10S,17E)-16-ethoxy-6-ethynyl-8,10,12-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0263] 2-[(10S,17E)-16-ethoxy-6-ethynyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0264] (2S)-2-[(10S,17E)-16-ethoxy-6-ethyl-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0265] (2S)-1-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan- 2-ol;

[0266] (2S)-2-[(10S,17E)-16-[(2H5)ethyloxy]-6,8,10,12-tetramethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0267] (2R)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan- 1-ol;

[0268] (2R)-2-[(10R,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan- 1-ol;

[0269] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0270] (2S)-2-[(10S,17E)-16-(ethylamino)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0271] (2S)-2-[(11R,17E)-16-ethoxy-6,8,11,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan- 1-ol;

[0272] 2-[(17E)-16-ethoxy-6,12-dimethyl-2,6,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:3'',4''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0273] (2S)-2-[(10S,17E)-16-[ethyl(methyl)amino]-6,8,10,12-tetramethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0274] (2S)-1-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0275] (2S)-2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0276] (2S)-2-[(11R,17E)-12-cyclopropyl-16-ethoxy-6,8,11-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0277] 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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-12-yl]ethan-1-one;

[0278] 2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0279] 2-[(11R,17E)-12-cyclopropyl-16-ethoxy-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0280] 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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-12-yl]prop-2-en-1-one;

[0281] (10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-14-[(2S)-1-(pyrrolidin-1-yl)propan-2-yl]- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine;

[0282] (10S,17E)-14-[(2S)-1-(azetidin-1-yl)propan-2-yl]-16-ethoxy-6,8,10,12-tetramethyl- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine;

[0283] (10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-14-[(2S)-1-(morpholin-4-yl)propan-2-yl]- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine;

[0284] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]-N- methylpropan-1-amine;

[0285] (2S)-2-[(10S,17E)-6,16-diethoxy-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan- 1-ol;

[0286] (10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-14-[(2S)-1-(piperidin-1-yl)propan-2-yl]- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine;

[0287] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]-N,N- dimethylpropan-1-amine;

[0288] (3S)-1-{(2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propyl}pyrrolidin-3-ol;

[0289] (3R)-1-{(2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propyl}pyrrolidin-3-ol;

[0290] 1-{[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]methyl}cyclopropan-1-ol;

[0291] (2S)-2-[(10S,17E)-16-ethoxy-6-(methoxymethyl)-8,10,12-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; and

[0292] (10S,17E)-6,8,10,12,15,16-hexamethyl-2,10,11,12,13,15-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine;

[0293] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0294] In some embodiments, the disclosure provides a compound of the formula (I)-(IV) selected from the group consisting of 2-[(10S,17E)-16-ethoxy-12-ethyl-8,10,20-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0295] 2-[(10S,17E)-16-ethoxy-8,10,12,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-30n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol;

[0296] 2-[(10R,17E)-16-ethoxy-12-ethyl-8,10,20-trimethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol;

[0297] 2-[(10R,17E)-16-ethoxy-8,10,12,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0298] 2-[(10S,17E)-8,10,12,20-tetramethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0299] (2S)-2-[(10S,17E)-16-ethoxy-8,10,12,20-tetramethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0300] 2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol;

[0301] 2-[(10S,17E)-8,10,12,16,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0302] {[(10S,17E)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,12,20-pentamethyl- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0303] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0304] (2S)-2-[(10S,17E)-6,8,10,12,16,20-hexamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0305] {[(10S,17E)-14-(2-hydroxyethyl)-6,8,10,12,20-pentamethyl-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0306] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl(20-2H)-10,11,12,13-tetrahydro- 8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14(2H)- yl]propan-1-ol;

[0307] 2-[(17E)-16-ethoxy-6,8,12,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0308] 2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-20-(2H3)methyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0309] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-20-(2H3)methyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0310] (2S)-2-[(10S,17E)-16-[(2H5)ethyloxy]-6,8,10,12,20-pentamethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0311] 2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl(20-2H)-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0312] 2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl(20-2H)-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0313] (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl(20-2H)-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0314] (2S)-1-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol;

[0315] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan- 1-ol;

[0316] (2S)-2-[(10S,17E)-16-(ethylamino)-6,8,10,12,20-pentamethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0317] (2R)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0318] (2S)-2-[(10S,17E)-16-ethoxy-20-methoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0319] (2S)-2-[(10R,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0320] (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-20-ol;

[0321] (2R)-2-[(10R,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0322] (2S)-2-[(10S,17E)-6,8,10,12,20-pentamethyl-16-(methylamino)-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0323] (2S)-2-[(10S,17E)-16-[ethyl(methyl)amino]-6,8,10,12,20-pentamethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0324] (10S,17E)-6,8,10,12,14,16,20-heptamethyl-2,10,11,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine;

[0325] (10S,17E)-6,8,10,14,16,20-hexamethyl-12-(propan-2-yl)-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine;

[0326] (11R,17E)-6,8,11,14,16,20-hexamethyl-12-(propan-2-yl)-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine;

[0327] 2-[(10S,17E)-6,8,10,16,20-pentamethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0328] (10S,17E)-6,8,10,12,16,20-hexamethyl-14-[2-(pyrrolidin-1-yl)ethyl]- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine;

[0329] (10S,17E)-6,8,10,12,16,20-hexamethyl-15-[2-(pyrrolidin-1-yl)ethyl]- 2,10,11,12,13,15-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine;

[0330] (2S)-2-[(10S,17E)-12-cyclopropyl-6,8,10,20-tetramethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0331] (2S)-2-[(11R,17E)-12-cyclopropyl-6,8,11,20-tetramethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0332] 1-[(10S,17E)-16-ethoxy-6,8,10,14,20-pentamethyl-2,8,10,11,13,14-hexahydro-12H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-12-yl]ethan-1- one;

[0333] (2S)-2-[(10R,11R,17E)-16-ethoxy-6,8,10,11,12,20-hexamethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0334] (2S)-2-[(10S,11R,17E)-16-ethoxy-6,8,10,11,12,20-hexamethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0335] 2-[(10S,17E)-12-cyclopropyl-6,8,10,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol;

[0336] 2-[(11R,17E)-12-cyclopropyl-6,8,11,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol;

[0337] 1-[(10S,17E)-16-ethoxy-6,8,10,14,20-pentamethyl-2,8,10,11,13,14-hexahydro-12H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-12-yl]propan- 1-one;

[0338] cyclopropyl[(10S,17E)-16-ethoxy-6,8,10,14,20-pentamethyl-2,8,10,11,13,14- hexahydro-12H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-12-yl]methanone;

[0339] 1-[(10S,17E)-16-ethoxy-6,8,10,14,20-pentamethyl-2,8,10,11,13,14-hexahydro-12H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-12-yl]-2- methylpropan-1-one;

[0340] 1-[(10S,17E)-6-[(cyclopropyloxy)methyl]-8,10,14,20-tetramethyl-2,8,10,11,13,14- hexahydro-12H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-12-yl]-2-(dimethylamino)ethan-1-one;

[0341] (2S)-2-[(10S,17E)-12-cyclopropyl-6-(methoxymethyl)-8,10,20-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0342] (2S)-2-[(11R,17E)-12-cyclopropyl-6-(methoxymethyl)-8,11,20-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0343] 2-(dimethylamino)-1-[(10S,17E)-6-(methoxymethyl)-8,10,14,20-tetramethyl- 2,8,10,11,13,14-hexahydro-12H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-12-yl]ethan-1-one;

[0344] (17E)-6,8,12,15,16,20-hexamethyl-2,10,11,12,13,15-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine;

[0345] 3-(dimethylamino)-1-[(10S,17E)-6-(methoxymethyl)-8,10,14,20-tetramethyl- 2,8,10,11,13,14-hexahydro-12H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-12-yl]propan-1-one;

[0346] (17E)-6,8,12,14,16,20-hexamethyl-2,10,11,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine;

[0347] (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10,20-tetramethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0348] (17E)-6,8,12,14,20-pentamethyl-2,10,11,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine;

[0349] (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-6-(methoxymethyl)-8,10,20-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0350] {[(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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0351] (2S)-2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10,20-tetramethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0352] (17E)-6,8,12,14,20-pentamethyl-2,10,11,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-16-carbonitrile;

[0353] {[(10S,17E)-12-(2,2-difluoroethyl)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,20- tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0354] {[(10S,17E)-12-cyclopropyl-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,20-tetramethyl- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0355] {[(11R,17E)-12-cyclopropyl-14-[(2S)-1-hydroxypropan-2-yl]-6,8,11,20-tetramethyl- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0356] (2S)-2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6-(methoxymethyl)-8,10,20-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0357] (2S)-2-[(11R,17E)-12-cyclopropyl-16-ethoxy-6-(methoxymethyl)-8,11,20-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0358] {[(11R,17E)-12-(2,2-difluoroethyl)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,11,20- tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0359] (2S)-2-[(10S,17E)-16-ethoxy-6-(methoxymethyl)-8,10,12,20-tetramethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0360] {[(10S,17E)-12-(2-fluoroethyl)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,20- tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0361] {[(11R,17E)-12-(2-fluoroethyl)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,11,20- tetramethyl-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0362] {[(17E)-6,8,12,14,20-pentamethyl-2,10,11,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16- yl]oxy}acetonitrile;

[0363] {[(10S,17E)-6,8,10,12,14,20-hexamethyl-2,10,11,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16- yl]oxy}acetonitrile;

[0364] (2S)-2-[(10S,17E)-16-ethoxy-6-(hydroxymethyl)-8,10,12,20-tetramethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0365] (2S)-1-[(10S,17E)-6,8,10,12,16,20-hexamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0366] (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0367] (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0368] {[(10R,17E)-10-(difluoromethyl)-6,8,12,14,20-pentamethyl-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0369] {[(10S,17E)-10-(difluoromethyl)-6,8,12,14,20-pentamethyl-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile;

[0370] (10S,17E)-6,8,10,12,15,16,20-heptamethyl-2,10,11,12,13,15-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine;

[0371] 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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0372] 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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0373] (2S)-2-[(4aS,7aS,13E)-12-ethoxy-1,3,8,21-tetramethyl-3,4a,5,7,7a,8,9,16-octahydro- 10H-19,17-(azenometheno)furo[3,4-b]tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-10-yl]propan-1-ol;

[0374] (2S)-2-[(4aR,7aR,13E)-12-ethoxy-1,3,8,21-tetramethyl-3,4a,5,7,7a,8,9,16-octahydro- 10H-19,17-(azenometheno)furo[3,4-b]tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-10-yl]propan-1-ol;

[0375] 2-[(10R,11R,17E)-16-ethoxy-6-(methoxymethyl)-8,10,11,12,20-pentamethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0376] 2-[(10S,11R,17E)-16-ethoxy-6-(methoxymethyl)-8,10,11,12,20-pentamethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0377] (10S,17E)-6-(methoxymethyl)-8,10,12,14,16,20-hexamethyl-2,10,11,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine;

[0378] 2-[(8aR,9S,19E)-1-ethoxy-9,11,13,21-tetramethyl-7,8,8a,9,11,17-hexahydro-6H- 14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1- c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0379] 2-[(8aR,9R,19E)-1-ethoxy-9,11,13,21-tetramethyl-7,8,8a,9,11,17-hexahydro-6H- 14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1- c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol;

[0380] (2S)-2-[(8aR,9S,19E)-1-ethoxy-9,11,13,21-tetramethyl-7,8,8a,9,11,17-hexahydro-6H- 14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1- c][1,4]oxazacyclopentadecin-3(4H)-yl]propan-1-ol;

[0381] (2S)-2-[(8aR,9R,19E)-1-ethoxy-9,11,13,21-tetramethyl-7,8,8a,9,11,17-hexahydro-6H- 14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1- c][1,4]oxazacyclopentadecin-3(4H)-yl]propan-1-ol; and

[0382] (2S)-1-[(10S,17E)-6,8,10,12,16,20-hexamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0383] or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

[0384] The following represent illustrative embodiments of compounds of Formula (I)-(IV):

[0385] and pharmaceutically acceptable salts, solvates, hydrates, or cocrystals thereof.

[0386] Those skilled in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected. ALTERNATIVE EMBODIMENTS

[0387] In some embodiments, the disclosure provides compounds or methods according to the following embodiments.

[0388] 1. A compound of the formula II

[0389] wherein

[0390] ring A and ring B are each independently a 5-membered heteroarylene;

[0391] each R1and R2, when present, is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2;

[0392] each R3, R4, R5, and R6is independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb,-NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or two of R3, R4, R5, and R6, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C3-C6cycloalkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0393] R7is H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7- membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; or R7and one of R3, R4, R5, or R6, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0394] R8is H, -S(O)2Rc, -S(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd,-P(O)2RcRd, -P(O)2NRcRd, or -P(O)2ORc;

[0395] R9is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C-(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2;

[0396] each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, and C1-C6alkylene-5- to 10-membered heteroaryl; or Raand Rbor Rcand Rdor Reand Rf, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, or C1-C6alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OC1-C6alkyl, -OC(O)- (H or C1-C6alkyl), -OC(O)N(H or C1-C6alkyl)2, -OC(O)N(C2-C6alkylene), -OS(O)-(H or C1-C6alkyl), -OS(O)2-(H or C1-C6alkyl), -OS(O)N(H or C1-C6alkyl)2, -OS(O)N(C2-C6alkylene), -OS(O)2N(H or C1-C6alkyl)2, -OS(O)2N(C2-C6alkylene), -S(H or C1-C6alkyl), -S(O)(H or C1-C6alkyl), -S(O)2(H or C1-C6alkyl), -S(O)N(H or C1-C6alkyl)2, -S(O)N(C2-C6alkylene), -S(O)2N(H or C1-C6alkyl)2, -S(O)2N(C2-C6alkylene), -N(H or C1-C6alkyl)2, -N(C2-C6alkylene), -N(H or C1-C6alkyl)C(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)O(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)C(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)2(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)2N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)2N(C2-C6alkylene), -C(O)-(H or C1-C6alkyl), -C(O)O(H or C1-C6alkyl), -C(O)N(C2-C6alkylene), -P(H or C1-C6alkyl)2, -P(C2-C6alkylene), -P(O)(H or C1-C6alkyl)2, -P(O)(C2-C6alkylene), -P(O)2(H or C1-C6alkyl)2, -P(O)2(C2-C6alkylene), -P(O)N(H or C1-C6alkyl)2, -P(O)N(C2-C6alkylene), -P(O)2N(H or C1-C6alkyl)2, -P(O)2N(C2-C6alkylene), -P(O)O(H or C1-C6alkyl), -P(O)2O(H or C1-C6alkyl), -CN, or -NO2;

[0397] m is 0, 1, 2, or 3;

[0398] n is 0, 1, 2, or 3;

[0399] p is 1, 2, 3, or 4; and

[0400] q is 1, 2, or 3;

[0401] or a pharmaceutically acceptable salt thereof.

[0402] 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, having the formula II

[0403] wherein each “ ” is independently a carbon-carbon single bond or a carbon- carbon double bond.

[0404] 3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, having the formula IIIIII

[0405] wherein

[0406] wherein each “ ” is independently a carbon-carbon single bond or a carbon- carbon double bond;

[0407] X1, X2, and X3are each independently -O-, -S-, =C(H)-, =C(R1)-, -N(H)-, -N(R1)- or =N- and ring A is a 5-membered heteroarylene, provided that at least one of X1, X2, and X3is not =C(H)-, or =C(R1)-; and / or

[0408] Y1, Y2, and Y3are each independently -O-, -S-, =C(H)-, =C(R2)-, -N(H)-, -N(R2)- or =N- and ring B is a 5-membered heteroarylene, provided that at least one of Y1, Y2, and Y3is not =C(H)-, or =C(R2)-.

[0409] 4. The compound of embodiment 3, having the formula IVIV

[0410] or a pharmaceutically acceptable salt thereof.

[0411] 5. The compound of embodiment 3 or 4, wherein

[0412] X2is =N- or -N(R1)-, X1and X3are each independently -O-, -S-, =C(H)-, =C(R1)-, -N(H)-, or -N(R1)-, and ring A is a 5-membered heteroarylene; and / or

[0413] Y2is =N-, Y1and Y3are each independently -O-, -S-, =C(H)-, =C(R2)-, -N(H)-, or -N(R2)-, and ring B is a 5-membered heteroarylene.

