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 / 717,089, filed November 6, 2024, the entire disclosure of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure relates to compounds (e.g., macrocyclic 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 the treatment. Different processes contribute to the emergence of tolerant persister cells, including pathway rebound through the release of negative feedback loops, transcriptional rewiringmediated 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 resi stance 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 (del 19) 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 (Del 19 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. Set 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 (Dell9 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 todacomitinib. J Thorac Oncol 2018; 13: 727-31). The third-generation EGFR inhibitor Osimertinib is also an irreversible inhibitor targeting both EGFR activating mutations (Dell9 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 (Exl9del)) 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, A746-750, A746-750 / C797S, L858R / T790M, L858R / T790M / C797S, 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,

[0009] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0010] wherein ring A, ring B, L, R1, R3, R4, R8, R9, X, m, n, and p are as described herein.

[0011] In another aspect, the disclosure relates to a compound of the formula I(a)-(h),

[0012] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0013] wherein ring A, ring B, L, R1, R3, R4, R8, R9, X, m, n, and p are as described herein.

[0014] In another aspect, the disclosure relates to a compound of the formula II,

[0015] or an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0016] wherein ring A, ring B, L, R1, R, R4, R8, R9, m, n, and p are as described herein are as described herein.

[0017] In another aspect, the disclosure relates to a compound of the formula II(a)-(h),R2.

[0018] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0019] wherein ring A, ring B, L, R1, R3, R4, R8, R9, m, n, and p are as described herein.

[0020] In another aspect, the disclosure relates to a compound of the formula 111,III

[0021] or an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0022] wherein ring A, ring B, L, R1, R, R4, R8, R9, m, n, and p are as described herein are as described herein.

[0023] In another aspect, the disclosure relates to a compound of the formula III(a)-(h),R2.

[0024] or an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0025] wherein ring A, ring B, L, R1, R3, R4, R8, R9, m, n, and p are as described herein.

[0026] In certain embodiments of the above aspects, the compound of Formula (I)-(III) is a compound selected from those species described or exemplified in the detailed description below.

[0027] In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(III), an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.

[0028] In further aspects, the disclosure relates to a compound of Formula (I)-(III), an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, for use as a medicament.

[0029] 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)-(III), an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0030] In further aspects, the disclosure relates to use of a compound of Formula (I)-(III), an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of disease, such as cancer, and the use of such compounds and salts for treatment of such diseases.

[0031] 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 of Formula (I)-(III), an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and / or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.

[0032] 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.

[0033] 1. A compound of the formula Ieach Lis independently -O-, -S-, -S(O)-, -S(O)2-, -N(R5)C(O)-, -C(O)N(R5)-, -N(R5)-, -N(R5)S(O)-, -S(O)N(R5)-, -N(R5)S(O)2-, -S(O)2N(R5)-, or -C(R6)(R7)-, provided that (L)udoes not comprise an O-O, S-O, or N-N bond;X is N or CH;each R1and R2, when present and covalently attached to a nitrogen atom, is independently deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, Ce-Cio aiyl, 5- to 10-membered heteroaryl, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, or -C(=NRa)NRaRh, wherein each hydrogen atom in Ci-Ce alkyl, C2-Cbalkenyl, C2-C, alkynyl, C3-C6 cycloalkyl, Cb-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10- membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci- Ce alkyl, Ci-Ce haloalkyl, -Rg, -Rh, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg,-OS(O)NRgRh, -OS(O)2NRgRh, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)R8, -C(O)OR8, -C(O)NR8Rh, -PRgRh, -P(O)RgRh, -P(O)2R8Rh, -P(O)NR8Rh, -P(O)2NR8Rh, -P(O)ORS, -P(O)2OR8, -CN, or -NO2; or, when present and covalently attached to a carbon atom, is independently deuterium, halogen, Ci-Cg alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Cs-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -ORa, -0C(0)Ra, -0C(0)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(0)2NRaRb, -0S(0)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)0Rb, -NRaC(0)NRaRb, -NRaS(0)Rb, -NRaS(O)2Rb, -NRaS(0)NRaRb, -NRaS(O)2NRaRb, -C(0)Ra, -C(O)ORa, -C(0)NRaRb, -PRaRb, -P(0)RaRb, -P(O)2RaRb, -P(0)NRaRb, -P(0)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Cs-Ce cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ct, alkyl, Ci-Ce haloalkyl, -Rg, -Rh, -ORg, -0C(0)Rg, -0C(0)NRgRh, -OS(O)Rg, -OS(O)2Rg, -0S(0)NRgRh, -0S(0)2NRgRh, -SRg, -S(O)Rg, -S(O)2Rg, -S(0)NRgRh, -S(0)2NRgRh, -NR8Rb, -NRgC(0)Rb, -NR8C(0)0Rb, -NRgC(0)NR8Rh, -NRgS(0)Rh, -NRgS(O)2Rh, -NR8S(0)NRgRh, -NR8S(O)2NR8Rh, -C(O)Rg, -C(0)0R8, -C(0)NRgRh, -PRgRh, -P(0)RgRh, -P(0)2RgRh, -P(0)NRgRh, -P(0)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2;each R3, when present, is independently deuterium, halogen, Ci-Cs alkyl, C>-C, alkenyl, C2-C, alkynyl, C3-C0 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -0C(0)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(0)NRaRb, -S(0)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)0Rb, -NRaC(0)NRaRb, -NRaS(0)Rb, -NRaS(0)2Rb, -NRaS(0)NRaRb, -NRaS(O)2NRaRb, -C(0)Ra, -C(O)ORa, -C(0)NRaRb, -PRaRb, -P(0)RaRb, -P(O)2RaRb, -P(0)NRaRb, -P(0)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in Ci-Ce alkyl, C2-C alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C& alkyl, Ci-Ce haloalkyl. -R8, -Rh, -OR8, -0C(0)R8, -0C(0)NR8Rh, -OS(O)R8, -OS(O)2Rg, -0S(0)NR8Rh, -0S(0)2NRgRh, -SR8, -S(O)R8, -S(O)2R8, -S(O)NR8Rh, -S(O)2NR8Rh, -NRgRh, -NRgC(0)Rh, -NRgC(0)0Rh, -NRgC(0)NRgRb, -NRgS(0)Rh, -NRgS(O)2Rh, -NRgS(0)NRgRh, -NRgS(0)2NRgRh, -C(O)Rg, -C(0)0Rg, -C(0)NRgRh, -PRgRh, -P(0)RgRh, -P(0)2RgRh, -P(0)NRgRh, -P(0)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2;R4is H, deuterium, Ci-C6alkyl, -C(O)RC. -C(0)0Rc, -C(0)NRcRd, -P(O)2RcRd,-P(O)2NRcRd, -P(O)2ORe, or -S(O)2ORC;each R', when present, is independently H, deuterium, Ci-Cg alkyl, C2-Cbalkenyl, C2-Cbalkynyl, Cs-Ce cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -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(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;each R6and R7, is independently H, deuterium, halogen, Ci-Ce alkyl, C2-Cbalkenyl, C2-C, alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cs-Cio aryl, 5- to 10-membered heteroaryl, -ORC, -OC(O)Re, -0C(0)NRcRd, -OC(=NRc)NRcRd, -OS(O)Re, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(0)Rd, -N(C(0)Rc)(C(0)Rd), -NRcC(0)0Rd, -NRcC(0)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NR S(O)2Rd. -NRcS(0)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)OR“, -C(0)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(0)NRcRd, -P(0)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2, wherein each hydrogen atom in Ci-Cg alkyl, C2-Cbalkenyl, C2-Cbalkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cic aryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cbalkyl, Ci-Cg haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;or two of R5, R6and R7, taken together with the atom or atoms to which they are attached, optionally combine to form a C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl formed when two of R5, R6and R7are taken together is independently optionally substituted by -ORe, -0C(0)Re, -0C(0)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(0)Rf, -NReC(O)ORf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(0)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(0)2NReRf,-P(O)ORe, -P(O)2ORe, -CN, or -NO2;R8and R9are each independently H, deuterium, halogen, C-C. alkyl, Ci-Cehaloalkyl, -ORa, -C(O)Ra, -C(O)ORa, or -C(O)NRaRb;each Ra, Rb, Rc, Rd, Re, Rf, R8, and Rhis independently selected from the group consisting of H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cg alkynyl, Cj-Ce cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, Ci-Cg alkylene-Cg-Cio aryl, 5- to 10-membered heteroaryl, and Ci-G, alkylene-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 C-C. alkyl, C -C, alkenyl, C -C alkynyl, C2-Ce cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, Ci-Ce alkylene-Ce-Cio aryl, 5- to 10-membered heteroaryl, or Ci-Cg alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C0 alkyl, Ci-Cehaloalkyl, -OH, -OCi-C6alkyl, -0C(0)-(H or Ci-C6alkyl), -0C(0)N(H or C1-C5 alkyl)2. -OC(O)N(C2-C6alkylene), -OS(O)-(H or Ci-C6alkyl), -OS(O)2-(H or Ci-C6alkyl), -OS(O)N(H or Ci-C6alkyl)2, -OS(O)N(C2-Ce alkylene), -OS(O)2N(H or Ci-Cg alkyl)2, -OS(O)2N(C2-Ce alkylene), -S(H or Ci-C6alkyl), -S(O)(H or Ci-C6alkyl), -S(O)2(H or Ci-C6alkyl), -S(0)N(H or Ci-C6alkyl)2, -S(O)N(C2-Ce alkylene), -S(O)2N(H or Ci-Cg alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or Ci-Ce alkyl)2, -N(C2-Ce alkylene), -N(H or Ci-Ce alkyl)C(O)-(H or Ci-Ce alkyl), -N(H or Ci-C6alkyl)C(O)O(H or Ci-C6alkyl), -N(H or Ci-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)C(O)N(C2-C6alkylene), -N(H or Ci-C6alkyl)S(O)-(H or Ci-C6alkyl), -N(H or Ci-C2alkyl)S(O)2(H or Ci-Ce alkyl), -N(H or Ci-G> alkyl)S(O)N(H or Ci-Ce alkyl)2, -N(H or C1-C5 alkyl)S(O)N(C2-C6alkylene), -N(H or Ci-C6alkyl)S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)S(O)2N(C2-C6alkylene), -C(O)-(H or Ci-C6alkyl), -C(0)0(H or Ci-C6alkyl), -C(O)N(C2-C6alkylene), -P(H or Ci-C6alkyl)2, -P(C2-C6alkylene), -P(0)(H or Ci-C6alkyl)2, -P(O)(C2-Ce alkylene), -P(O)2(H or Ci-Ce alkyl)2, -P(O)2(C2-Ce alkylene), -P(0)N(H or Ci-Ce alkyl)2, -P(O)N(C2-Cg alkylene), -P(0)2N(H or Ci-Cs alkyl)2, -P(O)2N(C2-Ce alkylene), -P(0)0(H or Ci-C6alkyl), -P(O)2O(H or Ci-C6alkyl), -CN, or -NO2;m is 0, 1, or 2;n is 4, 5, 6, 7, 8 or 9; andp is 0, 1, or 2;provided thatR2R2 / / R2(i) when X is CH or CR3and ring Bis(a) at least one of R8or R9is not H; or(b) (L)Pcomprises at least two consecutive -C(R6)(R7)-, wherein each R6is independently selected from deuterium, halogen, Ci-Ce alkyl, C2-C<, alkenyl, C2-C6 alkynyl, Ca-Ce cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)0Rb, -NRaC(0)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(0)NRaRb, -NRaS(O)2NRaRb, -C(0)Ra, -C(O)ORa, -C(0)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(0)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, and -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cb-Cio aryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-C, alkyl, Ci-Ce haloalkyl, -ORe, -0C(0)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re. -OS(O)NReRf, -OS(O)2NReRf. -SRe. -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(0)Re, -C(0)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; andR2R2 / / N-N N-N / / / / V?R2^ y??(ii) when X is N and ring Bis or, then ring A is substituted by at least one R1, wherein R1is C--G, cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C3-C6 cycloalkyl and 3- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Cg alkyl, C|-C. haloalkyl, -Rg, -Rh, -OR8, -0C(0)R8, -0C(0)NRgRb, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRb, -OS(O)2NRgRh, -SRS, -S(O)RS, -S(O)2R8, -S(O)NR8Rh, -S(0)2NR8Rh, -NR8Rh, -NR8C(0)Rh, -NR8C(0)0Rh, -NRgC(0)NRgRh, -NRgS(0)Rh, -NRgS(0)2Rh, -NRgS(0)NRgRh, -NRgS(0)2NRgRh, -C(0)Rg, -C(O)ORg, -C(0)NRgRh, -PRgRh, -P(0)RgRh, -P(0)2RgRh, -P(0)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; andprovided that the compound is not of the formulaN=

[0034] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0035] 2. The compound of clause 1, having the formula 11an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0036] 3. The compound of clause 1 or 2, an isotopically labeled form thereof, or a hydrate,R2N-N / / V? solvate, or pharmaceutically acceptable salt thereof, wherein ringB is orR2N-l /

[0037] 4. The compound of clause 1 or 2, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring Bis R2N-N

[0038] 5. The compound of clause 1 or 2, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring B is

[0039] 6. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A is

[0040] 7. The compound of any one of the clauses 1 to 5, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A is

[0041] 8. The compound of clause 1, having the formula IIIan isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0042] 9. The compound of clause 1 or 8, an isotopically labeled form thereof, or a hydrate,R2N-N R2-X^y * solvate, or pharmaceutically acceptable salt thereof, wherein ringB is or R2N-N7

[0043] 10. The compound of clause 1 or 8, an isotopically labeled form thereof, or a hydrate,R2N-Nsolvate, or pharmaceutically acceptable salt thereof, wherein ringB is R2N-N

[0044] 11. The compound of clause 1 or 8, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring B is

[0045] 12. The compound of any one of clauses 1 or 8 to 11, an isotopically labeled formthereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A is

[0046] 13. The compound of any one of the clauses 1 or 8 to 11, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A isR1

[0047] 14. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A isor

[0048] wherein each “ ' AAT •’ represents a point of covalent attachment.

[0049] 15. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A is

[0050] 16. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring B is

[0051] 17. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring B is

[0052] wherein each “' AA / '” represents a point of covalent attachment.

[0053] 18. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

[0054] 19. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein each R3, when present, is independently halogen, Ci-Ce alkyl, or -ORa.

[0055] 20. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R3, when present, is F, Cl, -CH3, or -OCH3.

[0056] 21. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R4is H or methyl.

[0057] 22. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein each L is independently -C(R6)(R )-, -C(O)-, -O-, or -N(R5)-, provided that (L)ndoes not comprise a -O-O- or a -O-N(R3)- bond, and the point of covalent attachment of (L)nto ring A or ring B does not form a -N-N- or a -O-N- bond.

[0058] 23. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein -(L)n- is -CR6R7-O(CR6R7)2O-, -CR6R7-O(CR6R7)3O-, -(CR6R7)C(O)N(R5)-(CR6R7)2-, -(CR R7)N(R5)C(O)-(CR6R7)2-, -O(CR6R7)2N(R5)C(O)-(CR’R7)O-, -N(R5)-C(O)(CR6R7)2O(CR6R7)2-, -CR6R7O(CR6R7)2O-(CR6R7)2, -O(CR6R7)2O(CR6R7)2O-, -CR6R7O-CR6R7-C(O)N(R5)-(CR6R7)2-, -(CR6R7)3O(CR6R7)2-, -(CR6R7)2O(CR6R7)3-, -CR6R7-N(R5)-(CR6R7)4O-, -CR6R7-N(R5)-(CR6R7)3O-, -CR6R7-N(R5)-(CR6R7)2O-, -CR6R7-N(R5)-(CR6R7)2-, -CR6R7-N(R5)-(CR6R7)3O-, -CR6R7-N(R5)-(CR6R7)3-, -O(CR6R7)2O-CR6R7-, -O(CR6R7)2O(CR6R7)2-, -O(CR6R7)2O(CR6R7)3-, -(CR6R7)2-N(R5)-(CR6R7)3-, -O(CR6R7)2-N(R5)-CR6R7-, -(CR6R7)2-N(R5)-(CR6R7)2-, -O-(CR6R7)2-, -O-(CR6R7)3-, -O-(CR6R7)4-, -O-(CR6R7)5-, -O-(CR6R7)2O-, -O-(CR6R7)3O-, -O-(CR6R7)4O-, or -O-(CR6R7)5O-.

[0059] 24. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein -(L)n- is -O(CR6R7)2O-CR6R7-, -O(CR6R7)2-N(R5)-CR6R7-, or -O-(CR6R7)3O-.

[0060] 25. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein each R, when present, is independently H, deuterium, or Ci-Ce alkyl.

[0061] 26. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein each R5, when present, is independently H, deuterium, methyl, or ethyl.

[0062] 27. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein each R6and R7, when present, is independently H, deuterium, or Ci-Cs alkyl.

[0063] 28. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein 0, 1, or 2 of R6is methyl, and the remaining R6and R' are independently H or deuterium.

[0064] 29. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein -(L)n- is -O-(CH2)2O-CH2-, -OC(H)(CH3)-CH2-O-CH2-, -CH2O-(CH2)2O-, -C(H)(CH3)-O-(CH2)2O-, -CH2N(H)-(CH2)2O-, -CH2N(CH3)-(CH2)2O-, -CH2N(CH2CH3)-(CH2)2O-, -O(CH2)2N(H)CH2-, -O(CH2)2N(CH3)CH2-, -OCH2-(C(H)(CH3))-N(CH3)CH2-, -OCH2-C(H)(CH2F)-N(CH3)CH2-, -OCH2-C(H)(CH2CH3)-N(CH3)CH2-,O(CH2)2N(C(O)CH3)CH2-, -OC(H)(CH3)CH2N(H)CH2-, -OC(H)(CH3)CH2N(CH3)CH2OC(H)(CH3)CH2N(CH2CH3)CH2-, -O(C(H)(CH3))-C((H)(CH3))N(CH3)CH2-O(C(H)(CH3))-C((H)(CH3))N(CH2CH3)CH2-, -OC(H)(CH2CN)CH2N(CH3)CH2-, -OC(H)(CH2CH3)CH2N(CH3)CH2-, -OC(H)(CH2F)CH2N(CH3)CH2-, -OC(H)(CHF2)CH2N(CH3)CH2-, -OC(H)(CH2OH)CH2N(CH3)CH2-, -OC(H)(CH3)C(O)N(CH3)CH2-, -OC(H)(cyclobutyl)CH2N(CH3)CH2-, -OC(H)(CH3)CH2N(CH2CH3)CH2-, -OC(H)(CH3)CH2N(CH(CH3)2)-CH2-, -OC(H)(CH3)CH2N(CH3)-C(H)(CH3)-, -OC(H)(CH3)CH2N(CH(oxetan-3-yl)-CH2-, -OC(H)(CH3)CH2N(cyclopropyl)-CH2-, -OCH2C(H)(CH3)N(cyclopropyl)-CH2-, -OC(H)(CH3)CH2N(C(O)CH3)CH2-, -O(C(H)(CH3))CH2N(C(O)CH2CH3)CH2-, -CH2N(H)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-C(H)(CH3)-CH2O-, -CH2N(CH3)-(CH2)2(C(H)CH3)CH2O-, [2N(CH3)-(CH2)-(C(H)CH3)O-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, -O(CH2)3O-, -O(CH2)4O-, -O(CH2)5O-, -O-(C(H)(CH3)-(CH2)2O-, -O(CH2)2-C(H)(CH3)-O-, -O(CH2)2C(H)(CH3)CH2O-, -O(CH2)3C(H)(CH3)CH2O-, -O(CH2)2N(H)C(O)-(CH2)O-, -O(CH2)2N(CH3)C(O)-(CH2)O-, -O(CH2)2O(CH2)2O-, -OC(H)(CH3)CH2OCH2-, -O(CH2)2OCH2C(H)(CH3)O-, -O(CH2)2OC(H)(CH3)-CH2O-,or ^-O(CH2)2

[0065] 30. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein -(L)n- is -O-(CH2)2O-CH2-, -O(CH2)2N(CH3)CH2-, -OCH2-(C(H)(CH3))-N(CH3)CH2-,-OC(H)(CH3)CH2N(CH3)CH2-, -OC(H)(CH3)CH2N(CH2CH3)CH2-, -O(C(H)(CH3))- C((H)(CH3))N(CH3)CH2-, -O(C(H)(CH3))-C((H)(CH3))N(CH2CH3)CH2-, -O(CH2)3O-, or -O- (C(H)(CH3)-(CH2)2O-.

[0066] 31. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein -(L)n- is, wherein each “ / VW'” represents a point of covalent attachment.