[0414] 6. The compound of any one of embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

[0415] ring A is selected from the group consisting of

[0416] wherein each “” represents a point of covalent attachment.

[0417] 7. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of,

[0418] wherein each “ ” represents a point of covalent attachment.

[0419] 8. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of

[0420] wherein each “ ” represents a point of covalent attachment.

[0421] 9. The compound of any one of embodiments 1 to 4 or 6, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of,

[0422] wherein each “” represents a point of covalent attachment.

[0423] 10. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of

[0424] wherein each “” represents a point of covalent attachment.

[0425] 11. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein p is 2 or 3, and the portion

[0426] is an ethylene or propylene, wherein each R3and R4is independently H, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or at least one instance of R3and R4, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C3-C6cycloalkyl or 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or R7and one instance of R3or R4, taken together with the atomsto which they are attached, combine to form 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 7-membered heterocycloalkyl formed is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and each “” represents a point of covalent attachment.

[0427] 12. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein one R3is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and / or two R3and R4, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6cycloalkyl or 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and / or R7and one instance of R3or R4and, taken together with the atoms to which they are attached, combine to form a 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and any remaining R3and R4are H or deuterium.

[0428] 13. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein one R3is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and / or R7and one instance of R3or R4taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and any remaining R3and R4are H or deuterium.

[0429] 14. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein one instance of R3is C1-C6alkyl; and any remaining R3and R4are H or deuterium.

[0430] 15. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein one instance of R3is C1-C6alkyl; R7and one instance of R4, taken together with the atoms to which they are attached, combine to form a 4- to 7-membered heterocycloalkyl; and any remaining R3and R4are H or deuterium.

[0431] 16. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein one instance of R3is methyl, and any remaining R3and R4are H or deuterium.

[0432] 17. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R7is H, C1-C6alkyl, or C3-C6cycloalkyl; or R7and one instance of R3or R4, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl.

[0433] 18. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the portion [

[0435] is of the formularepresents a point of covalent attachment, and each hydrogen is independently optionally substituted with deuterium.

[0436] 19. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R5and R6are each H.

[0437] 20. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the portion [ [ ,attachment, and each hydrogen is independently optionally substituted with deuterium.

[0440] 21. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R8is H or C1-C6alkyl.

[0441] 22. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R9is H, deuterium, halogen, C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted with deuterium.

[0442] 23. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R9is H, deuterium, halogen, -CH3, or -CD3.

[0443] 24. The compound of embodiment 1, selected from the group consisting of,

[0444] or a pharmaceutically acceptable salt thereof.

[0445] 25. A pharmaceutical composition comprising a compound of any one of the preceding embodiments, and optionally one or more excipients.

[0446] 26. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of embodiments 1 to 24, or a pharmaceutical composition of embodiment 25.

[0447] 27. A compound according to any one of embodiments 1 to 24, for use in a method of treating disease in a subject.

[0448] 28. Use of a compound according to any one of embodiments 1 to 24, in the manufacture of a medicament for the treatment of disease in a subject. PHARMACEUTICAL COMPOSITIONS

[0449] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents,anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the disclosure are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.

[0450] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.

[0451] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the disclosure may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0452] For oral administration, the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0453] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0454] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0455] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg / kg / minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0456] For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier. The inventive compositions may be formulated for rectal administration as a suppository.

[0457] For topical applications, the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery.

[0458] As used herein, the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorderor disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.

[0459] The term “subject” refers to a mammalian patient in need of such treatment, such as a human.

[0460] Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation. As used herein, the term “cancer” includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER+breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, skin cutaneous melanoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial cancer. In some embodiments, cancer includes, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma. Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I 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, allergy, and inflammation from infection or injury.

[0461] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target tyrosine receptor kinases, in particular EGFR, including EGFR having one or more mutations, such as L858R, Δ746-750, Δ746-750 / C979S, L858R / T790M, L858R / T790M / C979S, and D770_N771insNPG . Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more of these kinases. In preferred embodiments, methods of treating a target cancer are described. In other embodiments, methods are for treating lung cancer, such as non-small cell lung cancer.

[0462] In the inhibitory methods of the disclosure, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to upregulation of EGFR, including a cancer cell having one or more EGFR mutations, such as L858R, Δ746-750, Δ746-750 / C979S, L858R / T790M, L858R / T790M / C979S, and D770_N771insNPG, while maintaining good selectivity over wild-type EGFR.

[0463] In treatment methods according to the disclosure, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).

[0464] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis. DRUG COMBINATIONS

[0465] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separatepharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure.

[0466] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the disclosure, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. For cancer indications, additional such agents include, but are not limited to, kinase inhibitors, such as ALK inhibitors (e.g., crizotinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatories such as NSAIDs. The pharmaceutical compositions of the disclosure may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents. CHEMICAL SYNTHESIS METHODS

[0467] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I)-(IV).

[0468] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:

[0469] The proposed targets can be prepared via the conventional chemistry or following thegeneral schemes as shown below.

[0470] The following starting materials and intermediates can be obtained from commercial sources or using known literature procedures: (2S)-2-methyloxirane, (2R)-2-methyloxirane, propan-2-amine, iodoethane, 2-bromoethoxy-tert-butyl-dimethyl-silane, (2R)-1- (isopropylamino) propan-2-ol, 5-bromo-1H-pyrazolo[3,4-c]pyridine, 2,5-dimethylpyrazol-3- ol, 2,4-dimethylpyridin-3-amine, 2,6-dimethylpyridine, 2-methylpyrazol-3-ol, methyl 3- methyl-1H-pyrazole-5-carboxylate (a.k.a. methyl 5-methyl-1H-pyrazole-3-carboxylate), 2- [tert-butyl(dimethyl)silyl]oxyethanol, (2R)-1-(ethylamino)propan-2-ol, (2S)-2-aminopropan- 1-ol, (2R)-2-aminopropan-1-ol, (2R)-propane-1,2-diol, (2S)-propane-1,2-diol, (2R)-1- (isopropylamino)propan-2-ol, (2S)-1-(isopropylamino)propan-2-ol, (2R)-1-tert- butoxycarbonylpyrrolidine-2-carboxylic acid, N-methoxymethanamine, 2- (methylamino)ethanol, ethanamine, 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)-pyrrolidin-2-yl]methanol, ethyl 2,4- dioxohexanoate, (R)-1-(ethylamino)propan-2-ol, 1,3-dimethylpyrazol-4-ol, [(1R)-2-(tert- butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate, ethynyl(triisopropyl)silane, cyclopropanamine, ethyl 2,4-dioxopentanoate, 5-(bromomethyl)-4-iodo-1,3-dimethyl- pyrazole, (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-methylpyrazol-4-ol, tert-butyl N-(2-hydroxyethyl)-N-methyl- carbamate, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, ethyl 5-methyl-1H- pyrazole-3-carboxylate, methyl 5-hydroxy-2-methyl-pyrazole-3-carboxylate, 1-iodoethane- 1,1,2,2,2-d5, 2-chloro-4-methyl-pyridin-3-amine, 2,2,2-trifluoro-N-[(2R)-2-hydroxypropyl]- N-methyl-acetamide, ethyl 2,5-dimethylpyrazole-3-carboxylate, ethyl 3,3-diethoxyprop-2- enoate, 2,2,2-trifluoro-N-[(2R)-2-hydroxypropyl]-N-methyl-acetamide, methyl 4-methoxy-3- oxo-butanoate, ethyl 1-hydroxycyclopropanecarboxylate, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- 1,3,2-dioxaborolane, 1-methyl-1H-pyrazol-5-ol, tert-butyl (2-bromoethyl)carbamate, tert- butyl (R)-(1-oxopropan-2-yl)carbamate, 1,3-dimethyl-1H-pyrazol-5-ol, tert-butyl (R)-(2- hydroxypropyl)carbamate, propanoyl chloride, cyclopropanecarbonyl chloride, cyclopropanol, ethyl 4-chloro-3-oxo-butanoate, 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.

[0471] General Method A: using Ex.1 as example.

[0472] 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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.1)

[0473] Step 1. A solution of commercially available (2R)-2-methyloxirane (5.00 g, 86.0 mmol, 1 eq) and commercially available propan-2-amine (15.2 g, 258 mmol, 3 eq) in MeOH (80 mL) was stirred at 25 °C for 14 hours. On completion, the mixture was concentrated to give (2R)- 1-(isopropylamino) propan-2-ol (8.60 g, 73.3 mmol, 85% yield) as a yellow oil.1H 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).

[0474] Step 2. To a solution of commercially available methyl 3-hydroxy-1H-pyrazole-5- carboxylate (15 g, 105.55 mmol, 1 eq), iodoethane (16.46 g, 105.55 mmol, 8.44 mL, 1 eq) in DMF (150 mL) was added K2CO3 (43.76 g, 316.65 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hr. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with water (200 mL× 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 give methyl 3-ethoxy-1H-pyrazole-5-carboxylate (10.4 g, 61.12 mmol, 58% yield) as a white solid. LCMS: (M+1:171.1)

[0475] Step 3. To a solution of methyl 3-ethoxy-1H-pyrazole-5-carboxylate (10 g, 58.77 mmol, 1 eq) and commercially available 2-bromoethoxy-tert-butyl-dimethyl-silane (21.09 g, 88.15 mmol, 1.5 eq) in DMF (100 mL) was added NaI (8.81 g, 58.77 mmol, 1 eq), K2CO3(24.37 g, 176.30 mmol, 3 eq), and the mixture was stirred at 60 °C for 16 hr. On completion, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with water (80 mL × 2),dried over Na2SO4, filtered, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:0 to 17:83) to give 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).

[0476] Step 4. To a solution of methyl 2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy- pyrazole-3-carboxylate (12 g, 36.53 mmol, 1 eq) in THF (120 mL) was added LiAlH4(1.39 g, 36.53 mmol, 1 eq) at 0 °C. The mixture was stirred at 0 °C for 2 hr. On completion, the mixture was quenched with MeOH (150 mL) at 0 °C, and the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 3:1) to give (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-1H-pyrazol-5- yl)methanol (12.7 g, 38.66 mmol, 66% yield) as a yellow liquid. LCMS: (M+1:301.1)

[0477] Step 5. To a solution of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-pyrazol-3- yl]methanol (7 g, 23.30 mmol, 1 eq) in ACN (70 mL) was added NIS (4.72 g, 20.97 mmol, 0.9 eq) at 0 °C, and the mixture was stirred at 25 °C for 2 hr . On completion, the mixture was quenched with sat. Na2SO3(200 mL) at 0oC and extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:0 to 80:20) to give (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)- 3-ethoxy-4-iodo-1H-pyrazol-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).

[0478] Step 6. To a solution of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo- pyrazol-3-yl]methanol (3.5 g, 8.21 mmol, 1 eq) and PPh3(2.58 g, 9.85 mmol, 1.2 eq) in DCM (35 mL) was added CBr4 (3.27 g, 9.85 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr . On completion, the mixture was diluted with water (50 mL) and extracted with DCM (30 mL × 3). The combined organic phase was dried over Na2SO4, filtered, and the filtrate wasconcentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:0 to 80:20) to give 5-(bromomethyl)-1-(2-((tert- butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazole (2.9 g, 5.93 mmol, 72% yield) (a.k.a. 2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1-yl]ethoxy-tert-butyl-dimethyl-silane) as a yellow oil. LCMS: (M+1:490.8).

[0479] Step 7. To a solution of (2R)-1-(isopropylamino) propan-2-ol (4.00 g, 34.1 mmol, 1.5 eq) in ACN (260 mL) was added K2CO3 (6.29 g, 45.5 mmol, 2 eq) and 5-(bromomethyl)-1-(2- ((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazole (11.1 g, 22.8 mmol, 1 eq). The mixture was stirred at 50 °C for 12 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THE=1:0 to 5:1) to give (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-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).

[0480] Step 8. To a solution of (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl-isopropyl-amino]propan-2-ol (11.9 g, 22.6 mmol, 1 eq) in DCM (120 mL) was added TEA (11.5 g, 113 mmol, 5 eq) and MsCl (7.82 g, 68.3 mmol, 3.02 eq). The mixture was stirred at 0 °C for 30 min. On completion, the mixture was quenched with dilute citric acid (120 mL) and extracted with DCM (60 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give [(1R)-2-[[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl-isopropyl-amino]-1- methyl-ethyl] methanesulfonate (12.7 g, 21.1 mmol, 93% yield) as a white oil.

[0481] Step 9. To a solution of commercially available 5-bromo-1H-pyrazolo[3,4-c]pyridine (23.0 g, 116 mmol, 1 eq), t-BuOK (26.0 g, 232 mmol, 2 eq) in THF (300 mL) was added a solution of I2 (32.4 g, 127 mmol, 1.1 eq) in THF (100 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 3 hrs. On completion, the mixture was quenched with sat. NaHSO3(100 mL), diluted with H2O (300 mL), and extracted with ethyl acetate (3 × 300 mL). The organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine (37.5 g, 115 mmol, 99.67% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.80 (s, 1H), 7.55 (s, 1H). LCMS: (M+1: 323.6).

[0482] Step 10. To a solution of 5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine (25.0 g, 77.1 mmol, 1 eq) in toluene (250 mL) was added TsOH (2.66 g, 15.4 mmol, 0.2 eq) and 3,4-dihydro- 2H-pyran (DHP) (16.2 g, 192 mmol, 2.5 eq). The mixture was stirred at 90 °C for 2 hrs. On completion, the mixture was washed with NH4Cl solution (2 × 100 mL), washed with brine (2 × 100 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue waspurified by column chromatography (SiO2, PE / EA=100 / 8) to give 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).

[0483] 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 eq), potassium vinyltrifluoroborate(19.7 g, 147 mmol, 5 eq) in a mixed solvent system of dioxane (120 mL) and H2O (24 mL) was added Pd(dppf)Cl2(2.15 g, 2.94 mmol, 0.1 eq) and Na2CO3 (9.35 g, 88.2 mmol, 3 eq). The mixture was stirred at 40 °C for 72 hrs under N2. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA=50 / 1) to give 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.1H 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).

[0484] 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 eq.) in dioxane (210 mL) was added K2CO3 (6.28 g, 45.4 mmol, 2 eq), commercially available 2,5-dimethylpyrazol-3-ol (3.06 g, 27.3 mmol, 1.2 eq) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[3,6-dimethoxy-2- (2,4,6-triisopropylphenyl)phenyl]phosphane (tBuBrettPhos Pd G3) (1.36 g, 1.59 mmol, 0.07 eq) under N2. The mixture was stirred at 130 °C for 12 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=1:0 to 15:1) to give 2,5-dimethyl-4-(1-tetrahydropyran- 2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol (5.10 g, 15.0 mmol, 66% yield) as a brown solid. LCMS: (M+1:340.1).

[0485] Step 13. To a solution of 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol (5.70 g, 16.8 mmol, 1 eq.) and [(1R)-2-[[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl-isopropyl-amino]-1- methyl-ethyl] methanesulfonate (12.2 g, 20.2 mmol, 1.2 eq) in DMF (330 mL) was added K2CO3 (6.96 g, 50.4 mmol, 3 eq). The mixture was stirred at 60 °C for 12 h. On completion, the mixture was quenched with water (660 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=1:0 to 1:2) to give (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-yl]oxy-N-isopropyl-propan-1-amine (8.83 g, 10.4 mmol, 62% yield) as a yellow solid. LCMS: (M+1:847.7).

[0486] Step 14. To a solution of (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy- 4-iodo-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-isopropyl-propan-1-amine (8.83 g, 10.4 mmol, 1 eq) in DMF (445 mL) was added TBAC (2.90 g, 10.4 mmol, 1 eq), NaHCO3 (2.19 g, 26.1 mmol, 2.5 eq) and Pd(OAc)2(468 mg, 2.09 mmol, 0.2 eq), the mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 140 °C for 1 h under N2 atmosphere. On completion, the mixture was quenched with water (890 mL) and extracted with ethyl acetate (450 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=1:0 to 1:1) to give (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (3.30 g, 4.59 mmol, 44% yield) as a yellow solid. LCMS: (M+1:719.8).

[0487] Step 15. 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- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (3.30 g, 4.59 mmol, 1 eq) in DCM (25 mL) was added TFA (38.4 g, 337 mmol, 73.3 eq). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was concentrated to give a brown solid (2.83 g, crude). This brown solid (2.83 g, 4.59 mmol, 1 eq) was dissolved in MeOH (29 mL), and K2CO3 (6.34 g, 45.9 mmol, 10 eq) was added. The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF=1:0 to 1:3) to give 2-[(10R,17E)-16-ethoxy-6,8,10- trimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (1.15 g, 2.21 mmol, 48.13% yield) as a white solid. LCMS: (M+1: 521.3).1H NMR for Ex.1 can be found in the below NMR table.The final structure was confirmed by X-ray crystal structure determination.

[0488] Preparation of 2-[(10S,17E)-8,10,12-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.5)

[0489] Step 1. To a solution of MeNH2(41.1 g, 397 mmol, 30% purity, 20 eq) in acetone (800 mL) was added K2CO3 (8.24 g, 59.6 mmol, 3 eq) at 0°C.Then 2-[5-(bromomethyl)-4-iodo-3- isopropoxy-pyrazol-1-yl]ethoxy-tert-butyl-dimethyl-silane, which was prepared according to the method described in Ex.3 / Ex. 4, (10 g, 19.8 mmol, 1 eq) in acetone (200 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 12 hr. On completion, the mixture was quenched with water (1000 mL) and extracted with ethyl acetate (1000 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=20:1 to 15:1) to give 1-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-isopropoxy-pyrazol-3-yl]- N-methyl-methanamine (7.00 g, 15.4 mmol, 77.7% yield) as a yellow oil. LCMS: (M+1: 454.1).

[0490] Step 2. A solution of commercially available (2R)-2-methyloxirane (1.92 g, 33.0 mmol, 2.32 mL, 3 eq) and 1-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-isopropoxy-pyrazol- 3-yl]-N-methyl-methanamine (5.00 g, 11.0 mmol, 1 eq) in EtOH (125 mL) was stirred at 80 °C for 12 hr. On completion, the mixture was concentrated to give (2R)-1-[[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-isopropoxy-pyrazol-3-yl]methyl-methyl- amino]propan-2-ol (5.5 g, 10.7 mmol, 97.5% yield) as a yellow oil. LCMS: (M+1:512.2).

[0491] Step 3. To a solution of commercially available 2-methylpyrazol-3-ol (3.06 g, 31.1 mmol, 1.2 eq), 5-bromo-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine, which was prepared according to the method described in Ex.1, (8.00 g, 25.9 mmol, 1 eq) in dioxane (80 mL) was added K2CO3 (10.7 g, 77.8 mmol, 3 eq) and [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;ditert-butyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (tBuBrettPhos Pd G3) (1.77 g, 2.08 mmol, 0.08 eq). The mixture was stirred at 100 °C for 2 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=20:1 to 15:1) to give 2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-ol (4.30 g, 13.2 mmol, 51% yield) as a red solid. LCMS: (M+1:326.0).

[0492] Step 4. To a solution of 2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-ol (699 mg, 2.15 mmol, 1.1 eq), (2R)-1-[[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-isopropoxy-pyrazol-3-yl]methyl-methyl- amino]propan-2-ol from step 2 (1.00 g, 1.95 mmol, 1 eq) in THF (15 mL) was added PPh3 (1.13 g, 4.30 mmol, 2.2 eq) and DBAD (990 mg, 4.30 mmol, 2.2 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF=2:1 to 1:1) to give (2S)- N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-isopropoxy-pyrazol-3-yl]methyl]-N- methyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol- 3-yl]oxy-propan-1-amine (1.50 g, 1.83 mmol, 94% yield) as a white solid. LCMS: (M+1:819.1).

[0493] Step 5. To a solution of (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5- isopropoxy-pyrazol-3-yl]methyl]-N-methyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-propan-1-amine (1.3 g, 1.59 mmol, 1 eq), TBAC (441 mg, 1.59 mmol, 1 eq) in DMF (130 mL) was added NaHCO3 (333 mg, 3.97 mmol, 2.5 eq) and Pd(OAc)2(71.2 mg, 317 μmol, 0.2 eq). The mixture was stirred at 130 °C for 2 h under N2 atmosphere. On completion, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (250 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=1:1 to 1:1) to give (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (250 mg, 362 μmol, 23% yield) as a yellow solid. LCMS: (M+1: 691.2).

[0494] Step 6. 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- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (200 mg, 289 μmol, 1 eq) in DCM (5.00 mL) was added TFA (153 g, 1.35 mol, 4650 eq). The mixture was stirred at 25 °C for 2h. On completion, the mixture was concentrated to give Ex.5 (58.7 mg, 119 μmol, 41% yield) as a yellow solid. LCMS: (M+1:493.1).1H NMR for Ex.5 can be found in the below NMR table.

[0495] Preparation of 2-[(10R,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex. 6) and 2-[(11S,17E)-16-ethoxy-12-ethyl- 8,11-dimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.7).

[0496] Step 1. To a solution of commercially available (2R)-2-methyloxirane (5 g, 86.1 mmol, 1 eq) in MeOH (50 mL) was added commercially available ethanamine (2 M, 129 mL, 3 eq). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was concentrated to give (2R)-1-(ethylamino) propan-2-ol (7.55 g, 73.2 mmol, 85% yield) as a brown solid.1HNMR (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).

[0497] 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 Ex. 1, (1.00 g, 2.04 mmol, 1.00 eq.) and (2R)-1-(ethylamino) propan-2-ol (316 mg, 3.07 mmol, 1.50 eq.) in DMF (10 mL) was added K2CO3(847 mg, 6.13 mmol, 3.00 eq). The mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was diluted with H2O (15 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with H2O (8 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:0 to 4:1) to give (2R)-1-[[2-[2-[tert-butyl (dimethyl) silyl] oxyethyl]-5-ethoxy-4-iodo-pyrazol-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).

[0498] Step 3. To a solution of (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl] methyl-ethyl-amino] propan-2-ol (1.00 g, 1.95 mmol, 1.00 eq) and DIEA (758 mg, 5.86 mmol, 3.00 eq) in DCM (10 mL) was added methylsulfonyl methanesulfonate (511 mg, 2.93 mmol, 1.50 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was diluted with H2O (15 mL) and extracted with DCM (12 mL × 3). The combined organic layers were washed with H2O (8 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give [(1R)-2-[[2-[2-[tert-butyl (dimethyl) silyl] oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl] methyl-ethyl-amino]-1-methyl-ethyl] methanesulfonate (1.10 g, crude) as an orange oil. LCMS: (M+1: 590.3).

[0499] Step 4. To a solution of [(1R)-2-[[2-[2-[tert-butyl(dimethyl)silyl] oxyethyl]-5-ethoxy- 4-iodo-pyrazol-3-yl] methyl-ethyl-amino]-1-methyl-ethyl] methanesulfonate (1.00 g, 1.70 mmol, 1.00 eq) in NMP (20 mL) was added 2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the methods described in Ex. 5, (552 mg, 1.70 mmol, 1.00 eq) and K2CO3 (703 mg, 5.09 mmol, 3.00 eq). The mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was diluted with H2O (150 mL) and extracted with EA (120 mL × 3). The combined organic layers were washed with H2O (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:0 to 1:1) to give (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl]-N-ethyl-2-[2-methyl-4- (1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-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).

[0500] Step 5. To a solution of (2S)-N-[[2-[2-[tert-butyl(dimethyl) silyl] oxyethyl]-5-ethoxy- 4-iodo-pyrazol-3-yl]methyl]-N-ethyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo [3,4-c]pyridin-5-yl)pyrazol-3-yl] oxy-propan-1-amine (830 mg, 1.01 mmol, 1.00 eq) in DMF (8 mL) was added Pd(OAc)2 (34.1 mg, 152 μmol, 0.15 eq), TBAC (563 mg, 2.03 mmol, 2.00 eq) and KOAc (497 mg, 5.07 mmol, 5.00 eq). The mixture was stirred at 80 °C for 16 h under N2. On completion, the reaction mixture was diluted with H2O (150 mL) and extracted with EA (200 mL × 3). The combined organic layers were washed with H2O (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=1:0 to 10:1) to give 2-[(10R,17E)-16-ethoxy-12-ethyl-8,10-dimethyl-2-(oxan-2-yl)-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol (100 mg, 139 μmol, 14% yield, 80% purity) as a red oil. LCMS: (M+1-114: 577.3).

[0501] Step 6. 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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (90.0 mg, 156 μmol, 1.00 eq) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 86.3 eq). The mixture was stirred at 25 °C for 3 hr. On completion, the reaction was concentrated in vacuum to give 1-[(10R,17E)-16-ethoxy- 12-ethyl-14-(2-hydroxyethyl)-8,10-dimethyl-11,12,13,14-tetrahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-2(10H)-yl]-2,2,2- trifluoroethan-1-one (90.0 mg, crude) as an orange oil. LCMS: (M+1: 589.2).

[0502] Step 7. To a solution of 1-[(10R,17E)-16-ethoxy-12-ethyl-14-(2-hydroxyethyl)-8,10- dimethyl-11,12,13,14-tetrahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-2(10H)-yl]-2,2,2-trifluoroethan-1-one (90.0 mg, 153 μmol, 1.00 eq) in MeOH (1 mL) was added K2CO3(106 mg, 765 μmol, 5.00 eq). The mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction was concentrated in vacuum to give a residue. The residue was purified by Prep-HPLC purification (column: Phenomenex luna C18150 * 25 mm * 10 um; mobile phase:[water (FA)-ACN]; gradient:10%-40% B over 8 min) to give Ex.6 (19.18 mg, 37.26 μmol, 24% yield, 95.69% purity) as a yellow solid. LCMS: (M+1: 493.2).1H NMR for Ex.6 can be found in the below NMR table.

[0503] A byproduct was also obtained as Ex.7 (2.75 mg, 5.25 μmol, 15% yield, 94.02% purity) as a white solid. LCMS: (M+1: 493.1).1H NMR for Ex. 7 can be found in the below NMR table.

[0504] 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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.8)

[0505] Step 1. To a solution of commercially available propan-2-amine (15.3 g, 258 mmol, 3 eq) in MeOH (80 mL) was added commercially available (2S)-2-methyloxirane (5.00 g, 86.1 mmol, 1 eq). The mixture was stirred at 25°C for 24 h. On completion, the mixture was concentrated to give (2S)-1-(isopropylamino) propan-2-ol (7.14 g, 60.9 mmol, 71% yield) as a white liquid.1H 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).

[0506] Step 2. To a solution of (2S)-1-(isopropylamino) propan-2-ol (848 mg, 7.24 mmol, 1.5 eq) in ACN (33 mL) was added K2CO3 (1.33 g, 9.65 mmol, 2 eq) and 5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazole, which was prepared according to the method described in Ex.1, (2.36 g, 4.82 mmol, 1 eq). The mixture was stirred at 50°C for 12 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THE=1:0 to 5:1) to give (2S)- 1-[[2-[2-[tert-butyl(dimethyl) silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl- isopropylamino] propan-2-ol (2.26 g, 4.30 mmol, 89% yield) as a colorless oil. LCMS: (M+1: 526.6).

[0507] Step 3. A mixture of (2S)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl-isopropyl-amino]propan-2-ol (650 mg, 1.24 mmol, 1 eq), 2,5- dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex. 1, (420 mg, 1.24 mmol, 1 eq), PPh3 (649 mg, 2.47 mmol, 2 eq) and DBAD (427 mg, 1.86 mmol, 1.5 eq) was degassed and purged with N2 for 3 times, and then THF (10 mL) added. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:1 to 1:1) to give (2R)-N-[[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-isopropyl- propan-1-amine (781 mg, 922 μmol, 74% yield) as a brown solid. LCMS: (M+1: 847.3).

[0508] Step 4. To a solution of (2R)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-yl]oxy-N-isopropyl-propan-1-amine (710 mg, 838 μmol, 1 eq) in DMF (35 mL) was added NaHCO3 (176 mg, 2.10 mmol, 2.5 eq) and TBAC (233 mg, 838 μmol, 1 eq) and Pd(OAc)2(37.6 mg, 167 μmol, 0.2 eq). The mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 130 °C for 1 h under N2 atmosphere. On completion, the reaction mixture was partitioned between EA (10 mL × 3) and water (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:1 to 1:1) to give (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (396 mg, 551 μmol, 66% yield) as a yellow solid. LCMS: (M+1: 719.6).

[0509] 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- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (366 mg, 509μmol, 1 eq) in DCM (3.5 mL) was added TFA (1.87 g, 16.42 mmol, 32.3 eq), the mixture was stirred at 25 °C for 2 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH= 15:1 to 15:1) to give 2-[(17E)-16-ethoxy-6,8,10-trimethyl-12-(propan-2-yl)-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (40 mg, 76.83 μmol, 15% yield) as a brown solid. LCMS: (M+1: 521.3).

[0510] Step 6. SFC separation: The product above was separated by SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [CO2-ACN / MeOH(0.1% NH3H2O)];B%:40%, isocratic elution mode) to give Ex.8 (4.4 mg, 8.45 μmol, 11% yield) as a white solid and Ex. 1 (4.7 mg, 9.03 μmol, 11.75% yield) as a white solid. LCMS: (M+1: 521.3).1H NMR for Ex.8 can be found in the below NMR table.

[0511] Preparation of 2-[(10S,17E)-16-ethoxy-8,10-dimethyl-12-(propan-2-yl)- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex. 11) and 2-[(10R,17E)-16-ethoxy-8,10- dimethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.12)

[0512] Step 1. To a solution of (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl-isopropyl-amino]propan-2-ol, which was prepared according to the method described in Ex.1, (600 mg, 1.14 mmol, 1 eq), 2-methyl-4-(1-tetrahydropyran-2-yl-3- vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the methoddescribed in Ex.5, (371 mg, 1.14 mmol, 1 eq) in THF (10 mL) was added PPh3(598 mg, 2.28 mmol, 2 eq) and DBAD (394 mg, 1.71 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF=1:1 to 1:1) to give (2S)-N-[[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl]-N-isopropyl-2-[2- methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy- propan-1-amine (662 mg, 794 μmol, 70% yield) as a white solid. LCMS: (M+1:833.2).

[0513] Step 2. To a solution of (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl]-N-isopropyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-propan-1-amine (640 mg, 768 μmol, 1 eq), TBAC (213 mg, 768 μmol, 1 eq) in DMF (20 mL) was added NaHCO3 (161 mg, 1.92 mmol, 2.5 eq) and Pd(OAc)2(17.2 mg, 76.8 μmol, 0.1 eq). The mixture was stirred at 130 °C for 2 h. On completion, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (250 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA=1:1 to 0:1) to give (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (230 mg, 326 μmol, 42% yield) as a yellow solid. LCMS: (M+1: 705.4).

[0514] 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- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (200 mg, 283 μmol, 1 eq) in DCM (0.3 mL) was added TFA (4.60 g, 40.3 mmol, 3.00 mL, 142 eq). The mixture was stirred at 25 °C for 2 h. On completion, the crude product was triturated with ACN (5 mL) at 25oC for 5 min to give 2-[(10S,17E)-16-ethoxy-8,10-dimethyl-12-(propan-2-yl)- 10,11,12,13-tetrahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14(2H)-yl]ethan-1-ol (65 mg, 128 μmol, 45.2% yield) as a white solid. LCMS: (M+1:507.2).

[0515] Step 4. SFC separation: the product above was purified by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [CO2-MeOH];B%:40%, isocratic elution mode) to give Ex.11 (32.97 mg, 65.08 μmol, 54.95% yield) as a white solid and Ex. 12 (8.41 mg, 16.60 μmol, 14.02% yield) as a white solid.

[0516] Ex. 11: LCMS: (M+1:507.1).1H NMR for Ex. 11 can be found in the below NMR table.

[0517] Ex. 12: LCMS: (M+1:507.2).1H NMR for Ex. 12 can be found in the below NMR table.

[0518] Preparation of 2-[(10S,17E)-12-ethyl-6,8,10,16-tetramethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex. 13) and 2-[(10R,17E)-12-ethyl-6,8,10,16- tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.14)

[0519] Step 1. The mixture of commercially available methyl 3-methyl-1H-pyrazole-5- carboxylate (20.0 g, 143mmol, 1 eq), commercially available 2-[tert- butyl(dimethyl)silyl]oxyethanol (50.3 g, 285 mmol, 2 eq) and PPh3(82.4 g, 314 mmol, 2.2 eq) in THF (120 mL) was degassed with N2 and stirred at 25 °C for 30 min under N2, then DIAD(63.5 g, 314 mmol, 61 mL, 2.2 eq) was added dropwise at 0 °C, the resulting mixture was stirred at 25 °C for another 5 h under N2. On completion, the mixture was triturated with petroleum ether (400 mL) and filtered to remove TPPO. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Tetrahydrofuran=1 / 0 to 10 / 1) to give methyl 2-[2-[tert- butyl (dimethyl) silyl] oxyethyl]-5-methyl-pyrazole-3-carboxylate (40.0 g, 134 mmol, 94% yield) as colorless oil.LCMS: (M+1 = 299.0).