[0067] 32. A compound selected from the group consisting of (25)-l-{(105,l 1 / ?,17E)-19- fluoro-8,10,ll,12-tetramethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14 / 7-3,5- ethenotripyrazolo[3,4- / :3',4'-j:4",3"- / i][l,4]oxazacyclopentadecin-14-yl}propan-2-ol;

[0068] (25)- 1 - { ( 1 OR, 11 R, 17E)- 19-fluoro-8, 10, 11, 12-tetramethyl- 16-[(propan-2-yl)oxy]- 2,8,10,ll,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo|3,4- / :3',4'- / :4",3"- n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0069] (25)-l-[(105,ll / ?,17E)-16-ethoxy-19-fluoro-8,10,ll,12-tetramethyl-2,8,10,ll,12,13- hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-rz][ 1,4]oxazacyclopentadecin-14- yl]propan-2-ol;

[0070] (25)-l-[(10 / ?,ll / ?,17E)-16-ethoxy-19-fluoro-8,10,ll,12-tetramethyl-2,8,10,l l,12,13- hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3’,4'-j:4",3"-n][l,4]oxazacyclopentadecin-14- yl]propan-2-ol;

[0071] (25)-l-{(105,ll / ?,17£)-12-ethyl-19-fluoro-8,10.11-trimethyl-16-[(propan-2-yl)oxy]- 2.8.10.1 1.12. l3-hexahydro-14 / / -3.5-ethenotripyrazolo|3.4- / :3’.4' / :4",3"- n\ [ 1,4]oxazacyclopentadecin- 14-y 1 }propan-2-ol;

[0072] (25)- 1 - { (10 / ?, 2-ethyl- 19-fluoro-8, 10, 11 -trimethyl- 16-[(propan-2-yl)oxy] - 2,8, 10, 11, 12, 13-hexahydro- 14 / / -3.5-ethenotii pyrazolo| 3,4- / ; 3',4'-j:4",3"- n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0073] (2S)- 1 - [( 1 OR, 11R,17E)-16-ethoxy- 12-ethyl- 19-fluoro-8, 10, 11 -trimethyl- 2,8, 10, 11, 12, 13-hexahydro- 14H-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-zi] [ 1,4]oxazacyclopentadecin- 14-y l]propan-2-ol;

[0074] (25)- 1 - [( 1 OR, 11 R, 17E)- 16-ethoxy-20-fluoro-8, 10, 11, 12-tetramethyl-2,8, 10,11.12,13-hexahydro-147 / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0075] (25)-l-[(105,llA,17E)-16-ethoxy-20-fluoro-8,10,ll,12-tetramethyl-2,8,10,ll,12,13-hexahydro- 14 / 7-3, 5-ethenotripyrazolo[3,4- / :3',4' / :4",3"-7i][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0076] (25)- 1 -{ (1 OR, 117?, 17E)-20-fluoro-8, 10, 11, 12-tetramethyl- 16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro- 14H-3,5-ethenotripyrazolo[3, 4- / : 3',4'-j:4",3"-TI] [ 1,4]oxazacyclopentadecin- 14-y 1 }propan-2-ol;

[0077] (25)-l-{(105,l l / ?,17£’)-20-fluoro-8,10,l 1.12-tetramethyl-16-[(propan-2-yl)oxyJ- 2.8.10.11.12.13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3', 4' -j:4", 3"-n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0078] (25)- 1-[( 105,1 l / ?,17E)-16-ethoxy-12-ethyl-19-fluoro-8,10,l 1-trimethyl- 2,8,10,1 l,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4;:3',4' / :4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl]propan-2-ol;

[0079] (25)-l-{(10 / ?,117?,17E)-12-ethyl-20-fluoro-8,10,ll-trimethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro-14H-3,5-ethenotripyrazolo[3,4 / :3',4'-j:4", 3"-n] [ 1,4]oxazacyclopentadecin- 14-y 1 }propan-2-ol;

[0080] (25)-l-{(105,l l / ?,17E)-12-ethyl-20-fluoro-8,10,ll-trimethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"- / i] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0081] (25)-l-[(105,l 17?,17E)-16-ethoxy-12-ethyl-20-fluoro-8,10,l 1-trimethyl- 2,8,10,1 l,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4;:3',4' / :4",3"-7i] [ 1,4]oxazacyclopentadecin-l 4-yl]propan-2-ol;

[0082] (25)- 1 - [( 1 OR, 11R,17E)-16-ethoxy- 12-ethyl-20-fluoro-8, 10, 11 -trimethyl- 2.8.10.11.12.13-hexahydro-14H-3,5-ethenotripyrazolo[3,4 / :3',4'-j:4",3"- 7i] [ 1,4]oxazacyclopentadecin- 14-yl]propan-2-ol;

[0083] ( 11 R, 17E)-20-methoxy-7, 11,12,14-tetramethy 1-2, 10, 11, 12, 13, 14-hexahydro-7 / 7-3,5-ethenodipyrazolo[3,4-:3',4'-j][l,2,3]triazolo[4,5-77][l,4]oxazacyclopentadecine;

[0084] (11 / ?, 17E)-20-methoxy-7, 11, 12, 14, 16-pentamethyl-2, 10, 11, 12, 13, 14-hexahydro-7 / 7-3,5-ethenodipyrazolo[3,4; / :3',4'-j][l,2,3]triazolo[4,5-7z][l,4]oxazacyclopentadecme;

[0085] (ll / ? J7E) 6-ethoxy-20-methoxy-7,l 1,12, 14-tetramethyl-2, 10,11,12,13,14-hexahydro-7H-3,5-ethenodipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-n] [ 1,4]oxazacyclopentadecine;

[0086] ( 11 R, 17£')-20-chloro-7, 11,12,14-tetramethy 1-2, 10, 11, 12, 13,14-hexahydro-7 / 7-3,5-ethenodipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecine;

[0087] (ll / ?,17£’)-20-chloro-7,ll,12,14,16-pentamethyl-2,10,ll,12,13,14-hexahydro-7H-3,5-ethenodipyrazolo[3,4- / :3',4'- / ][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecine;

[0088] (1 l / 7E)-20-chloro-16-ethoxy-7,l l,12,14-tetramethyl-2,10,l l,12,13,14-hexahydro-7H-3,5-ethenodipyrazolo[3,4-:3',4'- / ][l,2,3]triazolo[4,5- / z][l,4]oxazacyclopentadecine;

[0089] (17E)-20-methoxy-7, 14-dimethyl-2,7, 10, 11, 13, 14-hexahydro-3,5-ethenodipyrazolo[3',4':10,ll;4",3":14,15][l,4]dioxacyclopentadecino[6,7-d][l,2,3]triazol-6-amine; and

[0090] (17£’)-20-methoxy-7,14-dimethyl-2,ll,12,14-tetrahydro-7 / 7,10 / / -3,5-ethenodipyrazolo[3',4':10,ll;4",3":14,15][l,5]dioxacyclopentadecino[6,7- ][l,2,3]triazol-6-amine;

[0091] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0092] 33. A compound selected from the group consisting of (17E)-7,12,14-trimethyl- 2, 10,11, 12, 13, 14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-n] [ 1,4]oxazacyclopentadecine;

[0093] ( 17 )-6,7, 12, 14,20-pentamethyl-2, 10, 11, 12, 13, 14-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine;

[0094] (ll / ?,17£')-6,7,ll,12,14,20-hexamethyl-2,10,ll,12,13,14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-7i][l,4]oxazacyclopentadecine;

[0095] ( 17 )-7, 12.14,20-tetramethyl-2, 10, 11, 12, 13, 14-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4: / :3',4' / :4",3"-n][l,4]oxazacyclopentadecine;

[0096] (ll / ?,17E)-7,ll,12,14,20-pentamethyl-2,10,ll,12,13,14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4-:3',4'-j:4",3"-7z][l,4]oxazacyclopentadecine;

[0097] (25)-2-[( 105, 17E)- 16-ethoxy-7, 10, 12,20-tetramethy 1-2,7, 10, 11, 12, 13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- / :3,,4'-j':4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol;

[0098] (3 / ?,45)-4-[(105,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-14 / 7-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-n] [ 1,4]oxazacyclopentadecin- 14-y l]oxolan-3-ol;

[0099] (3S,4 / ?)-4-[(10S, 17E)-16-ethoxy-6,8, 10, 12,20-pentamethyl-2,8,10, 11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n] [1,4]oxazacyclopentadecin- 14-yl]oxolan-3-ol;

[0100] (2S)-2-[(10S,17E)-16-ethoxy-12-ethyl-7,10,20-trimethyl-2,7,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-7z][l,4]oxazacyclopentadecin-14-yl]propan-l-ol;

[0101] (lS,2S)-2-[(10S,17£’)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-147 / -5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j':4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl]cyclobutan- 1 -ol;

[0102] (lA,2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-14 / / -5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]cyclobutan-l-ol;

[0103] (lS,2 / Q-2-[(10S,17£’)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-14Z / -5,3-(azenometheno)tripyrazolo[3,4- / :3’,4'-j:4",3"-n] [1,4]oxazacyclopentadecin-14-yl]cyclobutan-l -ol;

[0104] (ll?,2Z?)-2-[(105,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2.8,10,ll,12,13-hexahydro-147 / -5,3-(azenometheno)tripyrazolo[3,4: / ’:3',4'- / :4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl]cyclobutan- 1 -ol;

[0105] l,5-anhydro-2,4-dideoxy-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- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]-L-r / zre,o-pentitol;

[0106] 1,5-anhydro-2,4-dideoxy-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-:3',4'- / :4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl] -D-th reo-pen ti tol;

[0107] l,5-anhydro-2,3-dideoxy-3-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2.8.10.11.12.13-hexahydro-14H-5,3-(azenonietheno)trip\Tazolo|3,4- / ':3',4’ / :4".3"- «][l,4]oxazacyclopentadecin-14-yl]-L-f / ireo-pentitol;

[0108] l,5-anhydro-2,3-dideoxy-3-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2.8.10.11.12.13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-n][l,4]oxazacyclopentadecin-14-yl]-D-z / zreo-pentitol;

[0109] ( 11 S, 17E)-7, 11, 12, 14,20-pentamethyl-2, 10, 11, 12, 13, 14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-72][l,4]oxazacyclopentadecine;

[0110] (2S)-2-[(10S,17E)-16-ethoxy-7,10,12,20-tetramethyl-2,7,10,ll,12,13-hexahydro-147 / -5,3-(azenometheno)dipyrazolo[3,4- / :3',4' / ][l,2,3]triazolo[4,5-n] [ 1,4]oxazacyclopentadecin- 14-y l]propan- 1 -ol;

[0111] (10S,17E)-7,10,12,14,16,20-hexamethyl-2,10,ll,12,13,14-hexahydro-7H-5,3- (azenometheno)dipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecine;

[0112] (2S)-2- [( 1 OS, 17E)- 16-ethoxy-8, 10, 12,20-tetramethy 1-2,8, 10, 11, 12, 13-hexahydro- 14H-5,3-(azenometheno)dipyrazolo[3,4: / ’:3',4'-j][l,2,3]triazolo[4,5-n] [ 1,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol;

[0113] (2S)-2-[(10S,17E)-16-ethoxy-6,10,12,20-tetramethyl-2,6,10,ll,12,13-hexahydro- 14H-5,3-(azenornetheno)dipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4.5-n] [ 1,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol;

[0114] (llS,17E)-7,ll,12,14,20-pentamethyl-2,10,ll,12,13,14-hexahydro-7H-5,3- (azenometheno)dipyrazolo[3,4-j:4',3'-ra][l,2,3]triazolo[4,5- |[l,4]oxazacyclopentadecine;

[0115] (17E)-7-ethyl-12,14,20-trimethyl-2,10,ll,12,13,14-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4; / :3',4' / :4",3"- / z][l,4]oxazacyclopentadecine;

[0116] (17£’)-12,14,20-trimethyl-7-(propan-2-yl)-2,10,ll,12,13,14-hexahydro-7 / / -5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-zz][l,4]oxazacyclopentadecine;

[0117] (17E’)-7-cyclopropyl-12,14,20-trimethyl-2,10,l l,12,13,14-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-ra][l,4]oxazacyclopentadecine;

[0118] ( 17E)-7-cyclobutyl- 12,14,20-trimethy 1-2, 10, 11, 12, 13, 14-hexahydro-7 / 7-5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-zz][l,4]oxazacyclopentadecine;

[0119] (17E’)-7-(methanesulfonyl)-12,14,20-trimethyl-2,10,ll,12,13,14-hexahydro-77 / -5,3- (azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-ra][l,4]oxazacyclopentadecine;

[0120] ( 17Z?)-7-[(niethanesulfonyl)methyl]-l 2, 14,20-trimethyl-2, 10, 11,12,13,14-hexahydro- 7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-zz][l,4]oxazacyclopentadecine;

[0121] ( 17E)-7, 14,20-trimethyl-2,7, 10, 11, 13, 14-hexahydro-5,3- (azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,4]dioxacyclopentadecino[6,7-c?][l,2,3]triazole;

[0122] (10S,17E)-7,10,14,20-tetramethyl-2,l l,12,14-tetrahydro-7 / f,10H-5,3- (azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,5]dioxacyclopentadecino[6,7-z / ][l,2,3]triazole;

[0123] ( 1 OS, 17E)-7, 10, 12, 15, 16, 20-hexamethyl-2, 10, 11, 12, 13, 15-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4: / :3',4' / :4",3"-zz][l,4]oxazacyclopentadecine; and

[0124] (17£)-7,12,15,16,20-pentamethyl-2,10,ll,12,13,15-hexahydro-77f-5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-zz][l,4]oxazacyclopentadecine;

[0125] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0126] 34. A pharmaceutical composition comprising a compound of any one of the precedingclauses, and optionally one or more excipients.

[0127] 35. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of clauses 1 to 33, an isotopically labeled form thereof, or a pharmaceutical composition of clause 34.

[0128] 36. A compound according to any one of clauses 1 to 33, for use in a method of treating disease in a subject.

[0129] 37. Use of a compound according to any one of clauses 1 to 33 in the manufacture of a medicament for the treatment of disease in a subject.DETAILED DESCRIPTION

[0130] 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.

[0131] 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.

[0132] 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.

[0133] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0134] 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 beinferred 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.

[0135] 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.

[0136] 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.

[0137] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD / Labs 2022.2.3 (Advanced Chemistry Development, Inc.) or ChemDraw Professional 22.2.0.3300 (PerkinElmer Informatics, Inc.).

[0138] As used herein and in connection with chemical structures depicting the various embodiments described herein, andeach represent a point of covalent attachment of the chemical group or chemical structure in which the identifier is shown to an adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure A-B, where A and B are joined by a covalent bond, in some embodiments, the portion of A-B defined by the group or chemical structure A can be represented by,_, orA>, where each of and “? ” 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,-, or?, where each of and “ represents a bond to B and the point of covalent bond attachment to A.

[0139] 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

[0140] As described herein, a “macrocycle” is a compound comprising a continuous chain of at least 12 atoms connected to form a ring, in which the continuous chain of atoms includes but is not limited to C, N, O, and S. The continuous chain of at least 12 atoms that forms a macrocycle, as described herein, can be counted along the shortest path in the chain of atoms within the ring. For example, in certain compounds of the Formula I, as described herein, the continuous chain of at least 12 atoms in the macrocycle ring can be counted starting from the oxygen atom covalently attached to ring B, where the atoms counted in the macrocycle includes the shortest path through ring B, followed by the shortest path of atoms through the bicycloheteroarylene portion, followed by the atoms in the ethenylene portion, followed by the shortest path of atoms through ring A, and finally the shortest path of atoms through the linker portion and terminating at the atom along the shortest chain that is attached to the oxygen that served as the starting point.

[0141] 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 Ci-Ce alkyl or Ci-C& alkylene. Examples of alkyl groups include methyl(Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec -butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CHs-)2), n-propylene ((-CFE-h), iso-propylene ((-C(H)(CH3)CH2-)), n-butylene ((-CHz-^), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0142] 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-C20 alkenyl, C2-C12 alkenyl, or C2-C6 alkenyl. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-l -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.

[0143] 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-C12 alkynyl, or C2-C6 alkynyl. Examples of alkynyl groups include acetylenyl (-C=CH) and propargyl (-CH2OCH), but-3-yn-l,4-diyl (-OC-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.

[0144] 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:>. D. O. O. O. O. o. O.0. 0In particular, a cyclopropyl moiety can be depicted by the structural formula. It will be 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.

[0145] The term “oxo” represents a carbonyl oxygen.

[0146] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.

[0147] The term “haloalkyl” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include -CFs, -(CEEjF, -CHF2, -CEEBr, -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 (Ce-Cio aryl). 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.

[0148] 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 mayoptionally 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:

[0149] A three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of threemembered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane. A five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-lH- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-lH-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1 -dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 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 monovalent or divalent radicals of piperidine, morpholine, 4H-l,4-thiazine, 1,2, 3, 4-tetrahydropyridine, piperazine, l,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1 -di oxide. A “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring.

[0150] As described herein, certain embodiments can include a heteroatom-C2-Ce alkylene moiety (e.g., -N(C2-Ce alkylene) or -P / OMCs-Ce alkylene)). Illustratively, -heteroatom-(C2-Ce alkylene) represents a cyclic group wherein the heteroatom atom (e.g., nitrogen, phosphorus, etc.) forms two covalent bonds with the C2-C6 alkylene group (e.g.,^c-4). For example, -OC(O)N(C2-Ce alkylene) can be depicted by the structural formula O

[0151] 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.

[0152] 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:

[0153] In some embodiments, a “monocyclic” heteroaryl can be an aromatic five- or sixmembered heterocycle. A five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include mono-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-limiting examples of five-membered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of six-membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-&]thiophene, 17 / -pyrrolo[2,3-Z?]pyridine, 1H-benzo|d|imidazole, benzo|c / |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-&]thiophene, I W-pyrrolo[2.3- / |pyridine. lH-benzo[ ]imidazole, benzo|d|oxazole, and benzo [6?]thiazole.

[0154] 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 N-NH

[0155] In particular, an azaindazolylene or pyrazolopyridylene moiety such as 1H-pyrazolo[3,4-c]pyridylene moiety can be depicted by the structural formula

[0156] 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.

[0157] 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.

[0158] As used herein, the phrase “taken together with the atoms to which each is attached” means that two substituents (e.g., R5and one of R6or R ) 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 R5and one of R6or R7, for R6,R7RNexample, on different ring atoms of, form a 4- to 7-membered ring with those ring atoms.

[0159] 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:

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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,nC,13C,14C,15N,18O,1O,31P,32P,35S,18F,36C1, 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.

[0164] As described herein, a compound may be of a particular formula (e.g., of Formula (I)-(III)), an isotopically labeled form thereof (e.g., an isotopically labeled form of the compound of Formula (I)-(III)), or a hydrate (e.g., a hydrate of the compound of Formula (I)-(III)) or a hydrate of the isotopically labeled form thereof), a solvate (e.g., a solvate of the compound of Formula (I)-(III) or a solvate of the isotopically labeled form thereof), or a pharmaceutically acceptable salt thereof (e.g., a pharmaceutically acceptable salt of the compound of Formula (I) -(III) or a pharmaceutically acceptable salt of the isotopically labeled form of the compound of Formula (I)-(III)).

[0165] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(III), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

[0166] 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.

[0167] 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-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0168] For a compound of Formula (I)-(III) 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.

[0169] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(III), 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)-(III). 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.

[0170] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(III), 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)-(III) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available inthe art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pham. 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).

[0171] 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, A746-750, A746-750 / C797S, L858R / T790M, L858R / T790M / C797S, 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 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

[0172] The present disclosure provides macrocyclic compounds that bind and / or modulate the activity of specific kinases. In some embodiments, the disclosure provides a compound of the formula I,

[0173] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0174] wherein ring A, ring B, L, R1, R3, R4, R8, R9, X, m, n, and p are as described herein.

[0175] In some embodiments, the disclosure relates to a compound of the formula II,

[0176] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0177] wherein ring A, ring B, L, R1, R3, R4, R8, R9, m, n, and p are as described herein.

[0178] In some embodiments, the disclosure relates to a compound of the formula III,III

[0179] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0180] wherein ring A, ring B, L, R1, R3, R4, R8, R9, m, n, and p are as described herein.

[0181] In some embodiments, the disclosure relates to a compound of the formula I(a)-(h),

[0182] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0183] wherein ring A, ring B, X, L, R1, R3, R4, R8, R9, m, n, and p are as described herein.

[0184] In some embodiments, the disclosure relates to a compound of the formula II(a)-(h),

[0185] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0186] wherein ring A, ring B, L, R1, R3, R4, R8, RQ, m, n, and p are as described herein.

[0187] In some embodiments, the disclosure relates to a compound of the formula III(a)-(g),RI

[0188] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0189] wherein ring A, ring B, L, R1, R3, R4, R8, R9, m, n, and p are as described herein.

[0190] In some embodiments, the disclosure relates to a compound of the following formula,

[0191] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0192] wherein L, R1, R3, R4, R\ R9, n, and p are as described herein.

[0193] In some embodiments, the disclosure relates to a compound of the following formula,

[0194] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,

[0195] wherein ring A, ring B, L, R1, R3, R4, R8, R9, m, n, and p are as described herein.wherein each “ ny r” represents a point of covalent attachment. It should be understoodthat each of the provided ring A structures is substituted by (R^m, for examplering A can be substituted by R1(e.g., a hydrogen present on C or N). For example, if m is 1,

[0197] 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 0. In some embodiments, m is 1. In some embodiments, m is 2.each “ JVW ” represents a point of covalent attachment. For example, ring A can bewherein each “dVW1” represents a point of covalent attachment. In some embodiments, ring A isOH OH OHwherein each “ A T ” represents a point of covalent attachment.R2R2N-N N-N

[0200] In some embodiments, ringB is or In some embodiments,R2N-NIn some embodiments, ring B iseach “'AAAT” represents a point of covalent attachment..N-N N-N

[0201] In some embodiments, ring B isrepresents a point of covalent attachment. In some embodiments, ring B isrepresents a point of covalent attachment.