[0520] Step 2. To a solution of methyl 2-[2-[tert- butyl (dimethyl) silyl] oxyethyl]-5-methyl- pyrazole-3-carboxylate (50.0 g, 168 mmol, 1 eq) in THF (400 mL) was added LiAlH4 (2.5 M, 67.0 mL, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 2.5 hr. On completion, the reaction mixture was quenched with water (6 mL) and adjusted with 15% NaOH (6 mL). Then, to the mixture was added water (18 mL) and filtered. The filtrate was concentrated under reduced pressure to give [2-[2-[tert- butyl (dimethyl) silyl] oxyethyl]-5-methyl-pyrazol-3-yl] methanol (45.0 g, 153 mmol, 91% yield, 92% purity) as a colorless oil. LCMS: (M+1 = 271.1).

[0521] Step 3. To a solution of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-methyl-pyrazol-3- yl]methanol (45.0 g, 166 mmol, 1 eq) in ACN (300 mL) was added NIS (37.4 g, 166 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 8 hr. On completion, the mixture was quenched with saturated solution of Na2SO3 (12 mL), and partitioned between water (300 mL) and ethyl acetate(100 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 1 to 1 / 2) to give [2-[2-[tert- butyl (dimethyl) silyl] oxyethyl]-4-iodo-5-methyl-pyrazol-3-yl] methanol (10.0 g, 25.2 mmol, 15% yield) as an amber solid.1H 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).

[0522] Step 4. To a solution of [2-[2-[tert-butyl (dimethyl) silyl] oxyethyl]-4-iodo-5-methyl- pyrazol-3-yl] methanol (4.80 g, 12.1 mmol, 1 eq), PPh3(3.81 g, 14.5 mmol, 1.2 eq) in DCM (48 mL). Then was added CBr4 (4.82 g, 14.5 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1hr. On completion, the mixture was diluted with water (150 mL), extracted with DCM (40 mL × 3), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Tetrahydrofuran=1 / 0 to 85 / 15) to give 2-[5-(bromomethyl)-4-iodo-3-methyl-pyrazol-1- yl]ethoxy-tert-butyl-dimethyl-silane (4.30 g, 9.36 mmol, 77% yield) as a white solid. LCMS: (M+1 = 460.9).

[0523] Step 5. A solution of 2-[5-(bromomethyl)-4-iodo-3-methyl-pyrazol-1-yl]ethoxy-tert- butyl-dimethyl-silane (1.00 g, 2.18 mmol, 1 eq) and commercially available (2R)-1- (ethylamino)propan-2-ol (449 mg, 4.36 mmol, 2 eq.) in DMF (6 mL) was added K2CO3(602 mg, 4.36 mmol, 2 eq). The mixture was stirred at 80 °C for 50 min. On completion, the reaction mixture was partitioned between ethyl acetate (10 mL × 3) and water (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Tetrahydrofuran=4 / 1 to 3 / 1) to give (2R)-1-[[2-[2-[tert-butyl (dimethyl) silyl] oxye- thyl]-4-iodo-5-methyl-pyrazol-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).

[0524] Step 6. A mixture of (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5- methyl-pyrazol-3-yl]methyl-ethyl-amino]propan-2-ol (875 mg, 1.62 mmol, 1 eq), 2,5- dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex. 1, (878 mg, 2.59 mmol, 1.6 eq), PPh3 (933 mg, 3.56 mmol, 2.2 eq), DBAD (819. mg, 3.56 mmol, 2.2 eq) was degassed and purged with N2for 3 times, and then to the mixture added 2-MeTHF (9 mL) and stirred at 25 °C for 1.5 hr under N2 atmosphere. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Tetrahydrofuran=2 / 1 to 1 / 1) to give (2S)-N-[[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methyl-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-ethyl-propan- 1-amine (650 mg, 810 μmol, 5% yield) as 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).

[0525] Step 7. A mixture of (2S)-N-[[2-[2-[tert- butyl (dimethyl) silyl] oxyethyl]-4-iodo-5- methyl-pyrazol-3-yl] methyl]-2-[2, 5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo [3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-ethyl-propan-1-amine (650 mg, 810 μmol, 1 eq), TBAC (225 mg, 810 μmol, 1 eq), NaHCO3 (170 mg, 2.02 mmol, 2.5 eq) and Pd(OAc)2 (36.4mg, 162 μmol, 0.2 eq) in DMF (7 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 140 °C for 1.5 h under N2 atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (30 mL × 3) and water (90 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Tetrahydrofuran=1 / 1 to 1 / 2) to give (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (210 mg, 311 μmol, 38% yield) as a brown solid. LCMS: (M+1 = 675.4).

[0526] 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- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (200 mg, 296 μmol, 1 eq) was added DCM (2.5 mL) and TFA (0.5 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC purification (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 10%-40% B over 10 min) to give 2-[(10S,17E)-12-ethyl-6,8,10,16-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (50.0 mg, 105 μmol, 35% yield) as a yellow solid.1H 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).

[0527] Step 9. SFC separation: the residue was separated by SFC (column: DAICEL CHIRALCEL OD (250mm*30mm,10um); mobile phase: [CO2- MeOH(0.1%NH3H2O)];B%:40%, isocratic elution mode) to give Ex.13 (5.93 mg, 12.4 μmol, 12% yield, 100% purity) as a white solid and Ex. 14 (5.93 mg, 12.44 μmol, 11.86% yield, 100% purity) as a white solid.

[0528] Ex.13: LCMS: (M+1 = 477.1).1H NMR for Ex. 13 can be found in the below NMR table.

[0529] Ex. 14: LCMS: (M+1 = 477.1).1H NMR for Ex. 14 can be found in the below NMR table.

[0530] Preparation of 2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.15)

[0531] Step 1. To a solution of 2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1-yl]ethoxy-tert- butyl-dimethyl-silane, prepared according to the method described in Ex. 1, (539 mg, 1.10 mmol, 1 eq), K2CO3 (304 mg, 2.20 mmol, 2 eq) in DMF (5 mL) was added commercially available (2R)-1-(ethylamino)propan-2-ol (170 mg, 1.65 mmol, 1.5 eq). The mixture was stirred at 80 °C for 1 h. On completion, the resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20mL), dried over Na2SO4and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / EA=1 / 0 to 1 / 1) to give (2R)-1-[[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl-ethyl-amino]propan-2- ol (500 mg, 918 μmol, 83% yield, 94% purity) as a yellow oil.1H 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).

[0532] Step 2. A mixture of (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl-ethyl-amino]propan-2-ol (457 mg, 893 μmol, 1 eq), 2,5-dimethyl-4- (1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex.1, (606 mg, 1.79 mmol, 2 eq), DBAD (452mg, 1.97 mmol, 2.2 eq), PPh3(515 mg, 1.97 mmol, 2.2 eq) in THF (10 mL) was stirred at 25 °C for 1 h. On completion, the mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=1 / 0 to 5 / 1) to give (2S)-N-[[2-[2- [tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl]-2-[2,5-dimethyl- 4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-ethyl- propan-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).

[0533] Step 3. To a solution of (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-yl]oxy-N-ethyl-propan-1-amine (400 mg, 480 μmol, 1 eq), NaHCO3(100 mg, 1.20 mmol, 2.5 eq) and Pd(OAc)2 (21.5 mg, 96.1 μmol, 0.2 eq) in DMF (35 mL) was added TBAC (133 mg, 480 μmol, 1 eq) at 25 °C. The mixture was stirred at 140 °C for 1 h under nitrogen atmosphere. On completion, the mixture was added brine (100 mL) and extracted with EA (50 mL × 3). The combined organic layer was washed with brine (50 mL × 2). The organic layer was concentrated in vacuum to give the residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 100:1 ~ 30:1) to give (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (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).

[0534] 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- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (150 mg, 144 μmol, 1 eq) in DCM (2 mL) was added TFA (3.54 g, 31.0 mmol, 2.31 mL, 214 eq) at 25 °C. The mixture was stirred at 25 °C for 1.5 h. On completion, the mixture was concentrated to give a yellow oil (103 mg, 105 μmol, 73% yield, 73% purity, TFA salt). LCMS: (M+1: 603.2). This yellow oil (103 mg, 144 μmol, 1 eq, TFA) was dissolved in MeOH (2 mL) and K2CO3(199 mg, 1.45 mmol, 10 eq) was added. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (4 g silica gel column, MeOH in DCM from 0% to 20%) to give 2-[(10S,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (50.0 mg, 98.7 μmol, 68% yield) as a white solid, which is further purified by Prep-SFC (column: DAICEL CHIRALCEL OD (250mm*30mm,10um); mobile phase: [CO2- MeOH(0.1%NH3H2O)];B%:30%, isocratic elution mode) to give Ex. 15 (25.01 mg, 47.39 μmol, 48.02% yield, 96% purity) as an off-white solid. LCMS: (M+1: 507.2).1H NMR for Ex. 15 can be found in the below NMR table.

[0535] Preparation of 2-[(11S,17E)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.16) and 2-[(10R,17E)-16-ethoxy-12-ethyl- 6,8,10-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.17)

[0536] Step 1. To a solution of commercially available (2S)-2-aminopropan-1-ol (553 mg, 7.36 mmol, 3 eq) and 5-(bromomethyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4- iodo-1H-pyrazole, which was prepared according to the method described in Ex. 1, (1.20 g, 2.45 mmol, 1 eq) in DMF (15 mL) was added K2CO3 (1.02 g, 7.36 mmol, 3 eq). The mixture was stirred at 70 °C for 2 h. On completion, the crude mixture was used for next step. (2S)-2- [[2-[2-[tert-butyl (dimethyl) silyl] oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl] methylamino] propan-1-ol (1.19 g, 2.46 mmol, 100% yield) was obtained as colorless oil. LCMS: (M+1 = 484.3).

[0537] Step 2. To a mixture of (2S)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methylamino]propan-1-ol (1.19 g, 2.46 mmol, 1 eq) and EtI (1.15 g, 7.38 mmol, 3 eq) in DMF (15 mL) was added K2CO3 (1.02 g, 7.38 mmol, 3 eq). The mixture was stirred at 70 °C for 2 h. On completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give crude. The residue was purified by CombiFlash chromatography (20 g silica gel column, EtOAc in PE from 0% to 100%). (2S)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3- yl]methyl-ethyl-amino]propan-1-ol (940 mg, 1.84 mmol, 74% yield) was obtained as yellow oil.1H 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).

[0538] Step 3. A solution of (2S)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl-ethyl-amino]propan-1-ol (900 mg, 1.76 mmol, 1 eq), 2,5-dimethyl- 4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex.1, (744 mg, 2.29 mmol, 1.3 eq), PPh3(1.02 g, 3.87 mmol, 2.2 eq), DBAD (891 mg, 3.87 mmol, 2.2 eq) in 2-MeTHF (10 mL) was stirred at 25 °C for 2 h. On completion, the mixture was concentrated in vacuum to give crude. The residue was purified by CombiFlash chromatography (20 g silica gel, EtOAc in PE from 0%to 100%). (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3- yl]methyl]-1-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5- yl)pyrazol-3-yl]oxy-N-ethyl-propan-2-amine (1.00 g, 1.20 mmol, 68% yield) was obtained as yellow solid. LCMS: (M+1 = 833.7).

[0539] Step 4. To a solution of (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl]-1-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-yl]oxy-N-ethyl-propan-2-amine (980 mg, 1.18 mmol, 1 eq), TBAC (327 mg, 1.18 mmol, 1 eq), NaHCO3(247 mg, 2.94 mmol, 2.5 eq) and Pd(OAc)2(52.8 mg, 235 μmol, 0.2 eq) in DMF (10 mL) was stirred at 140 °C for 1 h. On completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (15 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give crude. The residue was purified by CombiFlash chromatography (20 g silica gel column, EtOAc in PE from 0% to 100%). (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (540 mg, 766 μmol, 65% yield) was obtained as brown oil. LCMS: (M+1 = 705.4).

[0540] Step 5. 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- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (510 mg, 723 μmol, 1 eq) in DCM (6 mL) was added TFA (1.84 g, 16.2 mmol, 1.2 mL, 22.3 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was concentrated in vacuum to give a yellow oil (380 mg, 614 μmol, 85% yield). LCMS: (M+1 = 603.3). This yellow oil (380 mg, 614 μmol, 1 eq) was dissolved in MeOH (6 mL) and K2CO3 (424 mg, 3.07 mmol, 5 eq) was added. The mixture was stirred at 25 °C for 2 h. On completion, the mixture was filtered, and the filtrate was concentrated in vacuum to give crude. The residue was purified by Prep-HPLC (column: Welch Xtimate C18150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 13%-43% B). Ex. 16 (19.78 mg, 36.92 μmol, 6.01% yield, 94.55% purity) was obtained as orange solid and Ex.17 (3.03 mg, 5.61 μmol, 9.13e-1% yield, 93.79% purity) was obtained as white solid as a biproduct.

[0541] Ex. 16: LCMS: (M+1 = 507.3).1H NMR for Ex. 16 can be found in the below NMR table.

[0542] Ex. 17: LCMS: (M+1 = 507.3).1H NMR for Ex. 17 can be found in the below NMR table.

[0543] Preparation of 2-[(11R,17E)-16-ethoxy-12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.18)

[0544] Step 1. To a solution of 2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1-yl]ethoxy-tert- butyl-dimethyl-silane, prepared according to the method described in Ex. 1, (1.20 g, 2.45 mmol, 1.00 eq) and commercially available (2R)-2-aminopropan-1-ol (552 mg, 7.36 mmol, 573 μL, 3.00 eq) in DMF (12 mL) was added K2CO3 (1.02 g, 7.36 mmol, 3.00 eq). The mixture was stirred at 70 °C for 2 h. On completion, compound (2R)-2-[[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methylami-no]propan-1-ol (1.00 g, in DMF) was obtained as a colorless liquid.

[0545] Step 2. To a solution of (2R)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methylamino]propan-1-ol (1.00 g, in DMF) and iodoethane (1.29 g, 8.27 mmol, 4.00 eq) in DMF (12 mL) was added K2CO3(572 mg, 4.14 mmol, 2.00 eq). The mixture was stirred at 70 °C for 2 h. On completion, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried overanhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=3:1 to 1:1) to give (2R)-2- [[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-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).

[0546] Step 3. A mixture of (2R)-2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl-ethyl-amino]propan-1-ol (750 mg, 1.47 mmol, 1.00 eq), 2,5- dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex.1, (647 mg, 1.91 mmol, 1.30 eq), PPh3 (846 mg, 3.23 mmol, 2.20 eq), DBAD (743 mg, 3.23 mmol, 2.20 eq) was degassed and purged with N2 for 3 times. Then 2-MeTHF (7.5 mL) was added and the mixture was stirred at 25 °C for 2 h under N2atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=1:0 to 0:1) to give (2R)-N-[[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl]-1-[2,5-dimethyl-4-(1- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-ethyl-propan- 2-amine (840 mg, 917 μmol, 63% yield, 91% purity) as a colorless oil. LCMS: (M+1 = 833.3).

[0547] Step 4. A mixture of (2R)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl]-1-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-yl]oxy-N-ethyl-propan-2-amine (790 mg, 949 μmol, 1.00 eq), diacetoxypalladium (42.6 mg, 189 μmol, 0.20 eq), TBAC (264 mg, 949 μmol, 1.00 eq) and NaHCO3 (199 mg, 2.37 mmol, 2.50 eq) in DMF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 1 h under N2atmosphere. On completion, the mixture was quenched with water (40 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:1 to 1:1) to give (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (530 mg, 752 μmol, 79% yield) as a brown oil. LCMS: (M+1 = 705.6).

[0548] Step 5. 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- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (130 mg, 184 μmol, 1.00 eq) in DCM (1 mL) was added TFA (1.54 g, 13.5 mmol, 73.0 eq). The mixture wasstirred at 25 °C for 2 h. On completion, the mixture was concentrated to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150 *25mm *10um; mobile phase: [water (FA)-ACN];gradient:12%-42% B over 15 min) to give Ex.18 (15.49 mg, 27.75 μmol, 15.05% yield, 99% purity, FA) as a white solid. LCMS: (M+1 = 507.2).1H NMR for Ex.18 can be found in the below NMR table.

[0549] Preparation of (2S)-2-[(10S,17E)-16-ethoxy-8,10,12-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Ex.19)

[0550] Step 1. To a solution of commercially available (2R)-propane-1,2-diol (50.0 g, 657 mmol, 48.0 mL, 1 eq) in DCM (500 mL) was added TBSCl (99.0 g, 657 mmol, 1 eq) and imidazole (44.7 g, 657 mmol, 1 eq). The mixture was stirred at 0 °C for 2 h and then at 25 °C for 10 hr. On completion, the mixture was filtered and concentrated to give (2R)-1-[tert- butyl(dimethyl)silyl]oxypropan-2-ol (120 g, 630 mmol, 95% yield) as colorless oil.1H 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).

[0551] Step 2. A mixture of methyl 3-ethoxy-1H-pyrazole-5-carboxylate, which was prepared according to the method described in Ex. 1, (22.0 g, 129 mmol, 1 eq), (2R)-1-[tert- butyl(dimethyl)silyl]oxypropan-2-ol (49.2 g, 258 mmol, 2 eq), PPh3 (74.6 g, 284 mmol, 2.2 eq) in THF (250 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 0.5 h. Then DIAD (57.5 g, 284 mmol, 55.1 mL, 2.2 eq) was added at 0 °C, and then the mixture was stirred at 25 °C for 2 h. On completion, the mixture was concentrated in vacuum to give a residue, then added Petroleum ether / Ethyl acetate=5:1 (200 mL) and was stirred at 25 °C for 10 min. Then the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:0 to 5:1) to give methyl 2-[(1S)-2-[tert-butyl (dimethyl) silyl] oxy-1-methyl-ethyl]-5-ethoxy- pyrazole-3-carboxylate (36.0 g, 105 mmol, 81% yield) as transparent 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).

[0552] Step 3. To a solution of methyl 2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- ethyl]-5-ethoxy-pyrazole-3-carboxylate (36.0 g, 105 mmol, 1 eq) in THF (300 mL) was added LAH (2.5 M, 63.0 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was quenched with H2O (6 mL) and adjusted with 15% NaOH (6 mL). The combined organic layers were dried over Na2SO4 with stirring 10 min at 25 °C, filtered and concentrated under reduced pressure to give [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1- methyl-ethyl]-5-ethoxy-pyrazol-3-yl]methanol (30.0 g, crude) as transparent oil. LCMS: (M+1:315.3).

[0553] Step 4. To a solution of [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5- ethoxy-pyrazol-3-yl]methanol (29.5 g, 93.8 mmol, 1 eq) in ACN (400 mL) was added NIS (21.1 g, 93.8 mmol, 1 eq). The mixture was stirred at 0 °C for 2 h. On completion, the reaction mixture was quenched dropwise with sodium sulfite aqueous solution (300 mL), then was extracted with EA (200 mL × 3). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5:1 to 3:1) to give [2-[(1S)- 2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy-4-iodo-pyrazol-3-yl] methanol (25.6 g, 58.1 mmol, 61.9% yield) as white solid.1H 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).

[0554] Step 5. To a solution of [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5- ethoxy-4-iodo-pyrazol-3-yl]methanol (2.00 g, 4.54 mmol, 1 eq) in DCM (20 mL) was added PPh3(1.43 g, 5.45 mmol, 1.2 eq), and then CBr4(1.81 g, 5.45 mmol, 1.2 eq) was added at 0°C under N2. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:0 to 5:1) to give [(2S)-2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1- yl]propoxy]-tert-butyl-dimethyl-silane (1.7 g, 3.38 mmol, 74% yield) as a yellow oil. LCMS: (M+1:504.7).

[0555] Step 6. To a solution of MeNH2 (10.2 g, 99.3 mmol, 30% purity, 20 eq) in acetone (150 mL) was added K2CO3(2.06 g, 14.9 mmol, 3 eq). And then [(2S)-2-[5-(bromomethyl)-3- ethoxy-4-iodo-pyrazol-1-yl]propoxy]-tert-butyl-dimethyl-silane (2.50 g, 4.97 mmol, 1 eq) in acetone (150 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF=1:1 to 1:1) to give 1-[2-[(1S)-2-[tert- butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]-N-methyl- methanamine (1.83 g, 4.04 mmol, 81% yield) as a yellow oil. LCMS: (M+1:454.0).

[0556] Step 7. To a solution of 1-[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5- ethoxy-4-iodo-pyrazol-3-yl]-N-methyl-methanamine (1.70 g, 3.75 mmol, 1 eq), commercially available (2R)-2-methyloxirane (1.09 g, 18.7 mmol, 5 eq) in EtOH (20 mL). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=2:1 to 1:1) to give (2R)-1-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy-4-iodo- pyrazol-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).

[0557] Step 8. To a solution of (2R)-1-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- ethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl-methyl-amino]propan-2-ol (600 mg, 1.17 mmol, 1 eq), 2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex.5, (382 mg, 1.17 mmol, 1 eq) in THF (15 mL) was added PPh3(615 mg, 2.35 mmol, 2 eq) and DBAD (405 mg, 1.76 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 h under N2. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF) to give (2S)-N-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-ethoxy- 4-iodo-pyrazol-3-yl]methyl]-N-methyl-2-[2-methyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-propan-1-amine (700 mg, 854 μmol, 73% yield) as a white solid. LCMS: (M+1: 819.3).

[0558] Step 9. To a solution of (2S)-N-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- ethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl]-N-methyl-2-[2-methyl-4-(1-tetrahydropyran-2- yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-propan-1-amine (680 mg, 830 μmol, 1 eq), TBAC (230 mg, 830 μmol, 1 eq) in DMF (70 mL) was added Pd(OAc)2 (18.6 mg, 83.0 μmol, 0.1 eq) and NaHCO3 (174 mg, 2.08 mmol, 2.5 eq). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA=1:1 to 1:1) to give (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (280 mg, 405 μmol, 49% yield) as a white solid. LCMS: (M+1:691.3).

[0559] Step 10. To a solution of (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (200 mg, 289 μmol, 1 eq) in DCM (1 mL) was added TFA (30.7 g, 269 mmol, 930 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=30:1 to 15:1) to give Ex.19 (33.5 mg, 68.1 μmol, 23% yield) as a white solid. LCMS: (M+1:493.1).1H NMR for Ex.19 can be found in the below NMR table.

[0560] Preparation of 2-[(10R,17E)-6,8,10,16-tetramethyl-12-(propan-2-yl)-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex. 20) and 2-[(10S,17E)-6,8,10,16-tetramethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.21)

[0561] Step 1. To a solution of 2-[5-(bromomethyl)-4-iodo-3-methyl-pyrazol-1-yl]ethoxy- tert-butyl-dimethyl-silane, which was prepared according to the method described in Ex. 13 and 14, (2.30 g, 5.01 mmol, 1.00 eq), commercially available (2R)-1-(isopropylamino)propan- 2-ol (1.17 g, 10.0 mmol, 2.00 eq) in DMF (23 mL) was added K2CO3 (1.38 g, 10.0 mmol, 2.00 eq). The mixture was stirred at 80 °C for 1 hr. On completion, the reaction mixture was partitioned between ethyl acetate (40 mL × 3) and water (150 mL). The combined organic phase was washed with water (50 mL × 2) and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 60 / 40) to give (2R)-1-[[2-[2- [tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5-methyl-pyrazol-3-yl]methyl-isopropylamino]propan-2-ol (1.90 g, 3.83 mmol, 77% yield) as a yellow oil. LCMS: (M+1 = 496.1).

[0562] Step 2. A mixture of (2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5- methyl-pyrazol-3-yl]methyl-isopropyl-amino]propan-2-ol (964 mg, 1.94 mmol, 1.00 eq), 2,5- dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex.1, (858 mg, 2.53 mmol, 1.30 eq), PPh3(1.12 g, 4.28 mmol, 2.20 eq), DBAD (985 mg, 4.28 mmol, 2.20 eq) was degassed and purged with N2for 3 times, and then to the mixture added 2-MeTHF (30 mL) and stirred at 25 °C for 2 h under N2 atmosphere. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Tetrahydrofuran=2 / 1 to 1 / 1) to give (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]- 4-iodo-5-methyl-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-isopropyl-propan-1-amine (670 mg, 820 μmol, 42% yield) as a colorless solid. LCMS: (M+1 = 817.5).

[0563] Step 3. A mixture of (2S)-N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-iodo-5- methyl-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo [3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-isopropyl-propan-1-amine (330 mg, 404 μmol, 1.00 eq), TBAC (112 mg, 404 μmol, 1.00 eq), NaHCO3 (84.8 mg, 1.01 mmol, 2.50eq) and Pd(OAc)2 (18.1 mg, 80.8 μmol, 0.20 eq) in DMF (3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 130 °C for 2 h under N2 atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (30 mL × 3) and water (100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Tetrahydrofuran=2 / 1 to 1 / 1) to givebutyl(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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (120 mg, 174 μmol, 43% yield) as a brown solid. LCMS: (M+1 = 689.6).

[0564] Step 4. To a solution of (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- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (110 mg, 160 μmol, 1.00 eq) in DCM (0.5 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 3 hr. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC purification (column: Xtimate C18 150*40mm*10um;mobile phase: [water(TFA)-ACN];gradient:0%-28% B over 10 min) togive 2-[(10S,17E)-6,8,10,16-tetramethyl-12-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol (50.0 mg, 102 μmol, 64% yield) as a yellow solid.

[0565] Step 5. SFC purification: The product obtained above was separated by SFC (condition: column: Phenomenex-Cellulose-2 (250mm*30mm,10um);mobile phase: [CO2- MeOH(0.1%NH3H2O)];B%:40%, isocratic elution mode) to give Ex.20 (7.38 mg, 14.53 μmol, 13.85% yield, 96.6% purity) as an orange solid and Ex. 21 (28.43 mg, 57.60 μmol, 54.90% yield, 99.4% purity) as an orange solid.

[0566] Ex. 20: LCMS: (M+1 = 491.1).1H NMR for Ex. 20 can be found in the below NMR table.

[0567] Ex. 21: LCMS: (M+1 = 491.2).1H NMR for Ex. 21 can be found in the below NMR table.

[0568] Preparation of (2S)-2-[(10R,17E)-16-ethoxy-12-ethyl-6,8,10-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Ex. 24) and (2S)-2-[(11S,17E)-16-ethoxy- 12-ethyl-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Ex.25)

[0569] Step 1. To a solution of [(2S)-2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1- yl]propoxy]-tert-butyl-dimethyl-silane, which was prepared according to the method described in Ex.19, (960 mg, 1.91 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (791 mg, 5.72 mmol, 3 eq) and commercially available (2S)-2-aminopropan-1-ol (430 mg, 5.72 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hr. On completion, the yellow solution of (S)-2-(((1-((S)-1- ((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5- yl)methyl)amino)propan-1-ol (theoretical quantity: 948 mg, in DMF) was used for the next step directly. LCMS: (M+1 = 498.1).

[0570] Step 2. To the above DMF solution of (S)-2-(((1-((S)-1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5- yl)methyl)amino)propan-1-ol (theoretical quantity from Step 1, 948 mg) was added EtI (2.65 g, 17.0 mmol, 9 eq). The mixture was stirred at 80 °C for 2 hr. On completion, the reaction mixture was diluted with H2O (100 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give (S)-2-(((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan- 2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)(ethyl)amino)propan-1-ol (600 mg, 60% yield) as yellow oil. LCMS: (M+1 = 526.1).

[0571] Step 3. A mixture of (S)-2-(((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3- ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)(ethyl)amino)propan-1-ol (550 mg, 1.05 mmol, 1 eq), 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex.1, (462 mg, 1.36 mmol, 1.3 eq), PPh3 (604 mg, 2.30 mmol, 2.2 eq), and DBAD (530 mg, 2.30 mmol, 2.2 eq) in 2-MeTHF (6 mL) was degassed and purged with N2 for 3 times, and then stirred at 25 °C for 2 h under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give (2S)-N-((1-((S)-1-((tert-butyldimethylsilyl)oxy)propan- 2-yl)-3-ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)-1-((1,3-dimethyl-4-(1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-5-yl)oxy)-N-ethylpropan-2-amine (510 mg, 58% yield) as yellow oil. LCMS: (M+1 = 847.4).

[0572] Step 4. A mixture of the product from Step 3 (460 mg, 0.543 mmol, 1 eq), diacetoxypalladium (24.4 mg, 0.109 mmol, 0.2 eq), tetrabutylammonium chloride (151 mg, 0.543 mmol, 1 eq) and NaHCO3(114 mg, 1.36 mmol, 2.5 eq) in DMF (5 mL) was degassed and purged with N2for 3 times, and then stirred at 140 °C for 1 h under N2atmosphere. On completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EA (15 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (294 mg, 75% yield) as 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).

[0573] Step 5. To a solution of the product from Step 4 (260 mg, 0.362 mmol, 1 eq) in DCM (1 mL) was added TFA (3.22 g, 28.2 mmol, 2.10 mL, 78.1 eq). The mixture was stirred at 25 °C for 2 hr. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(FA)-ACN];gradient:17%-47% B) and prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)- ACN];gradient:10%-40% B over 8 min) to give Ex. 25 (34.36 mg, 17.34% yield) as yellow solid, and a byproduct Ex. 24 (41.0 mg, 21.56% yield) as yellow solid.1H NMR for Ex. 24 and Ex.25 are in the NMR table below.

[0574] Preparation of 2-[(8aR,9S,19E)-1-ethoxy-9,11,13-trimethyl-7,8,8a,9,11,17-hexahydro- 6H-14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1- c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol (Ex. 32) and 2-[(8aR,9R,19E)-1-ethoxy- 9,11,13-trimethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol (Ex.33)

[0575] Step 1. To a solution of commercially available (2R)-1-tert-butoxycarbonylpyrrolidine- 2-carboxylic acid (20.0 g, 92.9 mmol, 1 eq), commercially available N-methoxymethanamine (6.24 g, 102 mmol, 1.10 eq), DIEA (24.0 g, 185 mmol, 2.00 eq), HATU (38.8 g, 102 mmol, 1.10 eq) in DCM (200 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was diluted with water (300 mL) and extracted with DCM (60 mL × 3). The combined organic phase was washed with water (200 mL × 2) and dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=1:0 to 90:10) to give 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).

[0576] Step 2. To a solution of tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1- carboxylate (10.0 g, 38.7 mmol, 1.00 eq) in THF (100 mL) was added bromo(methyl)magnesium (3 M, 38.7 mL, 3.00 eq) at -78 °C under atmosphere. The mixture was stirred at -78 °C for 2 hr. On completion, the reaction mixture was quenched with sat. NH4Cl (200 mL) at 0 °C, and then diluted with H2O (150 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:0 to 1:1) to give tert-butyl (R)-2-acetylpyrrolidine-1- carboxylate (7.00 g, 32.8 mmol, 85% yield) as a yellow oil.1H 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).

[0577] Step 3. To a solution of tert-butyl (2R)-2-acetylpyrrolidine-1-carboxylate (6.50 g, 30.4 mmol, 1.00 eq) in MeOH (65 mL) was added NaBH4 (3.46 g, 91.4 mmol, 3.00 eq) at 0 °C. The mixture was stirred at 0 °C for 2 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:0 to 1:1) to give tert-butyl (2R)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (5.60 g, 26.0 mmol, 85% yield) as a yellow oil.1H 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).

[0578] Step 4. To a solution of tert-butyl (2R)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (1.00 g, 4.64 mmol, 1.00 eq) in DCM (10 mL) was added HCl / dioxane (4 M, 2.00 mL, 1.72 eq). The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was concentrated to give 1-((R)-pyrrolidin-2-yl)ethan-1-ol (700 mg, crude) as a white oil.