[0202] In some embodiments, each R1and R2, when present and covalently attached to a nitrogen atom, is independently deuterium, Ci-C, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cs-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, or -C(=NRa)NRaRb, wherein each hydrogen atom in Ci-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cs-Cs cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -R8, -Rh, -ORg, -OC(O)RS, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NRgRh, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORS, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; or, when present and covalently attached to a carbon atom, each R1and R2, is independently deuterium, halogen, Ci-Ce alkyl, C2-C, alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O);Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C alkyl, Ci-C6haloalkyl, -Rg, -Rh, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NRgRh, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2. In some embodiments, each R1and R2is independently Ci-Cs alkyl, for example methyl, ethyl, or propyl, and may be unsubstituted or substituted by -ORg(e.g., -OH). In some embodiments, an R1is Ci-Ce alkyl (e.g., methyl or propyl), which is optionally substituted by -ORg(e.g., -OH), and each R2isCi-Ce alkyl (e.g., methyl). In some embodiments, R1is -0Ra, for example -OCi-Cg alkyl such as methoxy, ethoxy, or propoxy. In some embodiments, R1is -OCi-Ce alkyl such as methoxy, ethoxy, or propoxy and each R2is Ci-Co alkyl (e.g., methyl). In some embodiments, an R1is Ci-Cs alkyl (e.g., methyl or propyl), which is optionally substituted by -ORg(e.g., -OH), another R1is -OCi-Ce alkyl such as methoxy, ethoxy, or propoxy, and each R2is Ci-Ce alkyl (e.g., methyl). In some embodiments, an R1is C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl) which is optionally substituted by -ORg(e.g., -OH), or 4- to 10-membered heterocycloalkyl (e.g., tetrahydrofuranyl or tetrahydropyranyl) which is optionally substituted by -ORS(e.g., -OH). In some embodiments, an R1is C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl) which is optionally substituted by -ORg(e.g., -OH), or 4- to 10-membered heterocycloalkyl (e.g., tetrahydrofuranyl or tetrahydropyranyl) which is optionally substituted by -OR8(e.g., -OH), another R1is -OCi-Ce alkyl such as methoxy, ethoxy, or propoxy, and each R2is Ci-Ce alkyl (e.g., methyl).

[0203] In some embodiments, each R3, when present, is independently deuterium, halogen, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb. -S(O)2NRaRh, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cehaloalkyl, -Rg, -Rh, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NRgRh, -SR8, -S(O)R8, -S(O)2R8, -S(O)NR8Rh, -S(O)2NR8Rh, -NR8Rh, -NRgC(O)Rh, -NR8C(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NR8S(O)NR8Rh, -NR8S(O)2NR8Rh, -C(O)R8, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRb, -P(O)ORg, -P(O)2ORg, -CN, or -NO2. In some embodiments, each R3, when present, is independently halogen, Ci-Ce alkyl, or -ORa. In some embodiments, R3, when present, is F, Cl, -CH3, or -OCH3.

[0204] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[0205] In some embodiments, X is N, CH, or CR3. In some embodiments, p is 0 and X is N or CH. In some embodiments, p is 1 and X can be N, CH, or CR3. In some embodiments, pis 2 and X can be N, CH, or CR’. In some embodiments, X is N. In some embodiments, X is CH. In some embodiments, X is CR3.

[0206] In some embodiments, p is 0 and the compound comprises the portionsuch as orR4. In some embodiments, p is 1 or greater, and the compoundcomprises a portion

[0207] In some embodiments, R4is H, deuterium, Ci-Cbalkyl, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -P(O)2RcRd, -P(O)2NReRd, -P(O)2ORC, or -S(O)2ORe. In some embodiments, R4is H or methyl.. In some embodiments, R4is H.

[0208] In some embodiments, each R5, when present, is independently H, deuterium, Ci-Cbalkyl, C2-C6alkenyl, C2-Cbalkynyl, O-G, cycloalkyl, 3- to 7-membered heterocycloalkyl, Cb-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Cs-Ce cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl 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)NRcRf, -S(O)2NRcRf, -NRcRf, -NRcC(O)Rf, -NRcC(O)ORf, -NRcC(O)NRcRf, -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 R5, when present, is independently H, deuterium, or Ci-Ce alkyl. In some embodiments, each R5, when present, is independently H, deuterium, methyl, or ethyl.

[0209] In some embodiments, each Rband R7, is independently H, deuterium, halogen, Ci-Ce alkyl, C2-Cbalkenyl, C2-Cbalkynyl, C2-Cbcycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRc)NR°Rd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NReRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NR CGNR JNR R1, -NRcS(O)Rd, -NRcS(O)2Rd,-NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Cg alkenyl, C2-C, alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cg-Cio aryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cg haloalkyl, -ORe, -OC(O)Re, -0C(0)NReRf, -OS(O)Re, -OS(O)2Re, -0S(0)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(0)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(0)NReRf, -NReS(0)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(O)2NReRf, -C(0)Re, -C(O)ORe, -C(0)NReRf, -PReRf, -P(0)ReRf, -P(0)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, each R6and R7, when present, is independently H, deuterium, or Ci-Cg alkyl. In some embodiments, 0, 1, or 2 of R° is methyl, and the remaining R6and R' are independently H or deuterium.

[0210] In some embodiments, two of Rb, R6and R', taken together with the atom or atoms to which they are attached, optionally combine to form a C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl formed when two of R5, R6and R' are taken together is independently optionally substituted by -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0211] In some embodiments, R8and R’ are each independently H, deuterium, halogen, Ci-Ce alkyl, Ci-C6haloalky 1, -ORa, -C(O)Ra, -C(O)ORa, or -C(O)NRaRb.

[0212] In some embodiments, each Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rhis independently selected from the group consisting of H, deuterium, C1-C3 alkyl, C2-Cg alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, Ci-Ce alkylene-Ce-Cio aryl, 5- to 10-membered heteroaryl, and Ci-Cg alkylene-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 Ci-C, alkyl, C2-C& alkenyl, C2-C, alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cg-Cio aryl, Ci-Ce alkylene-C -Cr aryl, 5- to 10-membered heteroaryl, or Ci-Cg alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, Ci-Cg alkyl, Ci-C. haloalkyl, -OH, -OCi-C6alkyl, -OC(O)-(H or Ci-C6alkyl), -OC(O)N(H or Ci-C6alkyl)2, -OC(O)N(C2-C6alkylene), -OS(O)-(H or Ci-C6alkyl), -OS(O)2-(H or Ci-C6alkyl), -OS(O)N(H or Ci-Cg alkyl)2, -OS(O)N(C2-C6alkylene), -OS(O)2N(H or Ci-C6alkyl)2,-OS(O)2N(C2-C6alkylene), -S(H or Ci-C6alkyl), -S(O)(H or Ci-C6alkyl), -S(O)2(H or Ci-C6alkyl), -S(O)N(H or Ci-C6alkyl)2, -S(O)N(C2-C6alkylene), -S(O)2N(H or Ci-C6alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or Ci-C, alkyl)2, -N(C2-Ce alkylene), -N(H or Ci-Ce alkyl)C(O)-(H or Ci-C6alkyl), -N(H or Ci-C6alkyl)C(O)O(H or Ci-C6alkyl). -N(H or Ci-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)C(O)N(C2-C6alkylene), -N(H or Ci-C6alkyl)S(O)-(H or Ci-C6alkyl), -N(H or Ci-C6alkyl)S(O)2(H or Ci-C6alkyl), -N(H or Ci-C6alkyl)S(O)N(H or Ci-C6alkyl)2. -N(H or Ci-C6alkyl)S(O)N(C2-Cbalkylene), -N(H or Ci-C6alkyl)S(O)2N(H or Ci-Ce alkyl)2, -N(H or Ci-Ce alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or Ci-C6alkyl), -C(O)O(H or Ci-C6alkyl), -C(O)N(C2-C6alkylene), -P(H or Ci-C6alkyl)2, -P(C2-Ce alkylene), -P(O)(H or Ci-Cbalkyl)2, -P(O)(C2-Ce alkylene), -P(O)2(H or Ci-Ce alkyl)2, -P(O)2(C2-Cbalkylene), -P(O)N(H or Ci-C alkyl)2, -P(O)N(C2-C alkylene), -P(O)2N(H or Ci-Cs alkyl)2, -P(O)2N(C2-Cbalkylene), -P(O)O(H or Ci-C6alkyl), -P(O)2O(H or Ci-C6alkyl), -CN, or -NO2.

[0213] In some embodiments, each L is independently -O-, -S-, -S(O)-, -S(O)2-, -N(R5)C(O)-, -C(O)N(R5)-, -N(R5)-, -N(R5)S(O)-, -S(O)N(R5)-, -N(R5)S(O)2-, -S(O)2N(R5)-, or - C(R6)(R')-, provided that (L)ndoes not comprise an O-O, S-O, or N-N bond. In some embodiments, each L is independently -C(R6)(R7)-, -C(O)-, -O-, or -N(R5)-, provided that (L)ndoes not comprise a -O-O- or a -0-N(R5)- bond, and the point of covalent attachment of (L)nto ring A or ring B does not form a -N-N- or a -O-N- bond.

[0214] In some embodiments, n is 4, 5, 6, 7, 8 or 9. In some embodiments, n is 5, 6, 7, 8 or 9. In some embodiments, n is 5, 6, 7, or 8. In some embodiments, n is 5, 6, or 7. In some embodiments, n is 5 or 6. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

[0215] In some embodiments, -(L)n- is -CR6R -O(CR6R7)2O-, -CR6R7-O(CR6R )3O-, -(CR6R7)C(O)N(R5)-(CR6R7)2-, -(CR6R7)N(R5)C(O)-(CR6R7)2-, -O(CR6R7)2N(R5)C(O)-(CR6R7)O-, -N(R5)-C(O)(CR6R7)2O(CR6R7)2-, -CR6R7O(CR6R7)2O-(CR6R7)2, -O(CR6R7)2O(CR6R7)2O-, -CR6R7O-CR6R7-C(O)N(R5)-(CR6R7)2-, -(CR6R7) O(CR6R7)2-, -(CR6R7)2O(CR6R7)3-, -CR6R7-N(R5)-(CR6R7)4O-, -CR6R7-N(R5)-(CR6R7)3O-, -CR6R7-N(R5)-(CR6R7)2O-, -CR6R7-N(R5)-(CR6R7)2-, -CR6R7-N(R5)-(CR6R7)3O-, -CR6R7-N(R5)-(CR6R7)3-, -O(CR' R )2O-CR6R7-, -O(CR6R7)2O(CRbR7)2-, -O(CR6R7)2O(CR6R7)3-, -(CR6R7)2-N(R5)-(CR6R7)3-, -O(CR6R7)2-N(R5)-CR6R7-, -(CR6R7)2-N(R5)-(CR6R7)2-, -O-(CR6R7)2-, -O-(CR6R7)3-, O-(CR6R7)4-, -O-(CR6R7)5-, I-(CR6R7)2O-, -O-(CR6R7)3O-,-O-(CR6R7)4O-, or -O-(CR6R7)5O-. In some embodiments, -(L)n- is -O(CR6R7)2O-CR6R7-, -O(CR6R7)2-N(R5)-CR6R7-, or -O-(CR6R7)3O-.In some embodiments, -(L)n- is -O-(CH2)2O-CH2-, -OC(H)(CH3)-CH2-O-CH2-, -CH2O- (CH2)2O-, -C(H)(CH3)-O-(CH2)2O-, -CH2N(H)-(CH2)2O-, -CH2N(CH3)-(CH2)2O-, -CH2N(CH2CH3)-(CH2)2O-, -O(CH2)2N(H)CH2-, -O(CH2)2N(CH3)CH2-, -OCH2-(C(H)(CH3))-N(CH3)CH2-, -OCH2-C(H)(CH2F)-N(CH3)CH2-, -OCH2-C(H)(CH2CH3)-N(CH3)CH2-, -O(CH2)2N(C(O)CH3)CH2-, -OC(H)(CH3)CH2N(H)CH2-, -OC(H)(CH3)CH2N(CH3)CH2-, -OC(H)(CH3)CH2N(CH2CH3)CH2-, -O(C(H)(CH3))-C((H)(CH3))N(CH3)CH2-, -O(C(H)(CH3))-C((H)(CH3))N(CH2CH3)CH -OC(H)(CH2CN)CH2N(CH3)CH2-, OC(H)(CH2CH3)CH2N(CH3)CH2-, -OC(H)(CH2F)CH2N(CH3)CH2OC(H)(CHF2)CH2N(CH3)CH2-, -OC(H)(CH2OH)CH2N(CH3)CH2OC(H)(CH3)C(O)N(CH3)CH2-, -OC(H)(cyclobutyl)CH2N(CH3)CH2- OC(H)(CH3)CH2N(CH2CH3)CH2-, -OC(H)(CH3)CH2N(CH(CH3)2)-CH2OC(H)(CH3)CH2N(CH3)-C(H)(CH3)-, -OC(H)(CH3)CH2N(CH(oxetan-3-yl)-CH2OC(H)(CH3)CH2N(cyclopropyl)-CH2-, -OCH2C(H)(CH3)N(cyclopropyl)-CH2- OC(H)(CH3)CH2N(C(O)CH3)CH2-, -O(C(H)(CH3))CH2N(C(O)CH2CH3)CH2CH2N(H)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-C(H)(CH3)-CH2O CH2N(CH3)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-(CH2)-(C(H)CH3)O-, -O(CH2)2O(CH2)3-, -O(CH2)4-, -O(CH2)3O -O(CH2)4O-, -O(CH2)5O-, -O-(C(H)(CH3)-(CH2)2O O(CH2)2-C(H)(CH3)-O-, -O(CH2)2C(H)(CH3)CH2O-, -O(CH2)3C(H)(CH3)CH2O O(CH2)2N(H)C(O)-(CH2)O-. -O(CH2)2N(CH3)C(O)-(CH2)O-, -O(CH2)2O(CH2)2O -OC(H)(CH3)CH2OCH2-, -O(CH2)2OCH2C(H)(CH3)O-, -O(CH2)2OC(H)(CH3)-CH2O-,|-O(CH2)2In some embodiments, -(L)n- is -O-(CH2)2O-CH2-, -O(CH2)2N(CH3)CH2-, -OCH2-(C(H)(CH3))-N(CH3)CH2-, -OC(H)(CH3)CH2N(CH3)CH2-, -OC(H)(CH3)CH2N(CH2CH3)CH2-, -O(C(H)(CH3))-C((H)(CH3))N(CH3)CH2-, -O(C(H)(CH3))-C((H)(CH3))N(CH2CH3)CH2-, -O(CH2)3O-, or -O-(C(H)(CH3)-(CH2)2O-. In some embodiments, -(L)n- is

[0216] In some embodiments, when X is CH or CR3and ring B is then(a) at least one of R8or R9is not H; or(b) (L)pcomprises at least two consecutive -C(R6)(R')-, wherein each R6is independently selected from deuterium, halogen, Ci-Ce alkyl, C2-C, alkenyl, Ck- alkynyl, C -C, cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, and -NO2, wherein each hydrogen atom in Ci-Cbalkyl, C2-Cbalkenyl, C2-Ce alkynyl, C3-Ce cycloalkyl, 3- to 7-memberedheterocycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and / / 2^^

[0217] (ii) when X is N and ring Bis or, then ring A is substituted by at least one R1, wherein R1is C3-C6 cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein each hydrogen atom in Ca-Cs cycloalkyl and 3- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -Rg, -Rh, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NRgRh, -SRg, -S(O)Rg. -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NR8Rh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NR8Rh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2.

[0218] In some embodiments, the compound is not of the formulaN=

[0219] In certain aspects, the compounds of the present disclosure are macrocycles. For example, in the compounds of Formula I, it will be appreciated that ring A and ring B are connected by a linker portion as described herein, wherein the linker portion comprises a chainof atoms, including but not limited to C, N, O, and S to provide a macrocycle.

[0220] In some embodiments, the disclosure provides a compound of the Formula (I)-(III) selected from the group consisting of

[0221] (2S)- 1 - { ( 105, 11 R, 17E)- 19-fluoro-8, 10, 11, 12-tetramethy 1- 16-[(propan-2-y l)oxy ] - 2,8,10,11,12,13-hexahydro-l 4 / 7-3, 5-ethenotripyrazolo[3,4- / :3', 4' -j:4", 3"-n\ [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0222] (2S)-1 -{ (107?, 1 ll?,17E)-19-fluoro-8,10,ll,12-tetramethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro- 14 / 7-3, 5-ethenotripyrazolo[3,4;:3',4'-j:4", 3"-n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0223] (2S)-l-[(10S,l l / ?,171?)-16-ethoxy-19-fluoro-8, 10,1 l,12-tetramethyl-2, 8, 10,11,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3,,4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0224] (25)-l-[(102?,112?,17E)-16-ethoxy-19-fluoro-8,10,ll,12-tetramethyl-2,8,10,ll,12,13-hexahydro-14Z / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0225] (25)-l-{(105,llZ?,17E)-12-ethyl-19-fluoro-8,10.11-trimethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro- 14 / 7-3, 5-ethenotripyrazolo[3,4;:3', 4'; / :4", 3"-n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0226] (25)-l-{(10 / ?,117?,17E)-12-ethyl-19-fluoro-8,10,ll-trimethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13 -hexahydro- 14 / 7-3, 5-ethenotripyrazolo[3,4 / :3',4'-j:4", 3"-n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;

[0227] (25)-l-[(10 / ?,l l / ?,17E)-16-ethoxy-12-ethyl-19-fluoro-8,10.11-trimethyl- 2.8.10.11.12.13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3', 4' -j:4", 3"-7i][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0228] (2S)-l-[(107?,l l / ?,17E)-16-ethoxy-20-fluoro-8,10,l l,12-tetramethyl-2,8,10,ll,12,13-hexahydro-147f-3,5-ethenotripyrazolo[3,4 / ’:3,,4' / :4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0229] (25)-l-[(10S,117?,17£)-16-ethoxy-20-fluoro-8,10,ll,12-tetramethyl-2,8,10,ll,12,13-hexahydro-l4 / / -3,5-ethenotripyrazolo|3,4- / :3,,4' / :4",3"- / / || I,4|oxazacyclopentadecin-I4-yl]propan-2-ol;

[0230] (25)-l -{ ( 10 / ?, 1 ll?,17E)-20-fluoro-8,10,l l,12-tetramethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-zi] [ 1,4]oxazacyclopentadecin- 14-yl } propan-2-ol;

[0231] (2S)- 1 - { ( 1 OS, 11 R, 17E)-20-fluoro-8, 10, 11, 12-tetramethyl- 16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [1,4]oxazacyclopentadecin- 14-yl}propan-2-ol;

[0232] (2S)-l-[(10S,112?,17E)-16-ethoxy-12-ethyl-19-fluoro-8,10,ll-trimethyl- 2.8.10.11.12.13-hexahydro-l 4H-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0233] (28)- 1 -{ (10 / ?, 1 ll?,17£)-12-ethyl-20-fluoro-8,10,ll-trimethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro-14H-3, 5-ethenotripyrazolo[3,4; / :3',4'-j:4", 3"-n] [ 1,4]oxazacyclopentadecin-l 4-yl }propan-2-ol;

[0234] (2S)-1-{(1OS,1 l / ?,17£)-12-ethyl-20-fluoro-8,10,ll-trimethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro-14H-3, 5-ethenotripyrazolo|3,4- / :3’,4’- / :4", 3"-n] [ 1,4]oxazacyclopentadecin- 14-yl } propan-2-ol;

[0235] (2S)-1-L(1OS,1 l / ?,17£’)-16-ethoxy-12-ethyl-20-fluoro-8,10,l 1-trimethyl- 2.8.10.11.12.13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3', 4' -j:4", 3"- / i][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0236] (28)- 1 - [( 1 OR.11 / ?, 1 IE)- 16-ethoxy- 12-ethy l-20-fluoro-8, 10, 11 -trimethyl- 2,8,10,1 l,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4;:3',4' / :4",3"-n] [ 1,4]oxazacyclopentadecin-l 4-yl]propan-2-ol;

[0237] (111?, 17£’)-20-methoxy-7, 11,12, 14-tetramethyl-2, 10, 11, 12, 13,14-hexahydro-7H-3,5-ethenodipyrazolo[3,4- / :3',4' / ][l,2,3]triazolo[4,5-zz][l,4]oxazacyclopentadecine;

[0238] (117?, 17E)-20-methoxy-7, 11, 12, 14, 16-pentamethyl-2, 10, 11, 12, 13, 14-hexahydro-727- 3.5-ethenodipyrazolo[3,4- / :3',4'; / ][l,2,3]triazolo[4,5- / z][l,4]oxazacyclopentadecine;

[0239] (1 ll?,17E)-16-ethoxy-20-methoxy-7,l l,12,14-tetramethyl-2,10,ll,12,13,14-hexahydro-7H-3,5-ethenodipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-n] [1,4]oxazacyclopentadecine;

[0240] (l l / ?,17E)-20-chloro-7,l l,12,14-tetramethyl-2,10,l l,12,13,14-hexahydro-7 / / -3,5-ethenodipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecine;

[0241] (117?,17£’)-20-chloro-7,ll,12,14,16-pentamethyl-2,10,ll,12,13,14-hexahydro-7 / / - 3.5-ethenodipyrazolo[3,4- / :3',4'- / ][l,2,3]triazolo[4,5-ra][l,4]oxazacyclopentadecine;