[0579] Step 5. To a solution of 1-((R)-pyrrolidin-2-yl)ethan-1-ol (284 mg, 1.87 mmol, 1 eq, HCl) and 2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1-yl]ethoxy-tert-butyl-dimethyl- silane, prepared according to the method described in Ex. 1, (1.01 g, 2.06 mmol, 1.1 eq) in DMF (10 mL) was added K2CO3 (777 mg, 5.62 mmol, 3 eq). The mixture was stirred at 80 °C for 1h. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 0:1) to give 1-[(2R)-1-[[2-[2- [tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl]pyrrolidin-2- yl]ethanol (1.07 g, 1.84 mmol, 98% yield, 90% purity) as off-white oil. LCMS: (M+1 = 524.0).

[0580] Step 6. A mixture of 1-[(2R)-1-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl]pyrrolidin-2-yl]ethanol (970 mg, 1.85 mmol, 1 eq), 2,5-dimethyl-4- (1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex.1, (1.01 g, 2.96 mmol, 1.6 eq), DBAD (939 mg, 4.08 mmol, 2.2 eq), PPh3(1.07 g, 4.08 mmol, 2.2 eq) in 2-MeTHF (10 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25 °C for 2h under N2atmosphere. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:0 to 0:1) to give compound tert-butyl- [2-[5-[[(2R)-2-[1-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5- yl)pyrazol-3-yl]oxyethyl]pyrrolidin-1-yl]methyl]-3-ethoxy-4-iodo-pyrazol-1-yl]ethoxy]- dimethyl-silane (1.00 g, 1.18 mmol, 64% yield) as 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).

[0581] Step 7. A mixture of tert-butyl-[2-[5-[[(2R)-2-[1-[2,5-dimethyl-4-(1-tetrahydropyran- 2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxyethyl]pyrrolidin-1-yl]methyl]-3- ethoxy-4-iodo-pyrazol-1-yl]ethoxy]-dimethyl-silane (420 mg, 497 μmol, 1 eq), diacetoxypalladium (22.3 mg, 99.4 μmol, 0.2 eq), TBAC (138 mg, 497 μmol, 1 eq) and NaHCO3(104 mg, 1.24 mmol, 2.5 eq) in DMF (10 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 120 °C for 1hr under N2 atmosphere. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=1:0 to 0:1) to give (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n]pyrrolo[2,1-c][1,4]oxazacyclopentadecine (327 mg, 456 μmol, 92% yield) as yellow solid. LCMS: (M+1 = 717.2).

[0582] Step 8. 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- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecine(313 mg, 437 μmol, 1 eq) in DCM (3 mL) was added TFA (40.4 mmol, 3 mL, 92.5 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtrated. The filtrate was purified by prep-HPLC(column: Phenomenex Luna C18 150*30mm*5um;mobile phase: [water(FA)-ACN];gradient:10%-40% B over 10 min) to give Ex. 32 (31.73 mg, 55.76 μmol, 12.77% yield, 99.22% purity, FA) as yellow solid and Ex.33 (34.49 mg, 66.50 μmol, 15.23% yield) as yellow solid.

[0583] Ex.32: LCMS: (M+1 = 519.3).1H NMR for Ex.32 is shown in the below NMR table.

[0584] Ex.33: LCMS: (M+1 = 519.2).1H NMR for Ex.33 is shown in the below NMR table.

[0585] Preparation of 2-[(17E)-16-ethoxy-6,8,12-trimethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol (Ex.68) B

[0586] Step 1. To 2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1-yl]ethoxy-tert-butyl- dimethyl-silane, prepared according to the method described in Ex. 1, (508 mg, 1.04 mmol) in Acetonitrile (5.09 mL) was added potassium carbonate (430.51 mg, 3.11 mmol) followed by commercially available 2-(methylamino)ethanol (93.58 mg, 1.25 mmol, 99.66 μL). The reaction mixture was stirred at 22 °C for 18 hr. The solution was diluted in DCM (5 mL) and cooled in an ice bath. The solids were filtered through a celite pad and washed thoroughly with DCM. The filtrate was concentrated via rotary evaporation and the residue was purified by flash column chromatography (automated system, 12g silica, 0- 10% Methanol in DCM) to provide 2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl-methyl-amino]ethanol (404 mg, 835.65 μmol, 80.48% yield) as a colorless oil.

[0587] Step 2. To the mixture of 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex. 1, (75 mg, 220.98 μmol) , 2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5- ethoxy-4-iodo-pyrazol-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) at 0 °C was added DBAD (81.41 mg, 353.57 μmol). The mixture was stirred at 22 °C for 18 hr. 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 layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated system, 12g silica, 0-100% EA in Hexanes) provided N-[[2-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl- ethanamine (114 mg, 141.64 μmol, 64.10% yield).

[0588] Step 3. To the solution of N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-ethanamine (114 mg, 141.64 μmol) in DMF (1.40 mL), was added sodium bicarbonate (36 mg, 424.9 μmol) and TBAC (43.3 mg, 155.8 μmol). The mixture was stirred as argon was bubbled through and palladium acetate (6.4 mg, 28.3 μmol) was then added. The vessel was sealed and heated to 140 °C for 1.5 hr. Reaction was diluted with DCM and water (4 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2 × 4 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated system, 12g silica, 0-100% EA in Hexanes) provided 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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (40 mg, 59.09 μmol, 41.72% yield) as a brown oil.

[0589] Step 4. To the mixture of 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- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (40 mg, 59.09 μmol) in DCM (2 mL) was added TFA (2.61 mmol, 0.2 mL). The mixture was stirred at 22 °C for 18 hr. On completion, the reaction mixture was concentrated under reduced pressure, and the residue was diluted in DCM (1mL) and 0.1mL of TEA was added. Flash column chromatography (automated system, 12g silica, 0-10% MeOH in DCM) provided Ex.68 (2.60 mg, 5.38 μmol, 9.11% yield, 99.03% purity). LC / MS: (M+1: 479.3).1H NMR for Ex. 68 is shown in the below NMR table.

[0590] Preparation of 2-[(17E)-16-ethoxy-6,8,12-trimethyl-2,6,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:3'',4''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1- ol (Ex.69)

[0591] Step 1. To 5-bromo-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine, which was prepared according to the method described in Ex. 1, (250 mg, 811.23 μmol) in 1,4- Dioxane (4 mL) was added commercially available 1,3-dimethylpyrazol-4-ol (109.2 mg, 973.5 μmol), potassium carbonate (336 mg, 2.43 mmol). Argon was bubbled through and tBuBrettphos Pd G3 (69 mg, 81.12 μmol) was added. The mixture was stirred at 130 °C for 1.5 hr. Reaction was diluted with DCM and water (10 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2 × 10mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated system, 12g silica, 20-80% EA in Hexanes) provided 1,3- dimethyl-5-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-4-ol.

[0592] Step 2. To 1,3-dimethyl-5-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5- yl)pyrazol-4-ol (10.7 mg, 31.53 μmol), 2-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy- 4-iodo-pyrazol-3-yl]methyl-methyl-amino]ethanol, which was prepared according to themethod described in Ex. 68, (23 mg, 47.3 μmol) , and triphenylphosphine (12.4 mg, 47.3 μmol) in dry Me-THF (0.2 mL) at°C was added DBAD (12 mg, 50.4 μmol). The mixture was stirred at 22 °C for 18 hrs. Flash column chromatography (automated system, 12g silica, 0- 100% EA in Hexanes) provided N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl]-2-[1,3-dimethyl-5-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-4-yl]oxy-N-methyl-ethanamine (7.85 mg, 9.75 μmol, 30.94% yield).

[0593] Step 3. To N-[[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-ethoxy-4-iodo-pyrazol-3- yl]methyl]-2-[1,3-dimethyl-5-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5- yl)pyrazol-4-yl]oxy-N-methyl-ethanamine (7.85 mg, 9.75 μmol) in anhydrous DMF (0.5 mL) was added Sodium bicarbonate (2.46 mg, 29.26 μmol, 1.14 μL) and TBAC (2.98 mg, 10.73 μmol) . The reaction mixture was stirred while Argon was bubbled through, and palladium acetate (2.19 mg, 9.75 μmol, 1 μL) was added. Argon was bubbled through for an additional 5 minutes. The vessel was sealed, and the reaction heated to 140 °C for 1.5 hr. Reaction was diluted with DCM and water (5 mL) and the layers were separated. The aqueous layer was extracted again with DCM (2 × 3mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (automated system, 12g silica, 30-100% EA in Hexanes, injected with 0.5mL of TEA) provided (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-(azenometheno)tripyrazolo[3,4-f:3',4'-j:3'',4''- n][1,4]oxazacyclopentadecine (2.29 mg, 3.38 μmol, 34.68% yield).

[0594] Step 4. To (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-(azenometheno)tripyrazolo[3,4- f:3',4'-j:3'',4''-n][1,4]oxazacyclopentadecine (2.29 mg, 3.38 μmol) in DCM (0.5 mL) was added TFA (1.31 mmol, 0.1 mL). The mixture was stirred at 22 °C for 18 hr. Volatiles were removed under reduced pressure. Then 0.2 mL of TEA was added and the residue was purified flash column chromatography (automated system, 12g silica, 0-40% MeOH in DCM) provided Ex.69 (0.8 mg, 1.67 μmol, 49.42% yield, LC / MS: (M+H: 479.3).1H NMR for Ex. 69 is shown in the below NMR table.

[0595] Preparation of (10S,17E)-6,8,10,14,16,20-hexamethyl-12-(propan-2-yl)- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (Ex. 106) and (11R,17E)-6,8,11,14,16,20-hexamethyl-12- (propan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecine (Ex.108).

[0596] Step 1. To a solution of commercially available (2S)-1-(isopropylamino)propan-2-ol (600 mg, 5.12 mmol, 1.5 eq) in ACN (6 mL) was added commercially available 5- (bromomethyl)-4-iodo-1,3-dimethyl-pyrazole (,1.08 g, 3.41 mmol, 1 eq) and K2CO3 (1.42 g, 10.2 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was filtered to remove K2CO3 and then was concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:0 to 1:1) to give (2S)-1-[(4-iodo-2,5-dimethyl-pyrazol-3-yl)methyl-isopropyl-amino]propan-2-ol (1.15 g, 3.21 mmol, 94% yield) as an orange oil.1H 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).

[0597] Step 2. To a solution of (2S)-1-[(4-iodo-2,5-dimethyl-pyrazol-3-yl)methyl-isopropyl- amino]propan-2-ol (1.05 g, 2.99 mmol, 1 eq) and DIEA (1.16 g, 8.97 mmol, 1.56 mL, 3 eq) in DCM (10 mL) was added methylsulfonyl methanesulfonate (1.04 g, 5.98 mmol, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture diluted with H2O (50 mL) and extracted with DCM (15 mL × 3). The combined organic phase was driedover anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give [(1S)- 2-[(4-iodo-2,5-dimethyl-pyrazol-3-yl)methyl-isopropyl-amino]-1-methyl-ethyl] methanesulfonate (1.37 g, crude) as an orange oil. LCMS: (M+1: 429.9).

[0598] Step 3. To a solution of [(1S)-2-[(4-iodo-2,5-dimethyl-pyrazol-3-yl)methyl-isopropyl- amino]-1-methyl-ethyl] methanesulfonate (1.37 g, 3.19 mmol, 1 eq) in DMF (14 mL) was added 2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5- yl)pyrazol-3-ol, which was prepared according to the method described in Ex.47, (1.13 g, 3.19 mmol, 1 eq) and K2CO3(1.32 g, 9.57 mmol, 3 eq). The mixture was stirred at 80 °C for 0.5 hour. On completion, the reaction mixture was diluted with H2O (150 mL) and extracted with EA (100 mL × 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 to 2:1) to give (2S)-2-[2,5- dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]p yridin-5-yl)pyrazol-3- yl]oxy-N-[(4-iodo-2,5-dimethyl-pyrazol-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).

[0599] Step 4. To a solution of the product from Step 3 (1.20 g, 1.75 mmol, 1 eq) in DMF (12 mL) was added NaHCO3 (734 mg, 8.74 mmol, 5 eq) and TBAC (971 mg, 3.50 mmol, 2 eq) and Pd(OAc)2(58.9 mg, 262 μmol, 0.15 eq) was degassed and purged with N2for 3 times. The mixture was stirred at 130 °C for 1 hour under N2 atmosphere. On completion, the reaction mixture was diluted with H2O (100 mL) and extracted with EA (100 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (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-(azenometheno)tripyrazolo[3,4-f:3’,4’- j:4’’,3’’-n][1,4]oxazacyclopentadecine (750 mg, crude) as a black brown oil. LCMS: (M+1: 559.4).

[0600] Step 5. To a solution of the product from Step 4 (600 mg, 1.07 mmol, 1 eq) in DCM (6 mL) was added HCl / EtOAc (4.00 M, 3 mL, 11.2 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction was concentrated in vacuum. The residue was purified by prep-HPLC purification (column: Phenomenex luna C18150 * 25 mm * 10 um; mobile phase: [water (FA)-ACN]; gradient: 12%-42% B over 11 min) to give Ex. 106 (94.81 mg, 17.63%yield) as a yellow solid and a byproduct Ex.108 (15.22 mg, 2.87% yield) as an off-white solid.1H NMR for Ex.106 and Ex.108 are in the below NMR table.

[0601] Preparation of (2S)-1-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4’’,3’’- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol (Ex.107)

[0602] Step 1. To a solution of commercially available (2S)-1-(cyclopropylamino)propan-2- ol (140 mg, 1.22 mmol, 1.5 eq.), [(1S)-2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1-yl]-1- methyl-ethoxy]-tert-butyl-dimethyl-silane (407 mg, 810 μmol, 1 eq), which was prepared according to the mehod described in Ex.86, in DMF (5 mL) was added K2CO3 (335 mg, 2.43 mmol, 3 eq). The mixture was stirred at 80 °C for 0.5 hours. On completion, the reaction mixture was partitioned between ethyl acetate (10mL × 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 give (2S)-1-[[2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl-cyclopropyl-amino]propan-2-ol (400 mg, 744 μmol, 91% yield) as yellow oil. LCMS: (M+1: 538.1).

[0603] Step 2. To a solution of the product from Step 1 (400 mg, 744 μmol, 1 eq) in DCM (4 mL) was added TEA (225 mg, 2.23 mmol, 3 eq) and methylsulfonyl methanesulfonate (324 mg, 1.86 mmol, 2.5 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was partitioned between dichloromethane (5 mL × 3) and water (5 mL); and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give [(1S)-2-[[2-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]-5-ethoxy-4- iodo-pyrazol-3-yl]methyl-cyclopropyl-amino]-1-methyl-ethyl] methanesulfonate (400 mg, 87% yield) as a yellow solid. LCMS: (M+1: 616.2).

[0604] Step 3. To a solution of the mesylate from Step 2 (240 mg, 389 μmol, 1 eq), 2,5- dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex. 1, (132 mg, 389 μmol, 1 eq) in DMF (4 mL) was added K2CO3(161 mg, 1.17 mmol, 3 eq). The mixture was stirred at 80 °C for 0.5 hours. On completion, the reaction mixture was partitioned between ethyl acetate (10 mL × 3) and water (12 mL); and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 0:1) to give N-[[2-[(2S)-2-[tert- butyl(dimethyl)silyl]oxypropyl]-5-ethoxy-4-iodo-pyrazol-3-yl]methyl]-N-[(2S)-2-[2,5- dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3- yl]oxypropyl]cyclopropanamine (140 mg, 41% yield) as yellow oil. LCMS: (M+1: 859.3).

[0605] Step 4. A mixture of the product from Step 3 (60.0 mg, 69.8 μmol, 1 eq), Cs2CO3 (68.2 mg, 209 μmol, 3 eq), ditert-butyl(cyclopentyl)phosphane, and dichloropalladium;iron (Pd(dtbpf)Cl2) (22.7 mg, 34.9 μmol, 0.5 eq) in dioxane (1 mL) was degassed and purged with N2for 3 times. Then the mixture was stirred at 80 °C for 10 min under N2atmosphere. On completion, the mixture was filtered, and the filtrate concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 0:1) to give (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-(azenometheno)tripyrazolo[3,4- f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine (10.0 mg, 19% yield) as yellow oil. LCMS: (M+1: 731.3).

[0606] Step 5. To a solution of the product from Step 4 (5.00 mg, 6.84 μmol, 1 eq) in DCM (1 mL) was added HCl / EtOAc (4 M, 0.5 mL, 3 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was filtered, and filtrate concentrated to give a residue. The crude product was purified by reversed-phase HPLC(column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:26%-56% B over 10 min) to give Ex. 107 (0.98 mg, 23% yield) as a yellow solid.1H NMR for Ex. 107 is shown in the below NMR table.