[0242] (117?, 17E)-20-chloro- 16-ethoxy-7, 11,12,14-tetramethyl-2, 10, 11, 12,13,14-hexahydro-7H-3,5-ethenodipyrazolo[3,4- / :3',4'- / ][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecine;

[0243] (17E)-20-methoxy-7,14-dimethyl-2,7,10,l l,13,14-hexahydro-3,5-ethenodipyrazolo[3',4':10,ll;4",3":14,15][l,4]dioxacyclopentadecino[6,7-( / ][l,2,3]triazol-6-amine; and

[0244] ( 17E’)-20-methoxy-7, 14-dimethyl-2, 11,12,14-tetrahydro-7 H, 1077-3,5-ethenodipyrazolo[3',4':10,ll;4",3":14,15][l,5]dioxacyclopentadecino[6,7-d][l,2,3]triazol-6-amine;

[0245] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the disclosure provides a compound of the Formula (I)-(III) selected from the group consisting of (17E)-7,12,14-trimethyl-2,10,ll,12,13.14-hexahydro-777-5, 3-(azenometheno)tripyrazolo[3,4:3',4'-j:4",3"-7z][l,4]oxazacyclopentadecine;

[0247] ( 17E)-6,7, 12, 14,20-pentamethyl-2, 10, 11, 12, 13,14-hexahydro-777-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-72][l,4]oxazacyclopentadecine;

[0248] ( 112?, 17E)-6,7, 11, 12, 14,20-hexamethyl-2, 10, 11,12,13,14-hexahydro-7H-5,3-tazenometheno)tripyrazolo|3,4- / .3',4' / :4".3"- / z|| 1.4|oxazacyclopentadecine;

[0249] ( 17£)-7, 12, 14.20-tetramethyl-2.10, 11, 12, 13, 14-hexahydro-777-5.3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-72][l,4]oxazacyclopentadecine;

[0250] (ll / ?,17E)-7,ll,12,14,20-pentamethyl-2,10,ll,12,13,14-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-n][l,4]oxazacyclopentadecine;

[0251] (2S)-2- [( 105, 1 IE)- 16-ethoxy-7, 10, 12,20-tetramethy 1-2,7, 10, 11, 12, 13-hexahydro-14 / 7-5,3-(azenometheno)tripyrazolo[3,4- / :3,,4'-j:4",3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol;

[0252] (37?,45)-4-[(105,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-1477-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j':4",3"-n] [ 1,4]oxazacyclopentadecin- 14-y l]oxolan-3-ol;

[0253] (35,4 / ?)-4-[(105,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-1477-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-n] [ 1,4]oxazacyclopentadecin- 14-y l]oxolan-3-ol;

[0254] (25)-2-[(105,17E)-16-ethoxy-12-ethyl-7,10,20-trimethyl-2,7,10,11.12,13-hexahydro- 1477-5, 3-(azenometheno)tripyrazolo[3, 4-f:3',4'-j:4", 3"- / z|| 1.4]oxazacyclopentadecin-14-yl]propan-l-ol;

[0255] (15,25)-2-[(105,17£)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-1477-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin- 14-y l]cyclobutan- 1 -ol;

[0256] (17?,25)-2-[(105,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-1477-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-n][l,4]oxazacyclopentadecin-14-yl]cyclobutan-l-ol;

[0257] (lS,2 / ?)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-147 / -5,3-(azenometheno)tripyrazolo[3,4- / :3,,4'-j:4",3"-n] [1,4]oxazacyclopentadecin- 14-yl]cyclobutan-l -ol;

[0258] (l / ?,2 / ?)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- / :3’,4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]cyclobutan-l-ol;

[0259] l,5-anhydro-2,4-dideoxy-2-[(10S,17£’)-16-ethoxy-6,8,10,12,20-pentamethyl- 2.8.10.11.12.13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4: / :3',4' / :4",3"-n][l,4]oxazacyclopentadecin-14-yl]-L-f / ireo-pentitol;

[0260] l,5-anhydro-2,4-dideoxy-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- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]-D-t / zreo-pentitol;

[0261] l,5-anhydro-2,3-dideoxy-3-[(10S,17£’)-16-ethoxy-6,8,10,12,20-pentamethyl- 2.8.10.11.12.13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-:3',4'- / :4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl] -L-threo-penti t< >1;

[0262] l,5-anhydro-2,3-dideoxy-3-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2.8.10.11.12.13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4: / :3',4' / :4",3"-«][l,4]oxazacyclopentadecin-14-yl]-D-r / ireo-pentitol;

[0263] ( 11 S, 17£)-7, 11, 12, 14,20-pentamethyl-2, 10, 11, 12, 13, 14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-ra][l,4]oxazacyclopentadecine;

[0264] (2S)-2-[( 1 OS, 17E)- 16-ethoxy-7, 10, 12,20-tetramethy 1-2,7, 10, 11, 12, 13-hexahydro-147 / -5,3-(azenometheno)dipyrazolo[3,4: / ':3',4'-j][l,2,3]triazolo[4,5-n] [ 1,4]oxazacyclopentadecin- 14-y l]propan- 1 -ol;

[0265] ( 1 OS, 17E)-7, 10, 12, 14, 16, 20-hexamethyl-2, 10, 11, 12, 13, 14-hexahydro-7H-5,3-(azenometheno)dipyrazolo[3,4- / :3',4' / ][l,2,3]triazolo[4,5-rz][l,4]oxazacyclopentadecine;

[0266] (2S)-2-[( 1 OS, 17 / 7)- 16-ethoxy-8, 10, 12,20-tetramethy 1-2, 8, 10, 11, 12, 13-hexahydro-147 / -5,3-(azenometheno)dipyrazolo[3,4- / :3’,4'-j][l,2,3]triazolo[4,5-n] [ 1,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol;

[0267] (2S)-2-[( 1 OS, 17E)- 16-ethoxy-6, 10, 12,20-tetramethy 1-2,6, 10, 11, 12, 13-hexahydro- 147 / -5,3-(azenonietheno)dipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-n] [ 1,4]oxazacyclopentadecin- 14-y l]propan- 1 -ol;

[0268] (HS,17E)-7,ll,12,14,20-pentamethyl-2,10,ll,12,13,14-hexahydro-7H-5,3-(azenometheno)dipyrazolo[3,4-j:4',3'-n][l,2,3]triazolo[4,5- |[l,4]oxazacyclopentadecine;

[0269] ( 17Z )-7-ethy 1- 12, 14,20-trimethyl-2, 10, 11, 12, 13, 14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine;

[0270] (17E’)-12,14,20-trimethyl-7-(propan-2-yl)-2,10,ll,12,13,14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4-:3',4' / :4",3"- / j][l,4]oxazacyclopentadecine;

[0271] ( 17E)-7-cyclopropyl- 12,14,20-trimethyl-2, 10, 11,12, 13,14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-zz][l,4]oxazacyclopentadecine;

[0272] (l7E)-7-cyclobutyl-l2,14,20-trimethyl-2,l0,1 l,l2,!3,14-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-7j][l,4]oxazacyclopentadecine;

[0273] (17E)-7-(methanesulfonyl)-12,14,20-trimethyl-2,10,ll,12,13,14-hexahydro-7 / / -5,3-(azenometheno)tripyrazolo[3,4:3',4' / ':4",3"-n][l,4]oxazacyclopentadecine;

[0274] ( 17EJ-7- 1 (methanes ulfony I ) methyl I - 12, 14,20-trimethyl-2, 10, 11, 12, 13, 14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-n][l,4]oxazacyclopentadecine;

[0275] ( 17E)-7, 14,20-trimethyl-2,7, 10, 11, 13, 14-hexahydro-5,3- (azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,4]dioxacyclopentadecino[6,7-d][l,2,3]triazole:

[0276] (10S,17E)-7,10,14,20-tetramethyl-2,ll,12,14-tetrahydro-7H,10H-5,3- (azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,5]dioxacyclopentadecino[6,7-d][l,2,3]triazole;

[0277] ( 1 OS.17E)-7, 10, 12, 15, 16, 20-hexamethyl-2, 10, 11, 12, 13, 15-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"- / z][l,4]oxazacyclopentadecine; and

[0278] ( 17E)-7, 12, 15,16,20-pentamethyl-2,10, 11, 12, 13,15-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-n][l,4]oxazacyclopentadecine;

[0279] an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the compound is selected from Compound Table 1, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0281] The following in Compound Table represent illustrative embodiments of compounds of Formula (I)-(III):

[0282] Compound Table 1Ex. # Structure Name(2S)-1 -{ ( 1 OS, 11 R, 17E)- 19-fluoro- N-l / / 0H8, 10, 11, 12-tetramethyl- 16-[(propan-2- yl)oxy] -2,8, 10, 11, 12, 13-hexahydro- 14H- 1 L rN' 3,5-ethenotripyrazolo[3,4- / :3’,4'-j:4",3"- n] [ 1,4]oxazacy clopentadecin- 14-yl [propan- 2-olHN-N \Ex. # Structure Name(2S)-l-{(10 / ?,ll / ?,17 / y)-19-fluoro- N-l / ,0H8, 10, 11, 12-tetramethyl- 16-[(propan-2- \ yl)oxy] -2,8, 10, 11, 12, 13-hexahydro- 14H- 2 L rN' 3,5-ethenotripyrazolo[3,4- / :3',4’: / :4",3"- n] [ 1,4]oxazacyclopentadecin- 14-yl }propan- / 1 — 7 > 2-olvAHN-N I\ zr— / _xr~\ (25) - 1 - [( 1 OS.11 R, 1 IE) - 16-ethoxy- 19- fluoro-8, 10, 11, 12-tetramethyl- Ao 2,8,10,ll,12,13-hexahydro-14H-3,5- 3 Iethenotripyrazolo[3,4- / :3',4'-j:4",3"- w] [ 1,4]oxazacyclopentadecin- 14-yl]propan- 2-olN- / / 0H(2S)- 1 -[( 10 / ?, 11R, VIE)- 16-ethoxy-l 9- fluoro-8, 10, 11, 12-tetramethyl- «.>o t r\2,8,10,11,12, 13-hexahydro-14H-3,5- 4 F, A Y J rL / N>Nethenotripyrazolo[3,4- / :3',4'-j:4",3"- 7 n][l,4]oxazacyclopentadecin-14-yl]propan- 2-olHN-N / / 0H(2S)- 1 -{ ( 1 OS, 11 R, 17E)- 12-ethyl- 19-fluoro- NA / 1 A 8, 10, 11 -trimethyl- 16- 1 (propan-2-yl)oxy ]- O~° X_-N 2,8,10,ll,12,13-hexahydro-14 / 7-3,5- 5X A ethenotripyrazolo[3,4- / :3',4'-j:4",3”- n] [ 1,4]oxazacy clopentadecin- 14-yl Jpropan- X AX / / J X \ 2-olHN-N / -.. X J,°h(2S)- 1 -{ ( 10 / ?, 11 R, 1 IE)- 12-ethyl- 19-fluoro- N-\ / 7 r\ 8,10,ll-trimethyl-16-[(propan-2-yl)oxy]- |Q~° AN 2,8,10, 11, 12, 13-hexahydro- 1477-3,5- 6X Jc? ethenotripyrazolo[3,4- / :3',4'-j:4",3"- X jX zi] [ 1,4]oxazacy clopentadecin- 14-yl } propan- A II \ 2-olHN-NEx. # Structure Name(25) - 1 - [( 1 OR, 11 R, 1 IE) - 16-ethoxy- 12-ethyl- 19-fluoro-8,10,ll-trimethyl- 2,8, 10, 11, 12, 13-hexahydro- 14Z7-3, 5- 7ethenotripyrazolo[3,4- / :3',4': / :4",3"- n] [ 1,4]oxazacyclopentadecin- 14-yl]propan- 2-ol(2S) - 1 - [( 1 OR, 11 R, 1 IE) - 16-ethoxy-20- fluoro-8, 10, 11, 12-tetramethyl- 2,8,10,ll,12,13-hexahydro-14H-3,5- 8ethenotripyrazolo[3,4- / :3',4'-j:4",3"- n] [ 1,4]oxazacy clopentadecin- 14-yl]propan- 2-olX x(25) - 1 - L( 1 OS, 11 R, 1 IE - 16-ethoxy-20- N-r / V^tA,0Hfluoro-8, 10, 11, 12-tetramethyl- yxo ( / 2,8,10, 11, 12, 13-hexahydro-14H-3,5- 9 L z — / A i rlzN'nethenotripyrazolo[3,4- / :3',4'-j:4",3"- £ 1 / z^ J h / n\ [ 1,4]oxazacyclopentadecin- 14-yl]propan- / ! \ 1 / ! X - 1 - ' ' 2-olHN-NA \ z / ^ — X ' 1 OH / "-. XNN-N / (25)- 1 -{ ( 1 OR, 11 R, 17E)-20-fluoro- | 1 / >8, 10, 11, 12-tetramethy 1- 16-[(propan-2- Q10-0yl)oxy] -2,8, 10, 11, 12, 13-hexahydro- 14H- 3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"- Q / A n] [ 1,4]oxazacy clopentadecin- 14-yl }propan- 2-olF N-NH,. 1 x,0H(25)-l-{(105.11 / ?,17E)-20-fluoro- 4 n A 8, 10, 11, 12 -tetramethyl- 16-[(propan-2- yl)oxy]-2,8, 10, 11, 12, 13-hexahydro-14H- 11 A-0v\3,5-ethenotripyrazolo[3,4- / :3',4': / :4",3"- A n] [ 1,4] ox azacy cl opentadeci n - 14-yl } propan- »X2-olFHN'NEx. # Structure Name\ \ OH' W X (2S)- 1 - [( 1 OS, 11 R, 1 IE)- 16-ethoxy- 12-ethyl- NA I l 19-fluoro-8, 10, 11 -trimethy 1- 2,8,10,11,12, 13-hexahydro-14H-3,5- 12ethenotripyrazolo[3,4- / :3',4’-j:4",3”- n] [ 1,4]oxazacy clopentadecin- 14-yl]propan- 2-olHN'NH1 \ OH(2S)- 1 -{ ( 1 OR, 11 R, 1 IE)- 12-ethyl-20-fluoro- 8, 10, 11 -trimethyl- 16- [(propan-2-yl)oxy ]- 2,8, 10, 11, 12, 13-hexahydro- 1477-3,5- 13ethenotripyrazolo[3,4- / :3',4'- / :4",3"- n\ [ 1,4]oxazacyclopentadecin- 14-yl Jpropan- 2-olFHN'N1 \ OH / W (2S)- 1 -{ ( 1 OS, 11 R, 17E)- 12-ethyl-20-fluoro- 8, 10, 11 -trimethyl- 16-[(propan-2-yl)oxy]- 2,8,10,ll,12,13-hexahydro-14H-3,5- 14ethenotripyrazolo[3,4- / :3',4'-j:4",3"- 'E n] [ 1,4]oxazacyclopentadecin-l 4-yl }propan- 2-olFHN'N / KLj,oh(2S)- 1 - [( 1 OS.11 R, 1 IE)- 16-ethoxy- 12-ethyl- 20-fluoro-8, 10, 11 -trimethyl- 2,8,10,ll,12,13-hexahydro-1477-3,5- 15ethenotripyrazolo[3,4- / :3',4'-j:4".3"- w] [ 1,4]oxazacyclopentadecin- 14-yl]propan- 2-olFHN'N, I ) °,HN -r ^N U (2S)-l-[(10 / ?,ll / ?,17E)-16-ethoxy-12-ethyl- 20-fluoro-8, 10, 11 -trimethy 1- 2,8,10,11,12, 13-hexahydro-14H-3,5- 16ethenotripyrazolo[3,4- / :3',4'-j:4",3"- n] [ 1,4]oxazacy clopentadecin- 14-yl]propan- 2-olFHN'NEx. # Structure NameXN-NUA ( / ( 17£)-7, 12.14-trimethy 1-2, 10, 11, 12, 13, 14- L J riN' hexahydro-7H-5,3- 17 zA, N / (azenometheno)tripyrazolo[3,4- / :3’,4’- O / VZO^'=\ z -u j:4",3"-n][l,4]oxazacyclopentadecine A Y H ' / T- HJNzy 1-N’ y i —XN'NAYAO \ Z \ — / I. _ ( 17E)-6,7, 12, 14,20-pentamethyl - z —x / _ / L r / \x / \N' 2, 10, 11, 12, 13, 14-hexahydro-7H-5,3- 18 JL V / -NV- (azenometheno)tripyrazolo [3,4- / :3’,4’- / :4",3"-ra][l,4]oxazacyclopentadecinez / \HN-NXN-NAAO ( / ( 117?, 17 ZT) -6, 7, 11, 12, 14,20-hexamethyl- 2, 10, 11, 12, 13, 14-hexahydro-7H-5,3- 19 L rN' (azenometheno)tripyrazolo[3,4- / :3’,4’- n A / :4",3"-n][l,4]oxazacyclopentadecine \ / / HN-N( 17 E)-7, 12, 14, 20-t etram ethyl - 2, 10, 11, 12, 13, 14-hexahy dro-7H-5.3- 20(azenometheno)tripyrazolo [3,4- / :3’,4’- / :4",3"-ra]! 1,4]oxazacyclopentadecineXN-N A'A(11 / ?, 17£’)-7, 11,12,14,20-pentamethyl- 2, 10, 11, 12, 13, 14-hexahydro-7H-5,3- 21(azenometheno)tripyrazolo [3,4- / :3',4’- j:4",3"- / z][l,4]oxazacyclopentadecine HN-N(111?, 17E)-20-methoxy-7, 11,12,14- tetramethyl-2, 10, 11, 12, 13,14-hexahydro- 22 7H-3,5-ethenodipyrazolo[3,4- / :3',4'- j][l,2,3]triazolo[4,5- rz][l,4]oxazacyclopentadecineEx. # Structure Name( 11 R, 17E) -20-methoxy-7,11,12,14,16- pentamethyl-2, 10, 11, 12, 13,14-hexahydro- 23 / O o 7H-3,5-ethenodipyrazolo[3,4- / :3’,4’-z\ \ Fz-\= _ j][l,2,3]triazolo[4,5- / > / ' AX -r -r— n] [ 1,4]oxazacyclopentadecine) 1 ' 1 > 1 — > I — I — ' / z °^~^ / \ \ z — / _\z—y _x= / A ( 11 R, 17E ) - 16-ethoxy-20-methoxy-x / \ 7,11,12,14-tetramethyl-2, 10,11,12,13,14- 24 hexahydro-7H-3,5-ethenodipyrazolo[3,4-. / :3',4'- / ][l,2,3]triazolo[4,5- n] [ 1,4]oxazacy clopentadecine( 11 R, 17E) -20-chloro-7, 11,12,14- z A — ' A / = \tetramethyl-2, 10, 11, 12, 13,14-hexahydro- 25 7 / / -3,5-ethenodipyrazolo|3,4- / :3’,4'- / ! X 1 - j][l,2,3]triazolo[4,5- n] [ 1,4]oxazacyclopentadecineQZ \ZZ' / XN-N ( 11 R, 1 IE) -20-chloro-7, 11,12,14,16- N<S / 'O ( / pentamethy 1-2, 10, 11, 12, 13, 14-hexahydro- 26 L 1 r1ZN'N 7H-3,5-ethenodipyrazolo[3,4- / :3',4'- / ] [1,2,3]triazolo[4,5- XAJ ' n] [ 1,4]oxazacy clopentadecine ci^ A ifHN-N(111?, 17E)-20-chloro- 16-ethoxy-7, 11,12,14- tetramethyl-2, 10, 11, 12, 13,14-hexahydro- 27 7H-3,5-ethenodipyrazolo [3,4-f.3',4'- j ] [ 1, 2, 3 ] tri azolo [4, 5 - n] [ 1,4]oxazacyclopentadecine\ X / < OHN-N Y N \ y (25)-2-[( 1 OS, 17E)- 16-ethoxy-7, 10, 12,20- Q-° V tetramethyl-2,7, 10, 11, 12, 13-hexahydro- 28 J0N14 / / -5,3-(azenometheno)tripyrazolo[3,4-n\\ / A \ ' 1 / 1 ^ / :3',4'; / :4",3"-n][l,4]oxazacyclopentadecin- °-> / \ it \ 14-yl]propan-l-olHN-NEx. # Structure Name(3 / ?,4S)-4-[(10S,17E)-16-ethoxy- 6,8,10, 12,20-pentamethyl-2,8, 10, 11,12,13- l >0 '°Hhexahydro- 14H-5,3- 29 JQN(azenometheno)tripyrazolo[3,4- / :3’,4’- / :4”,3"-n] [ 1,4]oxazacyclopentadecin- 14- Z ' O / — / \ / ^ \= II \ yl]oxolan-3-olHN-N\ z z—x\ / z°>N-N AzV (3S,4 / ?)-4- [( IOS, 17E)-16-ethoxy- jY'2J 6,8, 10, 12,20-pentamethyl-2,8, 10, 11, 12, 13- VN’OHhexahydro-14 / 7-5,3- 30 oI (azenometheno)tripyrazolo [3,4- / : 3’,4’-N\ II ' j':4",3"- / z][l,4]oxazacyclopentadecin-14- / '■'< II \ yl]oxolan-3-olHN-NX K 3 < OH (2S)-2- [( 1 OS, 1777) - 16-ethoxy- 12-ethyl- N-N y N \ y7, 10,20-trimethyl-2,7, 10, 11, 12, 13- hexahydro-14H-5,3- 31 S^°k J VUNN(azenometheno)tripyrazolo[3,4- / :3’,4’- N \ II '\\ A J* j: 4",3 " -n] [ 1,4]oxazacy clopentadeci n- 14- / \ ii \ yl]propan-l-olHN-NN-N O-,, ( 1 S,2S)-2- [( 1 OS, 17E)- 16-ethoxy- JCH VNOH6,8, 10, 12,20-pentamethyl-2,8, 10, 11, 12, 13- hexahydro-l4 / / -5,3- 32 JQN(azenometheno)tripy razolo [3,4- / : 31,4’ -N\\ \ II 0 ' ^ j:4", 3"- / z][l, 4]oxazacyclopentadecin- 14- / \ II \HN-N yl] cyclobutan-1 -ol(l / ?,2S)-2-[(10S,17E)-16-ethoxy- 6,8,10, 12,20-pentamethyl-2,8, 10, 11,12,13- hexahydro-14 / 7-5,3- 33 (azenometheno)tripyrazolo [3,4- / : 3’,4’- / :4", 3"-«J[l, 4Joxazacyclopentadecin- 14- yl] cyclobutan-1 -olN-N W Q ( 1 S,2 / ?)-2- [( 1 OS, 17E)- 16-ethoxy - AA W "OH6,8,10, 12,20-pentamethyl-2,8, 10, 11.12, 13- hexahydro-1477-5,3- 34n\\z=(azenometheno)tripyrazolo [3, 4- / 3’, 4’- ^\ / / o' -^;:4",3"-n] [ 1,4]oxazacyclopentadecin- 14- \ II \HN-N yl] cyclobutan- 1 -olEx. # Structure Name(l / ?,2 / ?)-2-[(10S,17E)-16-e±oxy- 6,8,10, 12,20-pentamethyl-2,8, 10, 11,12,13- hexahydro- 14 / 7-5,3- 35(azenometheno)tripyrazolo [3,4- / : 3’,4’- / :4", 3"-«][l, 4]oxazacyclopentadecin- 14- yl] cyclobutan-1 -oll,5-anhydro-2,4-dideoxy-2-[(105,17E)-16- N-N y_7ethoxy-6,8, 10, 12,20-pentamethyl- A / 0VN '0H2,8,10, 11, 12,13-hexahydro-14 / / -5,3- 36(azenometheno)tripyrazolo[3,4- / :3’,4’- N / A II '\\ O> / :4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl]- / \ II \ L- / #reo-pentitolHN-NO1,5-anhydro-2,4-dideoxy-2-[(l OS, 17E)- 16- ethoxy-6,8, 10, 12,20-pentamethyl- JI 2-0 k N~0H2,8,10, 11,12, 13-hexahydro-14H-5, 3- 37(azenometheno)tripyrazolo [3,4- / : 3’,4’ - JQNj:4",3"- / z] [ 1,4]oxazacyclopentadecin- 14-yl] - D-t / zreo-pentitol / A II \ HN-N / -0l,5-anhydro-2,3-dideoxy-3-L(10S,17£’)-16- ethoxy-6,8, 10, 12,20-pentamethyl- A A° AN> OH2,8,10, 11, 12, 13-hexahydro- 1477-5,3- 38(azenometheno)tripyrazolo[3,4- / :3',4’- JQNN'A H k j:4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl] - » AJ 0>L-t / zreo-pentitol / A II \HN-N / -0l,5-anhydro-2,3-dideoxy-3-[(10S,17E)-16- N'N / S^V / YA ethoxy-6,8, 10, 12,20-pentamethyl- A A0AN'OH2,8,10,11,12, 13-hexahydro-14H-5,3- 39(azenometheno)tripyrazolo[3,4- / :3',4'- Jc?j:4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl] -NAJ U D-z / z / w-pentitol z A / / \HN-NEx. # Structure NameXN'N( 11 S, 17E)-7, 11, 12, 14,20-pentamethyl- k / ^0 ( / 2,10,11,12,13,14-hexahydro-7H-5,3- 40A Ls, J rI zN'N(azenometheno)tripyrazolo[3,4- / :3’,4’- j:4",3"-n][l,4]oxazacyclopentadecine II HN-Nv / <OH(25)-2-[( 1 OS, 17E)- 16-ethoxy-7, 10, 12,20- tetramethyl-2,7, 10, 11, 12, 13-hexahydro- 147 / -5,3-(azenometheno)dipyrazolo[3,4- 41 X XX / :3',4'-j][l,2,3]triazolo[4,5- iXj X n\ [ 1,4]oxazacyclopentadecin- 14-yl]propan- / \ / / \HN-N l-ol\ / — l / ( 1 OS, 17£)-7, 10, 12, 14, 16,20-hexamethyl- V-0 S-NN= / JkzN2, 10, 11, 12, 13, 14-hexahydro-7H-5,3- 42 (azenometheno)dipyrazolo[3,4- / :3',4'- n P. / ][l,2,3]triazolo[4,5- n] [ 1,4]oxazacyclopentadecine / ~VNH / K / < OHN-N y N X — / (2S)-2- [( IOS, 17E)-16-ethoxy-8, 10, 12,20- ° \_-N tetramethyl-2,8, 10, 11, 12, 13-hexahydro- 14H-5,3-(azenometheno)dipyrazolo[3,4- 43 X xx / :3’,4’-j][l,2,3]triazolo[4,5- yj l n] [ 1,4]oxazacy clopentadecin- 14-yl]propan- / \ II \HN-N l-ol / < OH (2S)-2- [( 1 OS, 17E)- 16-ethoxy-6, 10, 12,20- N'\ / y \—7tetramethyl-2,6, 10, 11, 12, 13-hexahydro- 147 / -5,3-(azenometheno)dipyrazolo[3,4- 44 X XX / :3',4'-j][l,2,3]triazolo[4,5-N\\ A \ J H 0 ' ^ n] [ 1,4]oxazacyclopentadecin- 14-yl]propan- / \ II \HN-N l-olXN-N ( 11 S, 17 E) -7, 11, 12, 14, 20-pentamethyl- W^o { / 2, 10, 11, 12, 13, 14-hexahydro-7H-5,3- 45 L rN' (azenometheno)dipyrazolo[3,4-j:4’,3'- JL 'N«][l,2,3]triazolo[4,5- XX j " f\ [ 1,4] oxazacy clopentadecineHN-NEx. # Structure Name\l~N(17E)-7-ethyl-12,14,20#rimethyl- 2, 10, 11, 12, 13, 14-hexahydro-7H-5,3- 46(azenometheno)tripyrazolo[3,4- / :3',4’- j:4",3"-«][l,4]oxazacyclopentadecine HN-N( 17E)- 12, 14,20-trimethyl-7 -(propan-2-yl)- [ / 2, 10, 11, 12, 13, 14-hexahydro-7H-5,3- 47 L J rLZN'N (azenometheno)tripyrazolo[3,4- / :3',4'- O j j:4",3"-n][l,4]oxazacyclopentadecine II HN-N^N-N ( 1rlE)-'l -cyclopropyl- 12, 14,20-trimethyl- I / 2, 10, 11, 12, 13, 14-hexahy dro-7H-5,3- 48A Lts J rL / N'N (azenometheno)tripyrazolo [3,4- / :3',4'- / :4",3"-«l [ 1,4]oxazacyclopentadecine 'zH \N-N 1 / Q N- N( 17£)-7 -cyclobutyl- 12, 14,20-trimethyl- %X~o I / 2, 10, 11, 12,13, 14-hexahydro-7H-5,3- 49A L s, J rL zN'N (azenometheno)tripyrazolo L3,4- / :3',4'- j:4",3"-n][l,4]oxazacyclopentadecine H \N-N II?'zO—sxN-N <^N^ ( 11E)-1 -(methanesulfonyl)- 12, 14,20- trimethyl-2, 10, 11, 12, 13,14-hexahydro-7H- 505,3-(azenometheno)tripyrazolo [3,4- / :3',4'- j:4",3"-n][l,4]oxazacyclopentadecine HN-NO^^N-N (17E)-7-[(methanesulfonyl)methyl]- AZ" O ( / 12,14,20-trimethyl-2, 10, 11, 12, 13, 14- 51 I rN> hexahydro-7H-5,3- / As JL yN(azenometheno)tripyrazolo[3,4- / :3',4'- j:4",3"-n][l,4]oxazacyclopentadecine HN-NEx. # Structure Name \-N( 17 / 0-7,14,20-trimethyl-2,7, 10,11,13,14- 0^0 f / hexahydro-5,3- 52 L rN'As JL, N (azenometheno)dipyrazolo[3',4':10,ll;4",3":14, 15 ] [ 1,4]dioxacyclopentadecino[6,7- ' VXX / J / IN' 6?][l,2,3]triazoleH > iN i — *-NZ z O~X~\-N ( 1 OS, 17E) -7, 10, 14, 20-tetramethyl- O"0 \ ~Z / o- / 2,11,12,14-tetrahydro-7 / / , 10H-5,3- 53 L Jxn / T -Z ■ XN,'Z (azenometheno)dipy razolo [3',4': 10, 11;4", 3 ":N1 14,15][l,5]dioxacyclopentadecino[6,7- \ it 6 / ][l,2,3]triazoleHN-N\|-N(17£)-20-methoxy-7, 14-dimethyl- H H2N 'Y0( X_N / 2,7,10,11,13, 14-hexahydro-3, 5- 54 zS -A A ethenodipyrazolo [3', 4': 10, 11;4",3": 14, 15 ] [ 1,4]dioxacyclopentadecino[6,7- XXJ^Q> \ irN£ / ][l,2,3]triazol-6-amineHN-N\-N( 17£)-20-methoxy-7, 14-dimethyl- H MA / ° 0, / H2NI V-N 2, 1 l,12,14-tetrahydro-7 / / ,10H-3,5- 55 X. Ji, N ethenodipyrazolo[3',4': 10, 11;4",3": 14, 15] [ 1, rxjin' 5]dioxacyclopentadecino[6,7- d\ [1,2,3]triazol-6-amineHN-N(1 OS, 17 / 0-7, 10, 12, 15, 16,20-hexamethyl- 2, 10, 11, 12.13, 15-hexahydro-7H-5,3- 56(azenometheno)tripyrazolo[3,4- / :3',4'- / :4”,3"-n][l,4]oxazacyclopentadecineXN'N(17 / 0-7,12, 15, 16,20-pentamethyl- 2,10,ll,12,13,15-hexahydro-7 / / -5,3- 57(azenometheno)tripyrazolo[3,4: / :3',4'- X / A j:4",3"-n][l,4]oxazacyclopentadecine HN-N

[0283] and isotopically labeled forms thereof, or a hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0284] Those skilled in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected.PHARMACEUTICAL COMPOSITIONS

[0285] 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.

[0286] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multidose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 pg / kg / minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0292] 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.

[0293] For topical applications, the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. Fortopical 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.

[0294] As used herein, the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.

[0295] The term “subject” refers to a mammalian patient in need of such treatment, such as a human.

[0296] 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 fromchemotherapeutic 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.

[0297] 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, A746-750, A746-750 / C797S, L858R / T790M, L858R / T790M / C797S, 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.

[0298] 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, A746-750, A746-750 / C797S, L858R / T790M, L858R / T790M / C797S, and D770_N771insNPG, while maintaining good selectivity over wild-type EGFR.

[0299] 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).

[0300] 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, requireintermitent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.DRUG COMBINATIONS

[0301] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure.

[0302] 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 NSAlDs. 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

[0303] 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 othercompounds of Formula (I)-(III).

[0304] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:g gramseq equivalentsmmol millimolesmL millilitersMHz megahertzPPm parts per million5 chemical shifts singletd doublett tripletq quartetquin quintetbr broadm multipletHz hertzTHF tetrahydrofuran°C degrees CelsiusPE petroleum etherEA or EtOAc ethyl acetateRf retardation factorN normalJ coupling constantRT Room TemperaturemM millimolarpM or uM micromolarnM nanomolarmin minuteshr hoursMe methylEt ethyli-Pr isopropylTLC thin layer chromatographyM molarCompd# compound numberMS mass spectrumm / z mass-to-charge ratioMs methanesulfonylDMSO-& deuterated dimethyl sulfoxideDMSO dimethyl sulfoxideBoc tert-butyloxycarbonylTFA trifluoroacetic acidTFAA trifluoroacetic anhydrideDMAP 4-(dimethylamino)pyridineATP adenosine triphosphateIC50 half maximal inhibitory concentration U / mL units of activity per milliliterHex hexanesMeCN or ACN AcetonitrileDIPEA or DIEA or A, A-diisopropylethylamineHunig’s BaseTEA triethylamineKHMDS potassium bis(trimethylsilyl)amideDIAD diisopropyl azodicarboxylateDBAD di-tert-butyl azodicarboxylateMeTHF or 2 -MeTHF 2-methyltetrahydrofuranMOM methoxymethylDCM dichloromethaneDCE 1,2-dichloroethaneCPME cyclopentyl methyl etherDMF N, A-di methy Iform ami deDPPA diphenyl phosphoryl azideDPPF 1, l'-Bis(diphenylphosphino)ferroceneDBU l,8-diazabicyclo|5.4.0Jundec-7-eneAcOH Acetic AcidFA formic acidTBS Tert-ButyldimethylsilylTMS TrimethylsilylSEM [2-(Trimethylsilyl)ethoxy]methyl Pd(dppf)Cl2[1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dtbpf)Cl2[1,1 '-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) TPPO Triphenylphosphine oxidePd2(dba)3Tris(dibenzylideneacetone)dipalladium(0) Pd(MeCN)2Cl2Bis(acetonitrile)dichloropalladium (II) Pd(PPh3)4Tetrakis(triphenylphosphine)palladium (0) Pd(PPh3)2Cl2Bis(triphenylphosphine)palladium (II) chloride PPh3Triphenyl phosphineTos or Ts toluenesulfonylp-TSA or PTSA Para-Tolylsulfonic acidn-BuOH n-butanolt-BuOH Tert-ButanolPd(amphos)Cl2Dichlorobi s [di -tert-butyl(4- dimethylaminophenyl)phosphine]palladium(II) mCPBA Meto-Chloroperoxy benzoic acidBPD or B2Pin2or 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan Bis(pinacolato)diboron -2-yl)-l,3,2-dioxaborolaneHBPin or 4,4,5,5-Tetramethyl-l,3,2-dioxaborolane PinacolboraneMTBE Methy tert-Butyl EtherTBAC Tetrabutylammonium chlorideTBAF Tetrabutyl ammonium fluorideLAH Lithium aluminium hydrideHATU Hexafluorophosphate Azabenzotri azole Tetramethyl UroniumEDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide DMA or DMAc DimethylacetamidePPTS Pyridinium p-ToluenesulfonateDHP 3,4-DihydropyranTHP TetrahydropyranNMP N-Methyl-2-pyrrolidoneDIBAL-H Diisobutylaluminium hydrideOTf Triflate or trifluoromethanesulfonatefert-BuBrettPhos-Pd- [(2-Di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl- G3 1, 1 '-biphenyl)-2-(2'-amino-l, 1 '-biphenyl)]palladium(II)methanesulfonateCy3P Pd G3 [(Tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonateXphos dicyclohexyl-[2-(2,4,6-triisopropylphenyl) phenyl]phosphane Pd-PEPPSI [l,3-Bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) dichlorideOxone potassium monopersulfateNBS N -B romosuccinimideNIS N-Iodosuccinimide

[0305] The proposed targets can be prepared via conventional chemical means.

[0306] Intermediate synthesis

[0307] Intermediate Method I-1A

[0308] Preparation of 5-bromo-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazoleF' Na2CO3, Pd(dppf)CI2-CH2CI2dioxane / H201-1-1

[0309] Step 1. To a solution of 5-bromo-6-fluoro-lH-indazole (25 g, 116 mmol, 1.0 eq) in DMF (500 mL) was added I2(59.0 g, 232 mmol, 46.8 mL, 2.0 eq) and NaOH (14.0 g, 349 mmol, 3.0 eq). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was quenched with a saturated aqueous solution of Na\SO< (500 mL), water (2,000 mL) andextracted with ethyl acetate (500 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was triturated with PE / EA= 10 / 1 at 25 °C for 30 min to give 5-bromo-6-fluoro-3-iodo-lH-indazole (27.4 g, 79.6mmol, 68 % yield) as a yellow solid. LCMS: m / z 342.3 (M+l).

[0310] Step 2. To a solution of 5-bromo-6-fluoro-3-iodo-lH-indazole (27 g, 79.2 mmol, 1.0 eq) and 3,4-dihydro-2H-pyran (13.3 g, 158 mmol, 2.0 eq) in toluene (500 mL) was added TosOH (2.73 g, 15.8 mmol, 0.2 eq. The mixture was stirred at 90 °C for 16 hr. On completion, the mixture was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO. DCM / MeOH= 1:0) to give 5-bromo-6-fluoro-3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (33 g, 76.1 mmol, 96% yield) as a yellow solid. LCMS: m / z 426.4 (M+l)

[0311] Step 3. To a solution of 5-bromo-6-fluoro-3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (9.50 g, 22.4 mmol, 1 eq) in dioxane (100 mL) and H2O (20 mL) was added potassium trifluoro(vinyl)boranuide (2.99 g, 22.4 mmol, 1 eq), Na^CCh (7.11 g, 67 mmol, 3 eq) and Pd(dppf)C12- CH2Q2 (1.83 g, 2.24 mmol, 0.1 eq) at 25 °C under N2, then the mixture was stirred at 80 °C for 16 h. On completion, the reaction mixture was diluted with H2O (150 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-15% THF / Petroleum ether) to give 5-bromo-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (4.30 g, 13.2 mmol, 59% yield) as a yellow solid. LCMS: m / z 242.9 (M-81).

[0312] Intermediate Method LIB

[0313] Preparation of 5-bromo-7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (Ll-2):F\, FK-B^FPd(dppf)CI2, CH2CI2Cs2CO3, dioxane / H2O1-1-2

[0314] Step 1. To a solution of 5-bromo-7-fluoro-lH-indazole (48.0 g, 223 mmol, 1 eq) inTHF (480 mL) was added L> (85.0 g, 335 mmol, 67.5 mL, 1.5 eq) and t-BuOK (75.2 g, 670 mmol, 3 eq) at 0 °C. The mixture was stirred at 0-25 °C for 1.5 h. On completion, the reaction mixture was quenched by a saturated sodium sulfite solution (1 L) at 0 °C. The combined organic layers were washed with water (600 mL x 5), then washed with Petroleum ether (1000 mL x 2), filtered and concentrated under reduced pressure to give 5-bromo-7-fluoro-3-iodo-IH-indazole (78.0 g, crude) as a yellow solid. LCMS: m / z 342.8 (M+l)

[0315] Step 2. To a solution of 5-bromo-7-fluoro-3-iodo-lH-indazole (38.0 g, 111 mmol, 1 eq) in dioxane (380 mL) was added 3,4-dihydro-2H-pyran (18.8 g, 223 mmol, 20.4 mL, 2 eq) and 4-methylbenzenesulfonic acid (3.84 g, 22.3 mmol, 0.2 eq). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MeOH (150 mL) at 25 °C for 1 h to give 5-bromo-7-fluoro-3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (44.0 g, 104 mmol, 93.0% yield) as a white solid. ’H NMR (400 MHz, DMSO-rfc) 5 = 7.68 (br d, J = 11.2 Hz, 1H), 7.51 (s, 1H), 5.78 (br d, 7= 9.2 Hz, 1H), 3.89 (d, J = 11.2 Hz, 1H), 3.70 - 3.54 (m, 1H), 2.39 -2.26 (m, 1H), 2.04 (t, J= 13.2 Hz, 2H), 1.80 - 1.64 (m, 1H), 1.54 (br s, 2H); LCMS: m z 424.9 (M+l)

[0316] Step 3. A mixture of 5-bromo-7-fluoro-3-iodo-l-tetrahydropyran-2-yl-indazole (42.0 g, 98.8 mmol, 1 eq), potassium trifluoro(vinyl)boranuide (13.2 g, 98.8 mmol, 1 eq), Pd(dppf)C12. CH2C12 (8.07 g, 9.88 mmol, 0.1 eq) and CS2CO3 (96.6 g, 296 mmol, 3 eq) in dioxane (420 mL) and H2O (84 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere. On completion, the reaction mixture was diluted with H2O (2 L) and extracted with methyl cyclohexane (700 mL x 3). The combined organic layers were washed with brine (1 L x 2), dried over Na2SO+ filtered and concentrated under reduced pressure to give the crude product 5-bromo-7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (23.0 g, 70.5 mmol, 71.5% yield) as a brown solid. Analytical data shown in the table below.

[0317] Intermediate Method 1-1 C

[0318] Preparation of 5-bromo-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridine (1-1-3):1-1-3

[0319] Step 1 was carried out following the method shown in Step 1 of Intermediate Method LIB.

[0320] Step 2 was carried out following the method shown in Step 2 of Intermediate Method I-1B, using toluene as the solvent, at a temperature of 90 °C.

[0321] Step 3 was carried out following the method shown in Step 3 of Intermediate Method I-1B, using Pd(dppf)C12 as the catalyst.