[0607] 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-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4’’,3’’- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.109)

[0608] Step 1. The two starting materials were prepared as in Ex. 8 and Ex. 14. And the chemistry was carried out in the same manner as in Ex.8.

[0609] Step 2, Step 3, and Step 4 were carried out in the same manner as in Ex.108 using 2,5- dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3- ol in Step 3 as prepared according to the method described in Ex.47.

[0610] Step 5. To a solution of (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-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecine (85.0 mg, 0.121 mmol, 1 eq) in DCM (8 mL) was added HCl / EtOAc (2 M, 4 mL, 66 eq). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Welch Ultimate C18150*25mm*5um;mobilephase: [water(FA)-ACN];gradient:0%-30% B over 10 min) to give Ex.109 (19.97 mg, 31.09% yield) as a yellow solid.1H NMR for Ex.109 is in the below NMR table.

[0611] Preparation of (2S)-2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4’’,3’’- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Ex. 110) and (2S)-2-[(11R,17E)-12- cyclopropyl-16-ethoxy-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3’,4’-j:4’’,3’’-n][1,4]oxazacyclopentadecin-14-yl]propan-1- ol (Ex.111)

[0612] Step 1 through Step 4 were carried out in the same manner as in Ex. 107 using [(2S)- 2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1-yl]propoxy]-tert-butyl-dimethyl-silane, which was prepared according to the method described in Ex.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]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex. 1, in Step 3. Step 5 was carried out in the same manner as in Ex.109 to afford Ex.110 and byproduct Ex.111.1H NMR for Ex.110 and Ex. 111 are in the below NMR table.

[0613] Preparation of 2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex. 113) and 2-[(11R,17E)-12-cyclopropyl- 16-ethoxy-6,8,11-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex.114)

[0614] 2-[(10S,17E)-12-cyclopropyl-16-ethoxy-6,8,10-trimethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol (Ex. 113) and 2-[(11R,17E)-12-cyclopropyl-16-ethoxy-6,8,11-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol (Ex. 114) were prepared according to the method described in Ex.107 substituting Na2CO3 and DMF for the base and solvent in step 4 respectively, and using 2-[5-(bromomethyl)-3-ethoxy-4-iodo-pyrazol-1-yl]ethoxy-tert-butyl- dimethyl-silane and 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin- 5-yl)pyrazol-3-ol prepared according to the method described in Ex. 1.1H NMR for Ex. 113 and Ex.114 are shown in the below NMR table.

[0615] Preparation of (2S)-2-[(10S,17E)-12-cyclopropyl-6,8,10,20-tetramethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Ex. 127) and (2S)-2-[(11R,17E)-12- cyclopropyl-6,8,11,20-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Ex.128)

[0616] Step 1. To the mixture of commercially available methyl 1H-pyrazole-5-carboxylate (10.0 g, 79.3 mmol, 1 eq), (2R)-1-[tert-butyl(dimethyl)silyl]oxypropan-2-ol, which was prepared according to the method described in Ex.19, (22.6 g, 119 mmol, 1.5 eq), PPh3(41.6 g, 158 mmol, 2 eq) and DIAD (40.1 g, 198 mmol, 2.5 eq) was added THF (300 mL) dropwise at 0 °C, and the resulting mixture was stirred for another 2 h at 25 °C under N2. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (120 g silica gel, EA in Petroleum ether from 0% to 100%) to give methyl 2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrazole-3- carboxylate (22.4 g, 92% yield) as yellow oil.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).

[0617] Step 2. To a solution of methyl 2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- ethyl]pyrazole-3-carboxylate (21.0 g, 70.3 mmol, 1 eq) in THF (200 mL) was added LAH (2.5M, 30.9 mL, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was slowly added to water (3 mL) at 0 °C, 15% sodium hydroxide solution (3 mL) and water (9 mL) to quench at 0 °C. The reaction mixture was filtered and concentrated under reduced pressure to give [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]pyrazol-3- yl]methanol (17.0 g, 89% yield) as a colorless oil. LCMS: (M+1: 271.1).

[0618] Step 3. To a solution of [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- ethyl]pyrazol-3-yl]methanol (16.0 g, 59.1 mmol, 1 eq) in ACN (160 mL) was added NIS (14.6 g, 65.1 mmol, 1.1 eq) at 0 °C for 0.5 h. The mixture was stirred at 25 °C for 1.5 h. On completion, the reaction mixture was quenched by addition of saturated sodium sulfite solution (100 mL) at 0 °C, and then diluted with H2O (300 mL) and extracted with EA (150 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (220 g silica gel, EA in Petroleum ether from 0% to 100%) to give [2-[(1S)-2-[tert- butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodo-pyrazol-3-yl]methanol (17.0 g, 72% yield) as a colorless oil. LCMS: (M+1: 397.0).

[0619] Step 4. To a solution of [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4- iodo-pyrazol-3-yl]methanol (17.0 g, 42.9 mmol, 1 eq) in DCM (170 mL) was added CBr4 (17.1 g, 51.5 mmol, 1.2 eq) at 0 °C under N2, and then added PPh3 (13.5 g, 51.5 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 1h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (80 g silica gel, EA in Petroleum ether from 0% to 100%) to give [(2S)-2-[5- (bromomethyl)-4-iodo-pyrazol-1-yl]propoxy]-tert-butyl-dimethyl-silane (16.0 g, 81% yield) as a yellow oil. LCMS: (M+1: 460.9).

[0620] Step 5. To a solution of [(2S)-2-[5-(bromomethyl)-4-iodo-pyrazol-1-yl]propoxy]-tert- butyl-dimethyl-silane (1.50 g, 3.27 mmol, 1 eq) in DMF (15 mL) was added K2CO3(677 mg, 4.90 mmol, 1.5 eq) and commercially available (2S)-1-(cyclopropylamino)propan-2-ol (432 mg, 3.76 mmol, 1.15 eq). The mixture was stirred at 80 °C for 1 hr. On completion, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (15 mL × 2) and dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (4 g silica gel, EA in Petroleum ether from 0% to 100%) to give (2S)-1-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodo- pyrazol-3-yl]methyl-cyclopropyl-amino]propan-2-ol (1.58 g, 3.00 mmol, 91% yield, 93% purity) as a yellow oil. LCMS: (M+1: 494.1).

[0621] Step 6. To a solution of the product from Step 5 (1.40 g, 2.84 mmol, 1 eq) in DCM (14 mL) was added DIEA (1.10 g, 8.51 mmol, 1.48 mL, 3 eq) and methylsulfonyl methanesulfonate (988 mg, 5.67 mmol, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was diluted with water (40 mL) and extracted with DCM (15 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (10 mL × 2) and dried over Na2SO4, filtered and the filtrate was concentrated to give [(1S)-2-[[2- [(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodo-pyrazol-3-yl]methyl- cyclopropyl-amino]-1-methyl-ethyl] methanesulfonate (1.76 g, crude) as a colorless oil. LCMS: (M+1: 572.1).

[0622] Step 7. A mixture of the mesylate form Step 6 (1.50 g, 2.62 mmol, 1 eq), 2,5-dimethyl- 4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol (881 mg, 2.49 mmol, 0.95 eq), which was prepared according to the method described in Ex. 47, and K2CO3 (1.09 g, 7.87 mmol, 3 eq) in ACN (15 mL) was stirred at 60 °C for 2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel (12 g silica gel, EA in Petroleum ether from 0% to 100%) to give N-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodo- pyrazol-3-yl]methyl]-N-[(2S)-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxypropyl]cyclopropanamine (1.00 g, 45% yield) as a green solid. LCMS: (M+1: 829.4).

[0623] Step 8. To a solution of the product from Step 7 (220 mg, 0.265 mmol, 1 eq) in DMF (20 mL) was added Na2CO3(84.4 mg, 0.796 mmol, 3 eq) and cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (Pd(dppf)Cl2) (19.4 mg, 0.0265 mmol, 0.1 eq). The mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. On completion, the mixture was poured into H2O (80 mL) and extracted with EA (100 mL × 3). The combined organic phase was washed with H2O (100 mL × 3) and dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF=1:0 to 0:1) to give (10S,17E)-14-[(2S)-1-{[tert- butyl(dimethyl)silyl]oxy}propan-2-yl]-12-cyclopropyl-6,8,10,20-tetramethyl-2-(oxan-2-yl)- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (80.0 mg) as a green solid. LCMS: (M+1: 701.4).

[0624] Step 9. To a solution of the product from Step 8 (70.0 mg, 99.8 μmol, 1 eq) in MeOH (1.5 mL) was added HCl (12 M, 0.5 mL, 60.08 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The mixture was purified by Prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:15%-45% B over 8 min ), followed by further SFC separation(column: REGIS (R,R)WHELK-O1 (250mm*25mm, 10 um); mobile phase: [CO2- ACN / MeOH(0.1% NH3H2O)];B%:45%, isocratic elution mode ) to give Ex.127 (7.70 mg) as brown solid and a byproduct Ex.128 (5.02 mg) as brown solid.1H NMR for Ex.127 and Ex. 128 can be found in the below NMR table.

[0625] Preparation of (2S)-2-[(10S,17E)-12-cyclopropyl-6-(methoxymethyl)-8,10,20- trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Ex.139) and (2S)-2-[(11R,17E)-12- cyclopropyl-6-(methoxymethyl)-8,11,20-trimethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Ex.140):

[0626] Step 1. To a solution of 5-bromo-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H- pyrazolo[3,4-c]pyridine, which was prepared according to the method described in Ex.28 (5.40 g, 16.7 mmol, 1 eq), in dioxane (43 mL) was added 3-(methoxymethyl)-1-methyl-1H- pyrazol-5-ol, which was prepared according to the method described in Ex.130 (2.86 g, 20.1 mmol, 1.2 eq), K2CO3 (6.95 g, 50.3 mmol, 3 eq) and tBuBrettphos Pd G3 (1.43 g, 1.68 mmol, 0.1 eq) under N2atmosphere. The mixture was stirred at 130 °C for 1 hour under N2atmosphere. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane:Methanol = 1:0 to 10:1) to give 3-(methoxymethyl)-1-methyl-4-(7-methyl-1-(tetrahydro-2H-pyran-2-yl)-3- vinyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-5-ol (5.20 g, 13.5 mmol, 81% yield) as red oil. LCMS: (M+1: 384.2).

[0627] Steps 2 through 4 were performed in a similar manner to steps 7 through 9 in the synthesis of Ex.127 / 128, with DMF used as the solvent in step 7 rather than ACN.1H NMR for Ex.139 and Ex.140 can be found in the below NMR table.

[0628] Preparation of 2-[(8aR,9S,19E)-1-ethoxy-9,11,13,21-tetramethyl-7,8,8a,9,11,17- hexahydro-6H-14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n]pyrrolo[2,1- c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol (Ex.177) and 2-[(8aR,9R,19E)-1-ethoxy- 9,11,13,21-tetramethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometheno)tripyrazolo[3,4- f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol (Ex.178):

[0629] Step 1. To a solution of tert-butyl (2R)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate, which was prepared according to the method described in Ex.32 / Ex.33 (5.00 g, 23.2 mmol,1 eq,) in DCM (50 mL) was added HCl / dioxane (4.00 M, 50 mL, 8.61 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction was concentrated in vacuum to give 1-((R)-pyrrolidin-2-yl)ethan-1-ol (3.50 g, crude) as a yellow solid.1H NMR (400 MHz, DMSO-d6 ) δ = 9.96 - 9.37 (m, 1H), 8.70 (s, 1H), 3.96 (d, J = 4.4, 6.4 Hz, 1H), 3.81 - 3.69 (m, 1H), 3.13 - 3.04 (m, 2H), 1.98 - 1.85 (m, 2H), 1.84 - 1.74 (m, 1H), 1.64 - 1.51 (m, 1H), 1.17 - 1.05 (m, 3H).

[0630] Step 2. To a solution of 1-[(2R)-pyrrolidin-2-yl]ethanol (1.00 g, 6.59 mmol, 1 eq, HCl) in ACN (20 mL) was added K2CO3(2.73 g, 19.8 mmol, 3 eq) and (S)-5- (bromomethyl)-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H- pyrazole, prepared according to the method described in Ex.1 (3.23 g, 6.59 mmol, 1 eq). The mixture was stirred at 80 °C for 2 hours. On completion, the reaction solution was filtered to remove the K2CO3and then concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=1:0 to 5:1) to give 1-((R)- 1-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazol-5- yl)methyl)pyrrolidin-2-yl)ethan-1-ol (2.70 g, 4.74 mmol, 72% yield, 92% purity) as a colorless liquid.1H NMR (400 MHz, DMSO-d6) δ = 4.45 (d, J = 4.4 Hz, 1H), 4.36 - 4.21 (m, 1H), 4.18 - 4.08 (m, 3H), 4.06 - 3.96 (m, 1H), 3.81 (t, J = 4.8 Hz, 2H), 3.72 - 3.55 (m, 1H), 2.74 - 2.62 (m, 1H), 2.46 - 2.39 (m, 1H), 2.25 (d, J = 6.4, 9.2 Hz, 1H), 1.75 - 1.63 (m, 2H), 1.62 - 1.43 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H), 1.19 - 1.05 (m, 1H), 1.01 (d, J = 1.2, 6.0 Hz, 3H), 0.77 (d, J = 2.4 Hz, 9H), -0.09 (s, 3H), -0.10 - -0.13 (m, 3H); LCMS: (M+1: 524.4).

[0631] Step 3. A solution of 1-((R)-1-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4- iodo-1H-pyrazol-5-yl)methyl)pyrrolidin-2-yl)ethan-1-ol (926 mg, 1.77 mmol, 1 eq), 1,3- dimethyl-4-(7-methyl-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridin-5- yl)-1H-pyrazol-5-ol, which was prepared according to the method described in Ex.47 (500 mg, 1.41 mmol, 0.8 eq), and PPh3(927 mg, 3.54 mmol, 2 eq) in 2-methyltetrahydrofuran (10 mL) was degassed and purged with N2 atmosphere for 3 times. Then DBAD (896 mg, 3.89 mmol, 2.2 eq) was added, and the mixture was stirred at 25 °C for 2 hours under N2atmosphere. On completion, the reaction was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=1:0 to 3:1) to give 5-(5-(1-((R)-1-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-ethoxy-4-iodo-1H-pyrazol- 5-yl)methyl)pyrrolidin-2-yl)ethoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-7-methyl-1-(tetrahydro- 2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridine (750 mg, 0.655 mmol, 37% yield, 75% purity) as an orange oil. LCMS: (M+1: 859.3).

[0632] Step 4. To a solution of 5-(5-(1-((R)-1-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3- ethoxy-4-iodo-1H-pyrazol-5-yl)methyl)pyrrolidin-2-yl)ethoxy)-1,3-dimethyl-1H-pyrazol-4-yl)-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-c]pyridine (700 mg, 0.815 mmol, 1 eq) in DMF (7 mL) was added NaHCO3 (342 mg, 4.07 mmol, 5 eq), TBAC (453 mg, 1.63 mmol, 2 eq) and Pd(OAc)2(27.5 mg, 0.122 mmol, 0.15 eq). The mixture was stirred at 130 °C for 1 hour under N2 atmosphere. On completion, the reaction mixture diluted with H2O (100 mL) and extracted with EA (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=1:0 to 10:1) to give 2-[(8aR,19E)-1-ethoxy-9,11,13,21-tetramethyl-17-(oxan- 2-yl)-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol (380 mg, 0.616 mmol, 53% yield, 70% purity) as a black brown oil. LCMS: (M+1: 617.3).

[0633] Step 5. To a solution of 2-[(8aR,19E)-1-ethoxy-9,11,13,21-tetramethyl-17-(oxan-2- yl)-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol (340 mg, 0.551 mmol, 1 eq) in DCM (4 mL) was added HCl / EtOAc (4.00 M, 0.138 mL, 1 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC to give 2-[(8aR,9S,19E)-1-ethoxy-9,11,13,21- tetramethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol (15.35 mg, 0.029 mmol, 5.21% yield, 99.69% purity) as a white solid (Ex.177) and 2-[(8aR,9R,19E)-1-ethoxy- 9,11,13,21-tetramethyl-7,8,8a,9,11,17-hexahydro-6H-14,16-(azenometheno)tripyrazolo[3,4- f:3',4'-j:4'',3''-n]pyrrolo[2,1-c][1,4]oxazacyclopentadecin-3(4H)-yl]ethan-1-ol (12.24 mg, 0.021 mmol, 3.74% yield, 89.61% purity) as a white solid (Ex.178).1H NMR for Ex.177 and Ex.178 can be found in the below NMR table.