[0322] Intermediate Method I- ID

[0323] Preparation of 7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-viny 1- 1 H-indazole (I- 1 -5):

[0324] Step 1. To a solution of 5-bromo-7-methoxy-lH-indazole (5.00 g, 22.0 mmol, 1 eq) in THF (50 mL) was added t-BuOK (7.41 g, 66.0 mmol, 3 eq) and P (11.2 g, 44.0 mmol, 2 eq) at 0 °C. The mixture was stirred at 25°C for 4 h. On completion, the mixture was quenched with sat. Na: SO; (50 mL) and extracted with EA (50 mL x 3). The combined organic layerswere washed with brine (50 mLx 2), dried over NaaSCh, filtered and concentrated to give 5-bromo-3-iodo-7-methoxy-lH-indazole (8.20 g, crude) as a yellow solid. LCMS: m / z 352.8 (M+l).

[0325] Step 2. To a solution of 5-bromo-3-iodo-7-methoxy-lH-indazole (7.82 g, 22.1 mmol, 1 eq) in dioxane (80 mL) was added DHP (3.73 g, 44.3 mmol, 2 eq) and TsOH. FLO (843 mg, 4.43 mmol, 0.2 eq). The mixture was stirred at 70 °C for 2 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiOj, PE: THF= 1:0 to 5:1) to give 5-bromo-3-iodo-7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (5.50 g, 12.6 mmol, 57% yield) as a white solid. LCMS: m / z 436.9 (M+l).

[0326] Step 3. To a solution of 5-bromo-3-iodo-7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (5.30 g, 12.1 mmol, 1 eq) in dioxane (106 mL) and FLO (21.2 mL) was added CS2CO3 (11.8 g, 36.4 mmol, 3 eq), potassium vinyltrifluoroborate (1.79 g, 13.3 mmol, 1.1 eq) and Pd(dppf)C12 (887 mg, 1.21 mmol, 0.1 eq) under N2, and the mixture was stirred at 80 °C for 1 h. On completion, the mixture was dried over Na2SO4. filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: THF= 1:0 to 5:1) to give 5-bromo-7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (3.30 g, 9.79 mmol, 81% yield) as a white solid. LCMS: m / z 337.0 (M+l).

[0327] Step 4. To a solution of 5-bromo-7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-IH-indazole (3.20 g, 9.49 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4.82 g, 18.9 mmol, 2 eq) and KOAc (1.86 g, 18.9 mmol, 2 eq) in dioxane (32 mL) was added Pd(dppf)C12 (694 mg, 0.948 mmol, 0.1 eq) under N2. The mixture was stirred at 90 °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 9:1) to give 7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-vinyl-lH-indazole (2.10 g, 5.46 mmol, 57% yield) as a white solid. LCMS: m / z 385.3 (M+l).

[0328] Intermediate Method LIE

[0329] Preparation of 7-chloro-l-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyLl,3,2-dioxaborolan-2-yl)-3-vinyl- 1 H-indazole (I- 1 -6):Brt-BuOK, l2, THF DHP, PPTS DCM HN-N<^BF3K Pd(dppf)CI2, Na2CO3 Dioxane / H2O(BPin)2, Pd(dppf)CI2AcOK, Dioxane1-1-6

[0330] Step 1 was performed following the procedure outlined in Step 1 for Intermediate Method I- ID.

[0331] Step 2. To a solution of 5-bromo-7-chloro-3-iodo-lH-indazole (2.77 g, 7.75 mmol, 1 eq) in DCM (28 mL) was added DHP (1.96 g, 23.3 mmol, 3 eq) and PPTS (195 mg, 0.775 mmol, 0.1 eq). The mixture was stirred at 40 °C for 20 h. On completion, the mixture was quenched with sat. NaHCOs (20 mL) and extracted with DCM (25 mLx3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was triturated with MeOH (10 mL) at 25 °C for 2 h to give 5-bromo-7-chloro-3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (2.88 g, 6.52 mmol, 84% yield) as a yellow solid. H NMR (400 MHz, CDCh) 5 = 7.56 (s, 1H), 7.45 (d, 7 = 0.8 Hz, 1H), 5.85 - 5.77 (m. 1H), 4.11 (br d, J= 11.6 Hz, 1H), 3.82 - 3.73 (m, 1H), 2.77 - 2.63 (m, 1H), 2.28 - 2.04 (m, 2H), 1.90 - 1.56 (m, 3H); LCMS: m / z 464.8 (M+23).

[0332] Step 3 was performed following the procedure described in Step 3 for Intermediate Method I-1D, using Na^CO- as the base instead of CS2CO3.

[0333] Step 4 was performed following the procedure outlined in Step 4 for Intermediate Method LID to give 7-chloro-l-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-vinyl-lH-indazole (3.28 g, 7.85 mmol, 94% yield, 93% purity) as a whitesolid. LCMS: m / z 389.1 (M+l).

[0334] Intermediate Method I- IF

[0335] Preparation of (7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)boronic acid (1-1-7):OHBr HO-BN'==r\ n-BuLi, B(OMe)3, THF N^X J / N-N / N'NTHP THP1-1-4 1-1-7

[0336] A solution of 5-bromo-7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridine (2.20 g, 6.83 mmol, 1 eq) in THF (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at -78 °C for 10 min under N2 atmosphere. Butyllithium (2.5 M in THF, 4.10 mL, 1.5 eq) was then added at -78 °C under N2 atmosphere. After 20 min, trimethyl borate (1.06 g, 10.2 mmol, 1.16 mL, 1.5 eq) in THF (2 mL) was added. The mixture was stirred at -78 °C for 0.5 hours. On completion, the reaction mixture was quenched by addition H2O (40 mL) at 0 °C and extracted with EA (15 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)boronic acid (1.96 g, 6.83 mmol, 100% yield) as a white solid. LCMS: m / z 288.2 (M+l).

[0337] Intermediate Method I-1G

[0338] Preparation of 5-bromo-7-methyl-lH-pyrazolo[3,4-c]pyridine (1-1-8):

[0339] Step 1. To a solution of 2,4-dimethylpyridin-3-amine (2.90 kg, 23.7 mol, 1 eq) in DCM (30 L) was added NBS (4.44 kg, 24.9 mol, 1.05 eq) in batches at 0 °C, then the mixture was stirred at 0 °C for 1 h. On completion, the reaction mixture was quenched with Na SO? (30 L) at 25 °C and diluted with H2O (20 L). The combined organic layers were washed with H2O (20 L x 3) and brine (20 L x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-bromo-2,4-dimethyl-pyridin-3-amine (4.34 kg, crude) as a black oil, which solidified upon standing. ¹H NMR (400 MHz, CDCl₃) 5 = 6.93 (s, 1H), 3.59 (s, 2H), 2.29 (d,7= 1.8 Hz, 3H), 2.05 (d, J = 1.4 Hz, 3H); LCMS: m / z 200.9 (M+l).

[0340] Step 2. To a solution of 6-bromo-2,4-dimethyl-pyridin-3-amine (2.07 kg, 10.3 mol, 1 eq) in Tol. (10.3 L) and AcOH (4.13 L, 7.02 eq) was added KO Ac (2.02 kg, 20.5 mol, 2 eq) in batches at 0 °C, then isopentyl nitrite (1.80 kg, 15.4 mol, 1.5 eq) was added dropwise into the mixture at 25 °C and stirred for 1 h. On completion, the reaction mixture was diluted with H2O (10 L) and extracted with EA (8 L x 3). The combined organic layers were washed with brine (8 L x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 5- bromo-7-methyl-lH-pyrazolo[3,4-c]pyridine (4.80 kg, crude, 2 batches) as a brown solid. Analytical data shown in the table below.

[0341] Intermediate Method I-1H

[0342] Preparation of 5-bromo-7 -methyl- 1 -(tetrahydro-2H-pyran-2-y l)-3- ((triisopropylsilyl)ethynyl)-lH-pyrazolo[3,4-c]pyridine (1-1-10):BrTHP

[0343] A mixture of 5-bromo-3-iodo-7-methyl-l-tetrahydropyran-2-yl-pyrazolo[3,4- c]pyridine (10.0 g, 23.7 mmol, 1 eq), ethynyl(triisopropyl)silane (4.32 g, 23.7 mmol, 1 eq), Pd(PPh3)2Cl2(1.66 g, 2.37 mmol, 0.1 eq), Cui (451 mg, 2.37 mmol, 0.1 eq) and TEA (24.0 g, 237 mmol, 10 eq) in DMF (100 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25 °C for 12 hours under N2atmosphere. On completion, the mixture was poured into H2O (300 mL), and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 5 / 1 to 0 / 1) to give 2-(5-bromo-7-methyl-l- tetrahydropyran-2-yl-pyrazolo [3,4-c]pyridin-3-yl)ethynyl-triisopropyl-silane (8.60 g, 18.0 mmol, 76% yield) as a yellow oil. LCMS: m z 476.2 (M +1).

[0344] Intermediate Table 1# SM1Meth. Structure (m / z) 'll NMR [M+l]BrBrF^ / %- F- / A 242.91-1-1 I-1A (M- 7 ^ 81)HN-N?N-NTHP'# SM1Meth. Structure (mlz) H NMR [M+l](400 MHz, DMSO- d6) 5 = 8.11 (s, 1H).7.59 (d, J = 11.2 Hz, 1H), 7.01 (dd, J = 11.2, 17.9 Hz, 1H), Br 6.17 (d, J = 18.0Hz, Br 1H), 5.83 - 5.73 (m,1H), 5.57 (d, J = -1-2 I-1B 325.011.6 Hz, 1H), 3.95 -FHN-NF?^N'N3.87 (m, 1H), 3.69 - THP 3.61 (m, 1H), 2.42 - 2.34 (m, 1H), 2.05 (d,. / = 10.4 Hz, 2H), 1.78 - 1.68 (m, 1H), 1.55 (d, 7= 3.2 Hz, 2H)(400 MHz, CDCls) d = 8.88 (d, 7 = 1.2 Hz, 1H), 7.97 (d, J = I.2 Hz, 1H), 6.97 Br (dd, 7= 11.2, 18.0 Br Hz, 1H), 6.06 (d, 7 =N^\ 18.0 Hz, 1H), 5.77 -1-3 I-1C ft 310.07l (dd, 7= 2.4, 8.8 Hz, N'NHN'N1H), 5.60 (d, 7 = THP II.6 Hz, 1H), 4.08 - 3.67 (m, 2H), 2.54 - 2.36 (m, 1H), 2.22 - 2.02 (m, 2H), 1.81 - 1.69 (m, 3H) BrN^A-1-4 1-1-8 I-1C23-4ft 322.0Z A IIZ\l'NTHPBr-1-5 I-1D 385.3QjHN-NN-NTHP# SM1Meth. Structure (mlz) H NMR [M+l]Br-1-6 I-1E 389.1C JLXJ HN-N CI^ A / / N-NTHP'Br OHHO-B-1-7 I-1FN\j 288.2■YXTHP THPBr (400 MHz, DMSO- rfc) 5 = 1 fXXY 3.89 (s, -1-8NI-1G 1H), 8.14 (s, 1H), 'y ^NH2N\ >^ 212.07.81 (s, 1H), 2.73 (s, / A ”HN'N3H)(400 MHz, CDCI ) 5 = 7.37 (s, 1H), 5.82 (dd, J = 2.8, 9.6 Hz, 1H), 4.16 - 4.05 (m, Br1H), 3.84 - 3.72 (m, N' A 1H), 2.92 - 2.84 (m, I- IE5-1-9 1-1-8 423.8 JUL 3H), 2.69 - 2.56 (m,x\ / / 1H), 2.26 - 2.17 (m, N-NTHP' 1H), 2.10 - 2.01 (m,1H), 1.84 - 1.75 (m, 2H), 1.71 - 1.63 (m, 1H)Br / TIPSN \I-1H 476.2-1-10 1-1-9N'NTHP'Br-TIPS-1-11 I-1H I-l-5a 493.3, N-NTHP3SM: Starting Material(s)2Step 3 used Na2CO3 as base3Step 2 was carried out for 16 hours4Step 3 was carried out for 16 hours5Steps 1 and 2 only

[0345] Intermediate Method I-2A

[0346] Preparation of tert-butyl methyl(2-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-3-yl)oxy)ethyl)carbamate (1-2-2):zz^'N / I1z \M-N HOBocZZ"'N NBS N L A / -nu - ► \ NrNsx _ I > J B,0C- ► DIAD, PPh3, THF Ufe / 0 DMFBr

[0347] Step 1. A mixture of PPh3 (2.01 g, 7.65 mmol, 1.5 eq) in THF (5 mL) was degassed and purged with N2 for 3 times, and then was added DIAD (1.55 g, 7.65 mmol, 1.5 eq at 0 °C, followed by 1 -methyl- lH-pyrazol-3-ol (500 mg, 5.10 mmol, 1 eq) and tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.07 g, 6.12 mmol, 1.2 eq). Then, the mixture was stirred at 25 °C for 1 hour 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 / THF= 1:0 to 3:1) to give tert-butyl methyl(2-((l-methyl-lH-pyrazol-3-yl)oxy)ethyl)carbamate (680 mg, 2.66 mmol, 52% yield) as an off-white oil. 1H NMR (400 MHz, CDCI3) δ = 7.55 (s, 1H), 7.41 (d, J= 2.4 Hz, 1H), 5.89 (s, 1H), 4.51 (t, J= 5.2 Hz, 2H), 4.02 (s, 3H), 3.86 (s, 2H), 3.25 (s, 3H), 1.74 (s, 8H); LCMS: m / z 156.2 (M-100).

[0348] Step 2. To a solution of tert-butyl methyl(2-((l -methyl- lH-pyrazol-3-yl)oxy)ethyl)carbamate (0.650 g, 2.55 mmol, 1 eq) in DMF (6 mL) was added NBS (498 mg, 2.80 mmol, 1.1 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=1:0 to 0:1) to give tert -butyl (2-((4-bromo-l -methyl- lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (330 mg, 987 pmol, 39% yield) as an off-white oil. LCMS: m z 234.1 (M-100).

[0349] Step 3. A mixture of tert-butyl (2-((4-bromo-l-methyl-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (1.70 g, 5.09 mmol, 1 eq) in 2-MeTHF (15 mL) was degassed and purged with N2 for 3 times at -78 °C, then was added n-BuLi (2.5 M in THF, 6.10 mL, 3 eq) at -78 °C, and then the mixture was stirred at -78 °C for 0.5 hour under N2 atmosphere. Then, 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.14 g, 6.10 mmol, 1.2 eq) was added at -78 °C, and the mixture was stirred at -78 °C for 0.5 hour under N2 atmosphere. On completion, the mixture was quenched with NH4CI aqueous (50 mL) and was extracted with EA (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl methyl(2-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-3-yl)oxy)ethyl)carbamate (2.10 g, 4.96 mmol, 97% yield, 90% purity) as a yellow oil. LCMS: m / z 382.2 (M+l)

[0350] Intermediate Method I-2B

[0351] Preparation of tert-butyl (2-((l,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (1-2-3):NBS, MeCNHB-oPdCI2(MeCN)2, XPhosTEA, dioxane

[0352] Step 1. To a solution of but-2-ynoic acid (10.0 g, 118 mmol, 1 eq) in DCM (100 mL) was added DMAP (1.45 g, 11.8 mmol, 0.1 eq), then was added tert-butyl 1 -methylhydrazine-1-carboxylate (18.4 g, 126 mmol, 1.06 eq), and last was added EDCI (25.0 g, 130 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was quenched with HC1 (1 N, 100 mL) and extracted with dichloromethane(100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 2-(but-2-ynoyl)-l -methylhydrazine- 1 -carboxylate (25.0 g, 117 mmol, 99% yield) as a yellow oil.

[0353] Step 2. To a solution of tert-butyl 2-(but-2-ynoyl)-l-methylhydrazine-l-carboxylate (25.0 g, 117 mmol, 1 eq) in i-PrOH (125 mL) was added conc. HCl / H2O (12 M, 21.5 mL, 2.2 eq). The mixture was stirred at 60 °C for 30 hours. On completion, the mixture was filtered and concentrated to give a residue. The crude product was triturated with ACN (40 mL) at 75 °C for 15 minutes to give l,5-dimethyl-lH-pyrazol-3-ol (11.8 g, 105 mmol, 89% yield) as a white solid.1H NMR (400 MHz, MeOD-^) 5 = 5.76 (s, 1H), 3.78 (s, 3H), 2.37 (s, 3H)

[0354] Step 3. To a solution of l,5-dimethyl-lH-pyrazol-3-ol (3.00 g, 26.0 mmol, 1 eq) inDMF (60 mL) was added Cs2CO3 (26.1 g, 80.2 mmol, 3 eq) and tert-butyl (2-bromoethyl)carbamate (8.99 g, 40.1 mmol, 1.5 eq). The mixture was stirred at 80 °C for 1 hour. On completion, the reaction mixture was partitioned between ethyl acetate (60 mL x 3) and water (60 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 / THF= 1:0 to 0:1) to give tert-butyl (2-((l,5-dimethyl-lH-pyrazol-3-yl)oxy)ethyl)carbamate (5.10 g. 19.9 mmol, 74% yield) as a yellow oil. LCMS: m / z 200.1 (M+l).

[0355] Step 4. To a solution of tert-butyl (2-((l,5-dimethyl-lH-pyrazol-3-yl)oxy)ethyl)carbamate (5.10 g, 19.9 mmol, 1 eq) in DMF (50 mL) was added NaH (1.20 g, 29.9 mmol, 60% purity, 1.5 eq) and Mel (4.25 g, 29.9 mmol, 1.5 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched with a saturated solution of NH4CI (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl (2-((l,5-dimethyl-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (4.20 g, 15.5 mmol, 78% yield) as a yellow oil. LCMS: m / z 292.1 (M+1).

[0356] Step 5. To a solution of tert-butyl (2-((l,5-dimethyl-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (4.15 g, 15.4 mmol, 1 eq) in ACN (50 mL) was added NBS (4.11 g, 23.1 mmol, 1.5 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched with a saturated solution of Na2SO3 (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=l: O to 0:1) to give tert-butyl (2-((4-bromo-l,5-dimethyl-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (5.10 g, 14.6 mmol, 95% yield) as a yellow oil. LCMS: m / z 371.9 (M+l).

[0357] Step 6. A mixture of tert-butyl (2-((4-bromo-l,5-dimethyl-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (2.00 g, 5.74 mmol, 1 eq), 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.21 g, 17.2 mmol, 3 eq), XPhos (273 mg, 574 pmol, 0.1 eq), PdC12(MeCN)2 (149 mg, 574 pmol, 0.1 eq) and TEA (871 mg, 8.61 mmol, 1.5 eq) in dioxane (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 1 hour under N2 atmosphere. On completion, the mixture was quenched with water (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0: 1) to give tert-butyl (2-(( 1,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (2.20 g, 5.57 mmol, 96% yield) as a yellow oil. LCMS: m / z 396.1 (M+l).

[0358] Intermediate Method I-2C

[0359] Preparation of tert-butyl (R)-(l-((l,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-3-yl)oxy)propan-2-yl)(methyl)carbamate (1-2-4):HO NHBoc DCM MsO NHBoc Cs2CO3, DMF 1-2-4Pd(CH3CN)2CI2, X-Phos TEA, dioxane

[0360] Step 1. To a solution of tert-butyl (R)-(l-hydroxypropan-2-yl)carbamate (5.00 g, 28.5 mmol, 1 eq) in DCM (50 mL) was added DIEA (85.6 mmol, 14.9 mL, 3 eq) and methylsulfonyl methanesulfonate (7.46 g, 42.8 mmol, 1.5 eq at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was diluted with H2O (20 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with sat. citric acid (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (7.2 g, 28.4 mmol, 99% yield) as a yellow solid.

[0361] Step 2. To a solution of l,5-dimethyl-l,2-dihydro-3H-pyrazol-3-one (2.50 g, 22.3 mmol, 1 eq) in DME (25 mL) was added Cs2CO3 (21.7 g, 66.8 mmol, 3 eq) and (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (6.78 g, 26.7 mmol, 1.2 eq). The mixture was stirred at 80 °C for 1 hour. On completion, the reaction mixture was quenched by addition of H2O (200 mL) at 25 °C, then diluted with H O (20 mL) and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrousNa2SO4, filtered and concentrated under reduced pressure to give a residue. Then the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 100 / 1 to 80 / 20) to give tert-butyl (R)-(l-((l,5-dimethyl-lH-pyrazol-3-yl)oxy)propan-2-yl)carbamate (4.10 g, 14.9 mmol, 66% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 5.43 (s, 1H), 5.13 -4.50 (m, 1H), 4.04 - 4.00 (m, 2H), 3.61 (s, 3H), 2.1 (s, 3H), 1.44 (s, 9H), 1.25 (d, J = 6.4 Hz, 3H).

[0362] Step 3. To a solution of tert-butyl (R)-(l-((l,5-dimethyl-lH-pyrazol-3-yl)oxy)propan-2-yl)carbamate (4.00 g, 14.8 mmol, 1 eq) in DMF (40 mL) was added NaH (1.49 g, 37.1 mmol, 60% purity, 2.5 eq) at 0 °C. After addition, the mixture was stirred at this temperature for 30 minutes, and then MeI (29.7 mmol, 1.85 mL, 2 eq) was added dropwise at 0 °C. Then the mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched by addition of sat. NH4CI (50 mL) at 0 °C, was diluted with H2O (10 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give tert-butyl (R)-(l-((l,5-dimethyl-lH-pyrazol-3-yl)oxy)propan-2-yl)(methyl)carbamate (4.00 g, 14.1 mmol, 95% yield) as a yellow oil.1H NMR (400 MHz, CDCI3) 5 = 5.33 (s, 1H), 4.57 - 4.29 (m, 1H), 4.04 - 3.89 (m, 2H), 3.53 (s, 3H), 2.71 (s, 3H), 2.11 (s, 3H), 1.38 (s, 9H), 1.12 (d, J = 7.2 Hz, 3H).

[0363] Step 4. To a solution of tert-butyl (R)-(l-((l,5-dimethyl-lH-pyrazol-3-yl)oxy)propan-2-yl)(methyl)carbamate (3.90 g, 13.7 mmol, 1 eq) in ACN (40 mL) was added NBS (2.45 g, 13.7 mmol, 1 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched by addition of sat. Na2SO3 (20 mL) at 25 °C, and then diluted with H2O (10 mL) and extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (3 x 40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. Then the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 100 / 1 to 85 / 15) to give tert-butyl (R)-(l-((4-bromo-l,5-dimethyl-lH-pyrazol-3-yl)oxy)propan-2-yl)(methyl)carbamate (4.20 g, 11.4 mmol, 83% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 4.70 - 4.40 (m, 1H), 4.26 - 4.04 (m, 2H), 3.64 (s, 3H), 2.81 (s, 3H), 2.19 (s, 3H), 1.45 (s, 9H), 1.21 (d, 7 = 7.2 Hz, 3H). LCMS: m / z 384.0 (M+l).

[0364] Step 5. A mixture of tert-butyl (R)-(l-((4-bromo-l,5-dimethyl-lH-pyrazol-3-yl)oxy)propan-2-yl)(methyl)carbamate (4.90 g, 13.5 mmol, 1 eq), 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (27.0 mmol, 3.93 mL, 2 eq), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (1.29 g, 2.71 mmol, 0.2 eq, Pd(CH3CN)2C12 (350 mg, 1.35 mmol, 0.1 eq) and TEA (40.5 mmol, 5.65 mL, 3 eq) in dioxane (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N2atmosphere. On completion, the mixture was quenched with sat. NH4CI (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give a residue. Then the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 100 / 1 to 80 / 20) to give tertbutyl (R)-( 1 -((1,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l H-pyrazoL3-yl)oxy)propan-2-yl)(methyl)carbamate (5.01 g, 9.92 mmol, 73% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 4.56 - 4.38 (m, 1H), 4.22 - 4.13 (m, 2H), 3.60 (s, 3H), 2.88 (s, 3H), 2.33 (s, 3H), 1.44 (s, 9H), 1.28 (d, J = 2.4 Hz, 12H), 1.25 (s, 3H).

[0365] Intermediate Method I-2D

[0366] Preparation of tert-butyl (R)-(l-((5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)(methyl)carbamate (1-2-6):

[0367] Step 1. To a solution of 4,5-dibromo-2-methyl-2H-l,2,3-triazole (2.00 g, 8.30 mmol, 1 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.86 g, 20.7 mmol, 2.5 eq) in THF (20 mL) was added n-BuLi (2.5 M in n-hexane, 5.98 mL, 1.8 eq) dropwise at -78 °C under N2. The resulting mixture was stirred at -78 °C for 1 h. On completion, the mixture was quenched with sat. NH4CI (30 mL) and extracted with DCM: MeOH (10:1) (20 mL x 8). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 4-bromo-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-l,2,3-triazole (2.65 g, crude) as a colorless oil. LCMS: m / z 288.0 (M+l)

[0368] Step 2. To a solution of 4-bromo-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-l,2,3-triazole (2.55 g, 8.86 mmol, 1 eq) in THF (25.5 mL) was added NaOH (1 M in H2O, 22.1 mL, 2.5 eq) and oxone (3.72 g, 22.1 mmol, 2.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched with sat. Na2SO3 (20 mL), then the pH was adjusted to 3 with aq. citric acid (10 mL), and extracted with 2-MeTHF (20 mL x 3). The combined organic layers were washed with brine (30 mLx 2), dried over Na2SO4, filtered and concentrated to give 5-bromo-2-methyl-2H-l,2,3-triazol-4-ol (1.90 g, crude) as a yellowoil.

[0369] Step 3. To a solution of 5-bromo-2-methyl-2H-l,2,3-triazol-4-ol (1.80 g, 10.1 mmol, 1 eq) in DMF (18 mL) was added K2CO3 (4.19 g, 30.3 mmol, 3 eq) and (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (2.56 g, 10.1 mmol, 1 eq). The mixture was stirred at 80 °C for 1 h. On completion, the mixture was quenched with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mLx 2), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: THF= 1:0 to 5:1) to give tert-butyl (R)-(l-((5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)carbamate (350 mg, 1.04 mmol, 10% yield) as a colorless oil. LCMS: m / z 357.0 (M+23).

[0370] Step 4. To a solution of tert-butyl (R)-(l-((5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)carbamate (300 mg, 0.895 mmol, 1 eq) in DMF (3 mL) was added NaH (71.6 mg, 1.79 mmol, 60% purity, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then CH3I (190 mg, 1.34 mmol, 1.5 eq) was added to the mixture. The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was quenched with sat. NH4CI (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl (R)-(l-((5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)(methyl)carbamate (400 mg, crude) as a yellow oil. LCMS: m / z 249.0 (M+l-100).

[0371] Intermediate Method I-2E

[0372] Preparation of tert-butyl (S)-ethyl(2-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-3-yl)oxy)propyl)carbamate (1-2-8):MS2O, TEA MsO NH > DCM „ / Boe CS2CO3, DMFPdCI2(MeCN)2, XPhos, Br TEA, dioxane

[0373] Step 1. To a mixture of tert-butyl (R)-(2-hydroxypropyl)carbamate (33.0 g, 188 mmol, 1 eq) in DCM (300 mL) was added Triethylamine (57.2 g, 565 mmol, 78.6 mL, 3 eq) and methylsulfonyl methanesulfonate (49.2 g, 282 mmol, 1.5 eq), and then the mixture was stirred at 20 °C for 1 hour. On completion, the reaction mixture was diluted with water (200 mL) and extracted with DCM 150 mL (50 mL x 3). The combined organic layers were concentrated under reduced pressure to give (R)-l-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate (60.0 g, crude) as a yellow oil.

[0374] Step 2. To a mixture of 1 -methyl- lH-pyrazol-3-ol (20.0 g, 204 mmol, 1 eq) and (R)-l-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate (51.6 g, 204 mmol, 1 eq) in DMF (200 mL) was added Cs2CO3 (133 g, 408 mmol, 2 eq), then the mixture was stirred at 80 °C for 1 hour. On completion, the reaction mixture was diluted with water (200 mL) and extracted with EA (50 mL x 2). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / THF= 1 / 0 to 1 / 1). The eluent was concentrated under reduced pressure to give tert-butyl (S)-(2-((l-methyl-lH-pyrazol-3-yl)oxy)propyl)carbamate (50.0 g, 196 mmol, 96% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 7.13 (d, J= 2.0 Hz, 1H), 5.61 (d, J= 2.0 Hz, 1H), 5.07 (s, 1H), 4.68 - 4.50 (m, 1H), 3.73 (s, 3H), 3.53 - 3.43 (m, 1H), 3.29 - 3.20 (m, 1H), 1.44 (s, 9H), 1.31 (d, 7= 6.4 Hz, 3H); LCMS: m / z 256.2 (M+l).

[0375] Step 3. To a solution of tert-butyl (S)-(2-((l-methyl-lH-pyrazol-3-yl)oxy)propyl)carbamate (5.00 g, 19.6 mmol, 1 eq) in DMF (50 mL) was added NaH (1.57 g,39.2 mmol, 60% purity, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. EtI (3.36 g, 21.5 mmol, 1.72 mL, 1.1 eq) was then added at 0 °C, and the mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was quenched by addition of a saturated solution of NH4CI (30 mL) at 0 °C, diluted with water (10 mL), extracted with ethyl acetate (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography f SiOj, Petroleum ether / THF= 1:0 to 1: 1) to give tert-butyl (S)-ethyl(2-((l-methyl-lH-pyrazol-3-yl)oxy)propyl)carbamate (2.90 g, 10.2 mmol, 52% yield) as a white solid. H NMR (400 MHz, CDCI3) <5 = 7.11 (d, J = 1.6 Hz, 1H), 5.59 (d, J= 15.2 Hz, 1H), 4.81 - 4.65 (m, 1H), 3.72 (s, 3H), 3.58 - 3.22 (m, 4H), 1.46 (s, 9H), 1.30 (d, J= 6.4 Hz, 3H), 1.09 (d, J= 5.2 Hz, 3H); LCMS: m z 284.1 (M+l).

[0376] Step 4. To a solution of tert-butyl (S)-ethyl(2-((l-methyl-lH-pyrazol-3-yl)oxy)propyl)carbamate (2.89 g, 10.2 mmol, 1 eq) in ACN (30 mL) was added NBS (1.99 g, 11.2 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched by addition of a saturated solution of NaiSOg (30 mL) at 0 °C, diluted with water (10 mL), extracted with ethyl acetate (15 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 1:1) to give tert-butyl (S)-(2-((4-bromo-l-methyl-lH-pyrazol-3-yl)oxy)propyl)(ethyl)carbamate (3.40 g, 9.39 mmol, 92% yield) as a yellow oil. H NMR (400 MHz, CDCI3) S = 7.17 (s, 1H), 4.88 (dquin, J = 4.4, 6.4 Hz, 1H), 3.71 (s, 3H), 3.46 - 3.24 (m, 4H), 1.46 (s, 9H), 1.33 (d, J = 6.4 Hz, 3H), 1.11 (s, 3H); LCMS: m / z 364.1 (M+l)

[0377] Step 5. A mixture of tert-butyl (S)-(2-((4-bromo-l-methyl-lH-pyrazol-3-yl)oxy)propyl)(ethyl)carbamate (3.10 g, 8.56 mmol, 1 eq), 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.29 g, 25.7 mmol, 3.72 mL, 3 eq), XPhos (408 mg, 0.856 mmol, 0.1 eq), PdC12(MeCN)2 (222 mg, 0.856 mmol, 0.1 eq) and TEA (1.30 g, 12.8 mmol, 1.79 mL, 1.5 eq) in dioxane (32 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 1 hour under N2 atmosphere. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0: 1) to give tert-butyl (S)-ethyl(2-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-3-yl)oxy)propyl)carbamate (3.50 g, 8.55 mmol, 99% yield) as a yellow oil. LCMS:m / z 410.4 (M+l).

[0378] Intermediate Method I-2F

[0379] Preparation of l-ethyl-l,2-dihydro-3H-pyrazol-3-one (1-2-11):TEA, THF1-2-11

[0380] To a solution of methyl 2 -chloroacrylate (5.00 g, 41.5 mmol, 1 eq) and ethylhydrazine dihydrochloride (8.28 g, 62.2 mmol, 1.5 eq) in THF (15 mL) was added TEA (12.6 g, 124 mmol, 3 eq). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was quenched with water (20 mL) and extracted with 2-MeTHF (15 mL x 6), and the combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: THF=l:0 to 87:13) to give l-ethyl-l,2-dihydro-3H-pyrazol-3-one (2.70 g, 24.1 mmol, 58% yield) as a yellow solid. LCMS: m / z. 113.1 (M+l).

[0381] Intermediate Method L2G

[0382] Preparation of tert-butyl (2-((l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (1-2-12):H / \ / ~ N | i — X Cl N—Z1-2-11 I N NBS, ACN Boc i / Boc - *~ CS9CO3, DMF ' ' I-4-5Pd(MeCN)2CI2, XPhos, TEA HBPin, dioxane Br

[0383] Step 1. To a solution of tert -butyl (2-chloroethyl)(methyl)carbamate (6.74 g, 34.8 mmol, 1.5 eq) in DMF (26 mL) was added CS2CO3 (22.7 g, 69.6 mmol, 3 eq) and 1 -ethyl- 1,2-dihydro-3H-pyrazol-3-one (2.60 g, 23.2 mmol, 1 eq). The mixture was stirred at 80 °C for 1 h. On completion, the mixture was quenched with water (40 mL) and extracted with EA (25 mL x 3), and the combined organic layers were washed with brine (35 mLx 2), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO, PE: THF= 1:0 to 8:1) to give tert-butyl (2-((l -ethyl- lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (2.90 g, 10.7 mmol, 46% yield) as a colorless oil. LCMS: m z 270.1 (M+l).

[0384] Step 2. To a solution of tert-butyl (2-((l -ethyl- lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (2.80 g, 10.4 mmol, 1 eq) in ACN (28 mL) was added NBS (1.94 g, 10.9 mmol, 1.05 eq). The mixture was stirred at 0 °C for 1 h. On completion, the mixture was quenched with sat. Na\SO - (20 mL) and extracted with EA (15 mL x 3), and the combined organic layers were washed with brine (15 mL x 2), dried over Na^SO-i, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: THF= 1:0 to 8:1) to give tert-butyl (2-((4-bromo-l -ethyl- lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (3.30 g, 9.48 mmol, 91% yield) as a colorless oil. LCMS: m / z 348.0 (M+l)

[0385] Step 3. A mixture of tert-butyl (2-((4-bromo-l-ethyl-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (1.50 g, 4.31 mmol, 1 eq), TEA (653 mg, 6.46 mmol, 1.5 eq), XPhos (205 mg, 0.430 mmol, 0.1 eq) and Pd(MeCN)2C12 (111 mg, 0.430 mmol, 0.1 eq) in dioxane (15 mL) was degassed and purged with N2 for 3 times. Then 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.65 g, 12.9 mmol, 3 eq) was added, and the mixture was stirred at 110 °C for 1 h under N2 atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: THF= 1:0 to 5:1) to give tert-butyl (2-((l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (2.50 g, crude) as a colorless oil. LCMS: m / z 396.5 (M+l)

[0386] Intermediate Method I-2H

[0387] Preparation of l-(3-hydroxy-lH-pyrazol-l-yl)ethan-l-one (1-2-19):H AC2O, pyridine1-2-19

[0388] A mixture of lH-pyrazol-5-ol (10.0 g, 118 mmol, 1.00 eq) in Py (100 mL) was stirred at 95 °C for 0.5 h. Then acetyl acetate (12.1 g, 118 mmol, 11.1 mL, 1.00 eq) was dissolved in Py (30.0 mL) and was added in the reaction mixture, and the mixture was stirred at 95 °C for 2.5 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with PE (100 mL) at 30 °C for 10 min to give l-(3-hydroxy-lH-pyrazol-l-yl)ethan-l-one (14.8 g, 114 mmol, 96% yield, 97% purity) as a light yellow solid. LCMS: m / z 149.1 (M+23).

[0389] Intermediate Method I-2I

[0390] Preparation of (R)-N-(l-((5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)-2,2,2-trifhioro-N-methylacetamide (1-2-26):TFAA TFA TEA DCM DCM

[0391] Step 1. To a solution of teit-butyl (R)-(l-((5-bromo-2-methyl-2H-l,2,3-triazol-4- yl)oxy)propan-2-yl)(methyl)carbamate (7.20 g, 20.6 mmol, 1 eq) in DCM (75 mL) was added TFA (194 mmol, 14.4 mL, 9.40 eq), and the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give (R)-l-((5- bromo-2-methyl-2H-l,2,3-triazol-4-yl)oxy)-N-meth Iylpropan-2-amine (5.2 g, crude) as a Oyellow oil. LCMS: nt / z 250.9 (M+l).

[0392] Step 2. To a solution of (R)-l-5(( >5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)oxy)-N- methylpropan-2-amine (5.20 g, 20.9 mmol, 1 eq) in DCM (50 mL) was added TEA (6.34 g, 62.6 mmol, 8.72 mL, 3 eq) and TFAA (6.58 g, 31.3 mmol, 4.35 mL, 1.5 eq), and stirred at 0 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give (R)-N-(l-((5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)-2,2,2-trifluoro-N- methylacetamide (7.20 g, crude) as a yellow oil. LCMS: m / z 347.0 (M+l).

[0393] Intermediate Table 2# SM1(m / z)Meth. Structure 'H NMR [M+l]Commercially 1-2-1availableN^8>— OBoc1-2-2 and L2A 382.2B-o / iHO BoouOr v- o N—Boc1-2-3 L2B 396.1and^NBocNH2O N^ / OH (400 MHz, MeOD- cLi) 5 = 5.76 (s, 1H), I-2-3a I-2B —N73.78 (s, 3H), 2.37and (s, 3H)# SM1Meth. Structure (mlz) H NMR [M+l]XNBocNH2(400 MHz, CDCh) 5 = 4.56 - 4.38 (m, 1H), 4.22 - 4.13 (m, N < V-0 „ / 2H), 3.60 (s, 3H), -2-4 He / ^IHBoc \! BocI-2C 410.1 2.88 (s, 3H), 2.33 and ' B-0 (s, 3H), 1.44 (s, I-2-3a 9H), 1.28 (d, J =2.4 Hz, 12H), 1.25 (s, 3H).XN'\ / (He / ^IHBoc i y- o N— 418.1-2-5 Bocand I-2C2(M +23)7 °H\-NN '^ WZ-Br \-N <\'B°C249.01-2-6 Br I-2D 1 (M + 1-100)and Br1-4-2 / Commercially -2-7 N-NavailableH( / NHXN"\ VA / BocI-2E Boc1-2-8 and 410.4B-ON-^OHXN 1 ''|SL V- 0 / \He / NHBoc N—-2-9 a I-2C2Bocnd 395.7N^OH—N7 / (400 MHz, DMSO- N-N d6) 5 = 4.91 - 4.65 N^-Br N- / Y^N'BOCi (m, 1H), 3.82 (s,371.1-2-10 I-2D N^ / Z^-O 1 3H), 3.51 - 3.39 (m,Br (M+23)2H), 2.87 (s, 3H), and Br 1.38 (s, 9H), 1.24 1-4-4(d, J = 6.4 Hz, 3H)# SM1Meth. Structure (mlz)rH NMR [M+l]0H-2-11 Cl I-2F N^° 113.1H Z~NCZJ^N'NH21 v— 0 N—-2-12 1-4-5 BocI-2G 396.51-2-11X0 OH-2-13 Cl I-2F \ N^OH TY'NH2•"k'\? Vo N—1-4-5-2-14 I-2G Boc 410.11-2-130 (400 MHz, DMSO- d6) 6 = 7.43 - 7.35 (m, 1H), 5.43 - 5.36 -2-15 Cl I-2F (m, 1H), 3.72 - 3.62^0H(m, 1H), 0.94 - 0.86 ^\lH- NH2(m, 2H), 0.84 - 0.79(m, 2H)1 Vo N- 1-4-5-2-16 I-2G Boc 430.21-2-15 B-0(400 MHz, DMSO- 0 de) 3 = 9.73 - 9.48(m, 1H), 7.44 - 7.36 (m, 1H), 5.40 (d, J -2-17 Cl I-2F = 2.4 Hz, 1H), 4.58- 4.48 (m, 1H), 2.41 - 2.32 (m, 2H), 2.30 NH-NH2- 2.23 (m, 2H), 1.74- 1.67 (m, 2H)#1Meth. S (mlz) SM tructurerH NMR [M+l](400 MHz, CDCh) <5 = 7.55 (s, 1H), 4.54 (quin, 7= 8.3 1 V- 0 N— Hz, 1H), 4.38 - 4.29 1-4-6 (m, 2H), 3.59 (d, J -2-18 I-2G Boc1-2-17 B'O = 5.2 Hz, 2H), 3.04(s, 3H), 2.46 - 2.36 (m, 4H), 1.88 - 1.78 (m, 2H), 1.44 (s, 9H), 1.29 (s, 12H) HN^OH 8U / 0H 149.1-2-19 I-2H Ac- N" 7 (M+23)V HN-V0^N_1-4-6 Boc-2-20 I-2G 368.01-2-19XN"NA / \1-4-7 l ^—o OTBSH-2-21 N^° I-2G,B'O 383.5~N. J\-N1-4-8t / / W'^OTBSO-2-22 \-N I-2G3411.21-4-7 L / o °TBSN^ / OH MeOOC^ X^-2-23 I-2G3> O 441.3MeOOC\1-4-9 N— NN^OH MeOOC^y^o^- / ~'OTBS-2-24 — N T I-2G3455.3MeOOCXM"N> X SHO / NH 1 0 N—-2 Boc I-2C Boc-25 396.1N^ / OH—N7fv# SM1Meth. Structure (mlz) H NMR [M+l]VN AN- 1-2-26 1-2-6 1-21TFA1 347.0BrXN'NN< J^-Br\-N V^N'B0C249.01-2-27 Br I-2D (M- and Br 100+1)1-4-4XSM: Starting Material(s)2Step 1 used Triethylamine as base3Step 1 used K2CO3 as the base

[0394] Intermediate Method I-3A

[0395] Preparation of 4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l- methyl- lH-pyrazol-5-ol (1-3-1):|— NOH1-2-1 tBuBrettPhos Pd G3K2CO3, NMP 1-1-1

[0396] To a solution of 5-bromo-6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (2.00 g, 6.15 mmol, 1 eq) in NMP (40 mL) was added l-methyl-lH-pyrazol-5-ol (724 mg, 7.38 mmol, 1.2 eq), K2CO3 (2.55 g, 18.5 mmol, 3 eq) and tBuBrettPhos Pd G3 (526 mg, 0.615 mmol, 0.1 eq) under N2, then the mixture was stirred at 130 °C for 0.5 h. On completion, the reaction mixture was diluted with Brine (80 mL) and extracted with 2-Me-THF (20 mL x 6). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-100% THF / Petroleum ether) to give 4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH- indazol-5-yl)-l -methyl- lH-pyrazol-5-ol (600 mg, 1.75 mmol, 28% yield) as a yellow solid. Analytical data shown in the table below.