[0634] Ex. 179 and Ex. 180 were synthesized following the procedure described for the synthesis of Ex. 177 / Ex. 178, using (S)-5-(bromomethyl)-1-(1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-1H-pyrazole (which was prepared following the method described in Ex.19) in Step 2.1H NMR for Ex.179 and Ex.180 can be found in the below NMR table.

[0635] General Method B: using Ex.22 as example.

[0636] Preparation of {[(10S,17E)-14-(2-hydroxyethyl)-6,8,10,12-tetramethyl- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile (Ex.22)

[0637] Step 1. To a solution of commercially available ethyl 3-hydroxy-1H-pyrazole-5- carboxylate (1.00 g, 6.40 mmol, 1 eq) in DMF (10 mL) was added imidazole (1.31 g, 19.2 mmol, 3 eq), and then TBSCl (1.45 g, 9.61 mmol, 1.5 eq) was added at 0 °C under N2. Themixture was stirred at 25 °C for 12 h. On completion, the reaction mixture was partitioned between EA (30 mL × 3) and water (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:1 to 1:1) to give ethyl 3-{[tert- butyl(dimethyl)silyl]oxy}-1H-pyrazole-5-carboxylate (1.70 g, 6.29 mmol, 98% yield) as a white solid. LCMS: (M+1: 271.1).

[0638] Step 2. To a solution of ethyl 3-{[tert-butyl(dimethyl)silyl]oxy}-1H-pyrazole-5- carboxylate (1.70 g, 6.29 mmol, 1 eq) in THF (17 mL) was added commercially available 2- [tert-butyl(dimethyl)silyl]oxyethanol (1.11 g, 6.29 mmol, 1 eq) and PPh3 (3.63 g, 13.8 mmol, 2.2 eq), then DIAD (3.18 g, 15.7 mmol, 2.5 eq) was added at 0 °C under N2. The mixture was stirred at 25 °C for 2 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA=1:1 to 1:1) to give ethyl 5-[tert-butyl(dimethyl)silyl]oxy-2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazole-3- carboxy late(2.57 g, 5.99 mmol, 95% yield) as a brown solid. LCMS: (M+1: 429.6).

[0639] Step 3. To a solution of ethyl 5-[tert-butyl(dimethyl)silyl]oxy-2-[2-[tert- butyl(dimethyl) silyl] oxyethyl]pyrazole-3-carboxylate (2.27 g, 5.29 mmol, 1 eq) in THF (22 mL) was added LiAlH4 (2.5 M, 4.24 mL, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, water (0.4 mL) was added to the reaction solution, then 15% NaOH (0.4 mL) was added to the solution, then water (1.2 mL) was added, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1:1 to 1:1) to give 1-[2-[tert-butyl(dimethyl)silyl] oxyethyl]-5- (hydroxymethyl)pyrazol-3-ol (500 mg, 1.84 mmol, 35% yield) as a white solid. LCMS: (M+1: 273.1).

[0640] Step 4. To a solution of 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5- (hydroxymethyl)pyrazol-3-ol (450 mg, 1.65 mmol, 1 eq) in DMF (5 mL) was added 2- chloroacetonitrile (187 mg, 2.48 mmol, 1.5 eq) and K2CO3 (457 mg, 3.30 mmol, 2 eq). The mixture was stirred at 80 °C for 2 h. On completion, the reaction mixture was partitioned between EA (15 mL × 3) and water (15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=2:1 to 2:1) to give 2-[1-[2-[tert- butyl(dimethyl)silyl] oxyethyl]-5-(hydroxymethyl)pyrazol-3-yl]oxyacetonitrile (380 mg, 1.22 mmol, 74% yield) as a white solid. LCMS: (M+1: 312.1).

[0641] Step 5. To a solution of 2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5- (hydroxymethyl)pyrazol -3-yl]oxyacetonitrile (350 mg, 1.12 mmol, 1 eq) in ACN (4 mL) was added NIS (379 mg, 1.69 mmol, 1.5 eq) 0 °C. The mixture was stirred at 25 °C for 2 h. Oncompletion, the reaction mixture was partitioned between EA (5 mL × 3) and water (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=2:1 to 2:1) to give 2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-(hydroxylmethyl)- 4-iodo-pyrazol-3-yl]oxyacetonitrile (429 mg, 981 μmol, 87% yield) as a white solid. LCMS: (M+1: 438.0).

[0642] Step 6. To a solution of 2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5- (hydroxymethyl)-4-iodo-pyrazol-3-yl]oxyacetonitrile (389 mg, 889 μmol, 1 eq) in DCM (4 mL) was added PPh3 (280 mg, 1.07 mmol, 1.2 eq), then CBr4 (354 mg, 1.07 mmol, 1.2 eq) was added at 0°C under N2. The mixture was stirred at 25 °C for 2 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=3:1 to 3:1) to give 2-[5-(bromomethyl)-1-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-4-iodo-pyrazol-3-yl]oxyacetonitrile (350 mg, 699 μmol, 78% yield) as a yellow oil. LCMS: (M+1: 501.9).

[0643] Step 7. To a solution of 2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridin-5-yl)pyrazol-3-ol, which was prepared according to the method described in Ex. 1, (550 mg, 1.62 mmol, 1 eq) in NMP (5 mL) was added commercially available [(1R)-2-(tert- butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate (1.03 g, 4.05 mmol, 2.5 eq) and K2CO3(224 mg, 1.62 mmol, 1 eq). The mixture was stirred at 60 °C for 2 h. On completion, the reaction mixture was partitioned between 2-Me-THF (20 mL × 3) and water (20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:1 to 1:1) to give tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxyprop yl]carbamate (252 mg, 507 μmol, 31% yield) as a white solid. LCMS: (M+1: 497.2).

[0644] Step 8. To a solution of tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl- 3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxypropyl]carbamate (232 mg, 467 μmol, 1 eq) in DMF (5 mL) was added NaH (37.4 mg, 934 μmol, 60% purity, 2 eq) at 0 °C, the mixture was stirred at 0 °C for 0.5 h, then CH3I (99.5 mg, 701 μmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 2 h. On completion, saturated ammonium chloride (1 mL) was added to quench the reaction mixture, the mixture was partitioned between EA (15 mL × 3) and water (15 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:1 to 1:1) to give tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxyprop yl]-N-methyl-carbamate (183 mg, 358 μmol, 77% yield) as a white solid. LCMS: (M+1: 511.3).

[0645] Step 9. To a solution of tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl- 3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxypropyl]-N-methyl-carbamate (183 mg, 358 μmol, 1 eq) in DCM (2 mL) was added ZnBr2(403 mg, 1.79 mmol, 5 eq). The mixture was stirred at 25 °C for 12 h. On completion, the reaction mixture was partitioned between DCM (2 mL × 3) and water (2 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH=5:1 to 5:1) to give (2S)-2-[2,5-dimethyl-4-(1- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl- propan-1-amine (77.0 mg, 187 μmol, 52% yield) as a white solid. LCMS: (M+1: 411.1).

[0646] Step 10. To a solution of (2S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-1-amine (190 mg, 463 μmol, 1 eq) in ACN (2 mL) was added 2-[5-(bromomethyl)-1-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-4-iodo-pyrazol-3-yl]oxyacetonitrile (254 mg, 509 μmol, 1.1 eq) and K2CO3 (192 mg, 1.39 mmol, 3 eq). The mixture was stirred at 60 °C for 1 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:1 to 1:1) to give 2-[1-[2-[tert- butyl(dimethyl)silyl]oxyethyl]-5-[[[(2S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxypropyl]-methyl-amino]methyl] -4-iodo-pyrazol- 3-yl] oxyacetonitrile (329 mg, 396 μmol, 86% yield) as a white solid. LCMS: (M+1: 830.1).

[0647] Step 11. To a mixture of 2-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[[(2S)-2-[2,5- dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3- yl]oxyprop yl]-methyl-amino]methyl]-4-iodo-pyrazol-3-yl]oxyacetonitrile (309 mg, 372 μmol, 1 eq) in DMF (15 mL) was added NaHCO3(78.2 mg, 931 μmol, 2.5 eq), Pd(OAc)2(16.7 mg, 74.5 μmol, 0.2 eq) and TBAC (103 mg, 372 μmol, 1 eq) degassed and purged with N2 for 3 times, then the mixture was stirred at 130 °C for 0.5 h under N2atmosphere. On completion, the reaction mixture was partitioned between EA (45 mL × 3) and water (45 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:1 to 1:1) to give {[(10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6,8,10,12-tetramethyl- 2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'- j:4'',3''-n][1,4]oxazacyclopentadecin-16-yl]oxy}acetonitrile (223 mg, 317 μmol, 85% yield) as a white solid. LCMS: (M+1: 702.3).

[0648] Step 12. To a solution of {[(10S,17E)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)- 6,8,10,12-tetramethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16- yl]oxy}acetonitrile (203 mg, 289 μmol, 1 eq) in DCM (2 mL) was added TFA (3.07 g, 26.9 mmol, 93 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH=10:1 to 10:1) to give Ex.22 (52.78 mg, 105 μmol, 36.24% yield) as yellow solid. LCMS: (M+1: 504.1).1H NMR for Ex.22 is shown in the below NMR table.

[0649] Preparation of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (Ex.27)

[0650] Step 1. To a solution of (2S)-2-[2,5-dimethyl-4-(1-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl...

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula Iwherein ring A and ring B are each independently a 5-membered heteroarylene; each R1and R2, when present, is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; each R3, R4, R5, and R6is independently H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb,-NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or two of R3, R4, R5, and R6, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C3-C6cycloalkyl and 3- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; R7is H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -C(O)Rc, or -C(O)NRcRd, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; or R7and one of R3, R4, R5, or R6, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, 0173SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf,-P(O)ORe, -P(O)2ORe, -CN, or -NO2; R8is H, -S(O)2Rc, -S(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, or -P(O)2ORc; R9is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, and C1-C6alkylene-5- to 10-membered heteroaryl; or Raand Rbor Rcand Rdor Reand Rf, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, and C1-C6alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OC1-C6alkyl, -OC(O)- (H or C1-C6alkyl), -OC(O)N(H or C1-C6alkyl)2, -OC(O)N(C2-C6alkylene), -OS(O)-(H or C1-C6alkyl), -OS(O)2-(H or C1-C6alkyl), -OS(O)N(H or C1-C6alkyl)2, -OS(O)N(C2-C6alkylene), -OS(O)2N(H or C1-C6alkyl)2, -OS(O)2N(C2-C6alkylene), -S(H or C1-C6alkyl), -S(O)(H or C1-C6alkyl), -S(O)2(H or C1-C6alkyl), -S(O)N(H or C1-C6alkyl)2, -S(O)N(C2-C6alkylene), -S(O)2N(H or C1-C6alkyl)2, -S(O)2N(C2-C6alkylene), -N(H or C1-C6alkyl)2, -N(C2-C6alkylene), -N(H or C1-C6alkyl)C(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)O(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)C(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)2(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)N(C2-C6alkylene), -N(H or C1-C6alkyl)S(O)2N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)2N(C2-C6alkylene), -C(O)-(H or C1-C6alkyl), -C(O)O(H or C1-C6alkyl), -C(O)N(C2-C6alkylene), -P(H or C1-C6alkyl)2, -P(C2-C6alkylene), -P(O)(H or C1-C6alkyl)2, -P(O)(C2-C6alkylene), -P(O)2(H or C1-C6alkyl)2, -P(O)2(C2-C6alkylene), -P(O)N(H or C1-C6alkyl)2, -P(O)N(C2-C6alkylene), -P(O)2N(H or C1-C6alkyl)2, -P(O)2N(C2-C6alkylene), -P(O)O(H or C1-C6alkyl), -P(O)2O(H or C1-C6alkyl), -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; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

2. The compound of claim 1, having the formula IIII wherein each “ ” is independently a carbon-carbon single bond or a carbon-carbon double bond; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

3. The compound of claim 1 or 2, having the formula IIIwherein each “ ” is independently a carbon-carbon single bond or a carbon-carbon double bond; X1, X2, and X3are each independently -O-, -S-, =C(H)-, =C(R1)-, -N(H)-, -N(R1)- or =N-, provided that at least one of X1, X2, and X3is not =C(H)-, or =C(R1)-; and / or Y1, Y2, and Y3are each independently -O-, -S-, =C(H)-, =C(R2)-, -N(H)-, -N(R2)- or =N-, provided that at least one of Y1, Y2, and Y3is not =C(H)-, or =C(R2)-; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

4. The compound of claim 3, having the formula IVor a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

5. The compound of claim 3 or 4, wherein X2is =N- or -N(R1)-, X1and X3are each independently -O-, -S-, =C(H)-, =C(R1)-, -N(H)-, or -N(R1)-; and / or Y2is =N-, Y1and Y3are each independently -O-, -S-, =C(H)-, =C(R2)-, -N(H)-, or -N(R2)-; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

6. The compound of any one of claims 1 to 4, wherein: ring A is selected from the group consisting ofwherein each “ ” represents a point of covalent attachment; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

7. The compound of any one of the preceding claims, wherein ring A is selected from the group consisting of wents a point of covalent attachment; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

8. The compound of any one of the preceding claims, wherein ring A is selected from the group consisting ofwherein each “ ” represents a point of covalent attachment; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

9. The compound of any one of claims 1 to 4 or 6, wherein ring B is selected from the group consisting of, wherein each“ ” represents a point of covalent attachment; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

10. The compound of any one of the preceding claims, wherein ring B is selected from the group consisting ofwherein each“ ” represents a point of covalent attachment; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

11. The compound of any one of the preceding claims, wherein p is 2 or 3, and the portionis an ethylene or propylene, wherein each R3and R4is independently H, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or at least one instance of R3and R4, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C3-C6cycloalkyl and 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or R7and one instance of R3or R4, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 7-membered heterocycloalkyl formed is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and each “” represents a point of covalent attachment; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

12. The compound of any one of the preceding claims, wherein one R3is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and / or two R3and R4, taken together with the carbon or carbons to which they are attached, combine to form C3-C6cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C3-C6cycloalkyl and 4- to 7-membered heterocycloalkyl is independently optionally substituted by-ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and / or R7and one instance of R3or R4and, taken together with the atoms to which they are attached, combine to form a 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and any remaining R3and R4are H or deuterium; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

13. The compound of any one of the preceding claims, wherein one R3is C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and / or R7and one instance of R3or R4taken together with the atoms to which they are attached, combine to form 4- to 7- membered heterocycloalkyl, wherein each hydrogen atom in 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and any remaining R3and R4are H or deuterium; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

14. The compound of any one of the preceding claims, wherein one instance of R3is C1-C6alkyl; and any remaining R3and R4are H or deuterium; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

15. The compound of any one of the preceding claims, wherein one instance of R3is C1-C6alkyl; R7and one instance of R4, taken together with the atoms to which they are attached, combine to form a 4- to 7-membered heterocycloalkyl; and any remaining R3and R4are H or deuterium; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

16. The compound of any one of the preceding claims, wherein one instance of R3is methyl, and any remaining R3and R4are H or deuterium; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

17. The compound of any one of the preceding claims, wherein R7is H, C1-C6alkyl, C3-C6cycloalkyl, or -C(O)Rc; or R7and one instance of R3or R4, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6alkyl, C3-C6cycloalkyl, and 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

18. The compound of any one of the preceding claims, wherein the portion i,” represents a point of covalent attachment, and each hydrogen is independently optionally substituted with deuterium; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

19. The compound of any one of the preceding claims, wherein R5and R6are each H; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

20. The compound of any one of the preceding claims, wherein the portionis of the formula,, nt, and each hydrogen is independently optionally substituted with deuterium; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

21. The compound of any one of the preceding claims, wherein R8is H or C1-C6alkyl;or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

22. The compound of any one of the preceding claims, wherein R9is H, deuterium, halogen, C1-C6alkyl, or -ORa, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted with deuterium; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

23. The compound of any one of the preceding claims, wherein R9is H, deuterium, halogen, -OCH3, -CH3, or -CD3; or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

24. The compound of claim 1, selected from the group consisting of,or 25.,,or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof.

26. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, and optionally one or more excipients.

27. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a 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 disease in a subject.

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

Images