[0397] Intermediate Method I-3B

[0398] Preparation of 4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l-methyl- lH-pyrazol-5-ol (1-3-2)l-NOH1-2-1 tBuBrettPhos Pd G3K2CO3, 2-Me THFTHP1-1-2

[0399] To a solution of 5-bromo-7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazole (7.00 g, 21.5 mmol, 1 eq) and 1 -methyl- lH-pyrazol-5-ol (2.53 g, 25.8 mmol, 1.2 eq in 2-Me-THF (70 mL) was added K2CO3 (5.95 g, 43.1 mmol, 2 eq). The mixture was stirred at 25 °C for 10 min. The mixture was vacuum degassed and backfilled with N2 three times, then t-BuBrettphos Pd G3 (1.84 g, 2.15 mmol, 0.1 eq) was added and the mixture was vacuum degassed and backfilled with N2 three times. The mixture was then stirred at 80 °C for 2 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-50% MeOH / DCM) to give 4-(7-fluoro-l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)-2-methyl-pyrazol-3-ol (4.30 g, 9.42 mmol, 44% yield, 75% purity) as a brown solid. Analytical data shown in the table below. LCMS: m / z 424.9 (M+l).

[0400] Intermediate Method I-3C

[0401] Preparation of tert-butyl methyl(2-((l-methyl-4-(l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethyl)carbamate (1-3-3):Xphos Pd G2, CS2CO3Dioxane / H2O

[0402] A mixture of tert-butyl methyl(2-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-3-yl)oxy)ethyl)carbamate (0.850 g, 2.23 mmol, 1.2 eq), 5-bromo-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridine (572 mg, 1.86 mmol, 1 eq), Xphos-Pd-G2 (292 mg, 0.372 mmol, 0.2 eq), and CS2CO3 (1.82 g, 5.57 mmol, 3 eq) in dioxane (10 mL) and H2O (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 hour under N2atmosphere. On completion, themixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / THF= 1:0 to 0:1) to give compound tert-butyl methyl(2-((l-methyl-4-(l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridm-5-yl)-1H-pyrazol-3-yl)oxy)ethyl)carbamate (480 mg, 0.995 mmol, 54% yield) as a yellow oil. LCMS: m / z 483.2 (M+l).

[0403] Intermediate Method I-3D

[0404] Preparation of 5tert-butyl (2-((l,5-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (1-3-4):Pd(dppf)CI2, CS2CO3dioxane / H2O

[0405] A mixture of tert-butyl (2-((l,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (1.20 g, 3.04 mmol, 1 eq), 5-bromo-7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridine (1.08 g, 3.34 mmol, 1.1 eq), Pd(dppf)Cb (222 mg, 0.303 mmol, 0.1 eq) and CS2CO3 (2.97 g, 9.11 mmol, 3 eq) in dioxane (15 mL) and H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N2atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (20 mL x 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, Petroleum ether / THF= 1:0 to 0:1) to give tert-butyl N-[2-[l,5-dimethyl-4-(7 -methyl- 1 -tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxyethyl]-N-methyl-carbamate (960 mg, 1.88 mmol, 61% yield) as ayellow oil. LCMS: m / z 511.8 (M+l).

[0406] Intermediate Method I-3E

[0407] Preparation of tert-butyl ((2R)-l-((5-(7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)(methyl)carbamate(1-3-8):Br 1-2-6 Pd(dtbpf)CI2, K2CO3Dioxane / H2O

[0408] To a mixture of tert-butyl (R)-(l-((5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)(methyl)carbamate (370 mg, 1.06 mmol, 1.1 eq) and 7-methoxy-l- (tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-vinyl-lH-indazole (370 mg, 0.963 mmol, 1 eq) in dioxane (4 mL) and H2O (0.8 mL) was added K₂CO₃ (399 mg, 2.89 mmol, 3 eq and Pd(dtbpf)Cl₂ (62.8 mg, 0.0963 mmol, 0.1 eq). The mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 h under N2 atmosphere. On completion, the mixture was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: THF= 1:0 to 4:1) to give tert-butyl ((2R)-l-((5-(7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)(methyl)carbamate (450 mg, 0.854 mmol, 89% yield) as a yellow oil. LCMS: m / z 549.4 (M+23).

[0409] Intermediate Method I-3F

[0410] Preparation of (2R)-l-((5-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-2-methyl-2H-l,2,3-triazol-4-yl)oxy)-N-methylpropan-2-amine (1-3-9):Dioxane / H2O

[0411] Step 1. A mixture of 7-chloro-l-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl- 1.3.2-dioxaborolan-2-yl)-3-vinyl-lH-indazole (1.50 g, 3.86 mmol, 1 eq), (R)-N-(l-((5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)-2,2,2-trifluoro-N-methylacetamide (1.47 g, 4.24 mmol, 1.1 eq), Pd(dtbpf)C12 (252 mg, 0.386 mmol, 0.1 eq), CS2CO3 (3.77 g, 11.6 mmol, 3 eq) in Dioxane (15 mL) and H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 h under N2 atmosphere. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF= 1:0 to 3:1) to give N-((2R)-l-((5-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)- 2.2.2-trifluoro-N-methylacetamide (1.00 g, 1.90 mmol, 49% yield) as a brown solid. LCMS: m / z 527.2 (M+l)

[0412] Step 2. To a solution ofN-((2R)-l-((5-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-2-methyl-2H-l,2,3-triazol-4-yl)oxy)propan-2-yl)-2,2,2-trifluoro-N-methylacetamide ( 1.00 g, 1.90 mmol, 1 eq) in THF (10 mL) and H2O (2 mL) was added lithium hydroxide hydrate (239 mg, 5.69 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was quenched with water (10 mL) and extracted with EA(10 mLx3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (2R)-l-((5-(7-chloro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-2-methyl-2H-l,2,3-triazol-4-yl)oxy)-N-methylpropan-2-amine (790 mg, 1.83 mmol,97% yield) as a yellow solid. LCMS: mJz 431.1 (M+l).

[0413] Intermediate Table 3(m / z)# SM1Meth. Structure H NMR [M+l](400 MHz, DMSO-&) 5 = 7.03 - 6.92 (m, 1H), 6.87 (s, 1H), 6.64 (s, 1H), 6.08 (d, J= 18.0 Hz, 1H), 5.82 - 5.75 (m, 1-1-11-3-1 I-3A 343.0 1H), 5.55 (d, J = 12.0 1-2-1 Hz, 1H), 3.92 - 3.71 (m,2H), 3.54 (s, 3H), 2.42 - 2.30 (m, 1H), 2.09 - 1.85 (m, 3H), 1.81 - i \ 1.66 (m, 1H), 1.57 (brd, OJ = 3.6 Hz, 2H) (400 MHz, CDCh) 5 = 7.79 (s, 1H), 7.29 - 7.19 (m, 2H), 7.02 - 6.84 (m, N~l / 1H), 6.03 (d, 7= 18.0Hz, 1H), 5.91 - 5.76 (m, 1H), 5.49 (d, 7= 11.6 1-1-21-3-2 I-3B 342.9 Hz, 1H), 4.09 (d, 7= 9.6 1-2-1 Hz, 1H), 3.86 - 3.70 (m,1H), 3.57 - 3.44 (m,zN-N 3H), 2.70 - 2.50 (m, THP' 1H), 2.20 - 2.03 (m,2H), 1.84 - 1.70 (m, 2H), 1.62 (br d, 7 = 7.2 Hz, 1H)^2%— 0 B°c1-1-31-3-3 I-3C 483.21-2-2\\1)\-NTHPBoc1-1-41-3-4 I-3D 511.81-2-3 DjN-NTHP'(w / z)# SM1Meth. Structure H NMR [M+l](400 MHz, CDC13) 5 = 7.97 (d, J= 16.4 Hz, 1H), 7.04 (d, J= 10.8 Hz, 1H), 6.14 (s, 1H), 5.89 (d, J = 7.6 Hz, 1H), 5.56 (d, J= 11.2 Hz, ^N-N f^N^ 1H), 4.74 - 4.39 (m, Boc 1H), 4.24 (d, J = 5.6 Hz, 1-1-4 1H), 4.04 (d, J= 10.8 -3-5 I-3D 525.3 Hz, 1H), 3.76 (t, J = 1-2-410.4 Hz, 1H), 3.69 (s, \ / / 3H), 2.97 (s, 3H), 2.80 N-N (d, J= 19.2 Hz, 3H), THP'2.74 - 2.66 (m, 1H), 2.59 (s, 3H), 2.24 - 2.13 (m, 2H), 1.83 - 1.61 (m, 4H), 1.37 (d, 7= 4.0 Hz, 9H), 1.24 (d, J= 6.8 Hz, 3H)Boc1-1-4-3-6 I-3D 497.51-2-2ixj / / N-NTHP(400 MHz. DMSO-de) 5 = 8.06 - 8.03 (m, 1H), 8.01 - 7.92 (m, 1H), 7.17 - 6.95 (m, 1H), 6.18 - 6.02 (m, 1H), 5.97 (dd, J= 1.6, 9.2 Hz, 1H), 5.57 (d. J = Boc 11.6 Hz, 1H), 4.74 - 1-1-4 4.44 (m, 1H), 4.43 - -3-7 I-3D 511.4 4.10 (m, 2H), 3.98 - 1-2-53.87 (m, 1H), 3.75 (s, \ / / 3H), 2.90 (s, 3H), 2.81 - N-N 2.73 (m, 3H), 2.09 (d, J THP= 9.6 Hz, 2H), 1.86 - 1.71 (m, 1H), 1.58 (d, J = 3.2 Hz, 2H), 1.32 (d,. / = 1.2 Hz, 2H),1.25 (d, J = 8.0 Hz, 9H), 1.17 (d, J= 6.8 Hz, 3H)(?n / z) # SM1Meth. Structure ^NMR [M+l]\-NNx Xo 1 549.41-1-5-3-8 I-3E (M +1-2-623)~^C> \ IIN-NTHPXN-N / NHNJ'O 11-1-6-3-9 I-3F 431.11-2-26Oxj / ci^ A IIN-NTHP? / N'N°H1-1-4-3-10 I-3B2354.11-2-7iyjz "\ / / N-NTHP'VNA / — 0 Boc1-1-4-3-11 I-3D N7^ 525.41-2-8 v\ A / x / A IIN-NTHP'Az ~O Boc1-1-4-3-12 I-3D 511.61-2-9\ IIN-NTHP(m / z)# SM1Meth. Structure ^ NMR [M+l](400 MHz, DMSO-t / e) 5 = 8.19 (d, J = 16.4 Hz, 1H), 7.22 - 6.95 (m, 1H), 6.19 - 6.05 (m, 1H), 6.04 - 5.99 (m,XN'Ny_ J, Boc 1H),5.61 (t, J = 9.2 Hz,1H), 5.03 - 4.93 (m, 1-1-4-3-13 I-3D 1H), 4.07 (s, 3H), 3.92 1-2-27 (d, J= 12.0 Hz, 1H),3.83 - 3.62 (m, 2H), / yif 3.57 - 3.45 (m, 1H),2.95 THP (s, 3H), 2.88 (s, 3H),2.15 - 2.04 (m, 2H), 1.88 - 1.70 (m, 1H), 1.65 - 1.55 (m, 2H), 1.32 (s, 12H)(400 MHz, CDCh) 5 = 8.40 (s, 1H), 7.08 - 6.93 (m, 1H), 6.21 (d, J = 18.0 Hz, 1H), 5.95 - / 5.83 (m, 1H), 5.59 (d, J N'N\ 1 BOC = 11.6 Hz, 1H), 5.28 - 11 / / u 5.03 (m, 1H), 4.08 - 1-1-7 N-y-3-14 I-3D3512.2 4.02 (m, 1H), 3.90 (s, 1-2-10 hj 3H), 3.73 (s, 1H), 3.51 - 3.49 (m, 3H), 3.01 (s, 3H), 2.95 (d, J= 10.0 THP Hz, 1H), 2.88 (s, 1H),2.25 - 2.16 (m, 2H), 1.81 - 1.71 (m, 4H), 1.46 - 1.39 (m, 9H), 1.26 - 1.24 (m. 3H)XN-NBoc1-1-4-3-15 I-3E4511.71-2-9A jN-NTHP(?n / z) # SM1Meth. Structure H NMR [M+l]Boc1-1-4-3-16 I-3F 511.61-2-12 CjIfN-NTHP'^N-N^ / ~O Boc1-1-4-3-17 I-3F 525.41-2-14N-NTHP'^N-NBoc1-1-4-3-18 I-3F 523.31-2-16 NZ^1N-NTHP'N- NNBoc1-1-4-3-19 I-3F 537.31-2-18O sJz / " \ IIN-NTHP'HN-N^ / ~O Boc1-1-4-3-20 I-3F 483.31-2-20'" 'T IIN-NTHP(?n / z) # SM1Meth. Structure H NMR [M+l] / ^" OTBS1-1-4-3-21 I-3D 498.71-2-21 / / N-NTHP'\I-NOTBS1-1-10-3-22 I-3E4N^1 680.51-2-22 JI A. ^^--TIPSIl' "N-NTHP'J" J— 0 OTBS1-1-11 MeOOCzZ' \ / ==i / TIPS-3-23 I-3E4725.81-2-23THP\-NMeOOC^Y ~°0TBS1-1-11-3-24 I-3D3739.61-2-24N-NTHP'VNk J*— 0 Boc1-1-4-3-25 I-3D N^\ 511.41-2-25 II\ IIN-NTHP'XN-NBoc1-1-4-3-26 I-3E4497.81-2-21 / N-NTHP(m / z)SM1Meth. Structure H NMR [M+l](400 MHz, DMSO-t / e) 5 = 7.87 - 7.49 (m, 1H), 7.02 (dd, J= 11.6, 17.6 Hz, 1H), 6.10 (d, J = N-N 18.0 Hz, 1H), 5.89 - 5.72 (m, 1H), 5.63 - 1-1-2 5.44 (m, 1H), 3.91 (d, J 1-3-27 I-3B 357.2 = 11.6 Hz, 1H), 3.661-2-7(ddd, 7= 6.4, 7.6, 11.2 Hz, 1H), 3.54 (d, 7 = 4.8 N-NTHP' Hz, 1H), 3.34 - 3.23 (m,3H), 2.45 - 2.14 (m, 4H), 2.05 (d, J = 10.8 Hz, 2H), 1.83 - 1.68 (m,1H), 1.56 (s, 2H)!SM: Starting Material(s)2Dioxane was used as the solvent3K2COS was used as the base4CS2CC>3 was used as the base

[0414] Intermediate Method I-4A

[0415] Preparation of tert-butyl ((2R)-3-hydroxybutan-2-yl)carbamate (1-4-1):O Y MeMgBr, THFHO NHBocNHBoc1-4-1

[0416] To a solution of tert-butyl (R)-(l-oxopropan-2-yl)carbamate (3.90 g, 22.5 mmol, 1 eq) in THF (120 mL) was added MeMgBr (3 M in THF, 22.5 mL, 3 eq) and stirred at -78 °C for 2 h under N2. On completion, the reaction mixture was quenched by addition of a saturated aqueous NH4CI solution (50 mL) at -78 °C and then extracted with EA (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-80% Ethyl acetate / Petroleum ether) to afford teit-butyl ((2R)-3-hydroxybutan-2-yl)carbamate (4.40g, crude) as a yellow oil. Analytical data shown in the table below.

[0417] Intermediate Method I-4B

[0418] Preparation of (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (1-4-2):Ms2O, DIEAHO NHBoc DCM MsO NHBoc1-4-2

[0419] To a solution of tert-butyl (R)-(l-hydroxypropan-2-yl)carbamate (5.00 g, 28.5 mmol, 1 eq) in DCM (50 mL) was added DIEA (85.6 mmol, 14.9 mL, 3 eq) and methyl sulfonyl methanesulfonate (7.46 g, 42.8 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was diluted with H2O (20 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with sat. citric acid (2 x 200 mL), dried over anhydrous NaaSOzi, filtered and concentrated under reduced pressure to give (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (7.2 g, 28.4 mmol, 99% yield) as a yellow solid.

[0420] Intermediate Method I-4C

[0421] Preparation of (R)-l-(2,2,2-trifluoro-N-methylacetamido)propan-2-yl methanesulfonate (1-4-3):methanamine TFAA, TEAO-^ MeOH HOHDCMMS2O, TEA, DCM ) - HO A. MsO N—0 CF3 TFA'l-4-3a |.4.3

[0422] Step 1. To a solution of (R)-2-methyloxirane (20.0 g, 344 mmol, 1 eq) in MeOH (150 mL) was added methanamine (2 M, 516 mL, 3 eq). The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was concentrated in vacuo to give the compound (R)-l-(methylamino)propan-2-ol (25.0 g, 280 mmol, 81% yield) as a white solid. H NMR (400 MHz, CDCL) 5 = 3.67 - 3.48 (m, 3H), 3.30 (dt, J = 3.2, 5.6 Hz, 1H), 2.86 - 2.78 (m, 1H), 1.91 - 1.83 (m, 2H), 0.69 (tdd, 7= 2.4, 4.8, 7.2 Hz, 3H).

[0423] Step 2. To a solution of (R)-l -(methylamino )propan-2-ol (20.0 g, 224 mmol, 1 eq) in DCM (200 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (70.6 g, 336 mmol, 1.5 eq), TEA (113 g, 1.12 mol, 5 e ). The mixture was stirred at 0 °C for 18 hours. On completion, the reaction mixture was quenched by addition of H2O (500 mL) and extracted with DCM (200mL x 3). The combined organic layers were washed with a saturated solution of NaCl 500mL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / THF= 1:1) to give (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N-methylacetamide (9.80 g, 52.9 mmol, 23% yield) as a white solid. 'H NMR (400 MHz, CDCh) 5 = 4.05 - 3.96 (m, 1H), 3.38 (d, J = 3.6 Hz, 1H), 3.34 - 3.24 (m, 2H), 3.16 (d, J =1.6 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H).

[0424] Step 3. To a solution of (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N-methylacetamide (1.00 g, 5.40 mmol, 1 eq) in DCM (10 mL) was added methylsulfonyl methanesulfonate (1.13 g, 6.48 mmol, 1.2 eq and TEA (1.40 g, 10.8 mmol, 2 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was partitioned between DCM (10 mL x 3) and water (15 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (R)-l-(2,2,2-trifluoro-N-methylacetamido)propan-2-yl methanesulfonate (1.42 g, 5.39 mmol, 100% yield) as a yellow oil.

[0425] Intermediate Method I-4D

[0426] Preparation of tert-butyl (2-chloroethyl)(methyl)carbamate (1-4-5):(BOC)2O, TEA, Cl HN—THF / H2O

[0427] To a solution of BOC2O (7.97 g, 36.5 mmol, 0.95 eq) in THF (20 mL) was simultaneously added a solution of 2-chloro-N-methylethan-l -amine (5.00 g, 38.5 mmol, 1 eq, HC1) in H2O (20 mL) and TEA (3.89 g, 38.46 mmol, 5.35 mL, 1 eq) in THF (20 mL). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was quenched with sat. NaCl (40 mL) and extracted with DCM (30 mL x 3), and the combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO, PE: THF= 1:0 to 20:1) to give tert-butyl (2-chloroethyl)(methyl)carbamate (7.40 g, 38.2 mmol, 99% yield) as a colorless liquid. Analytical data shown in the table below.

[0428] Intermediate Method I-4E

[0429] Preparation of (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-yl methanesulfonate (1-4-8):TBSCI, imidazole OH OTBS HO DCM HOMS2O, TEAOTBS DCMMs01-4-8

[0430] Step 1. To a solution of (R)-butane-l,3-diol (25.0 g, 277 mmol, 1 eq) in DCM (250 mL) was added imidazole (37.8 g, 554 mmol, 2 eq) and TBSCI (46.0 g, 305 mmol, 1.1 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched with H2O (500 mL) and extracted with DCM (220 mL x 2), and the combined organic layers were washed with brine (150 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol (43.0 g, 210 mmol, 75% yield) as a brown oil.NMR (400 MHz, CDCL) 5 = 4.07 - 3.99 (m, 1H), 3.82 - 3.58 (m, 2H). 1.74 - 1.49 (m, 2H), 1.12 - 1.08 (m, 3H), 0.82 - 0.80 (m, 9H), 0.01 - -0.01 (m, 6H).

[0431] Step 2. To a solution of (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol (8.00 g, 39.1 mmol, 1 eq) in DCM (100 mL) was added TEA (11.8 g, 117 mmol, 3 eq) and methylsulfonyl methanesulfonate (10.2 g, 58.7 mmol, 1.5 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched by H2O (100 mL), and extracted with DCM (60 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give (R)-4-((tert-butyldimethylsilyl)oxy)butan-2-yl methanesulfonate (11.0 g, 38.9 mmol, 99% yield) as a brown oil.

[0432] Intermediate Method I-4F

[0433] Preparation of (R)-l-((tert-butyldimethylsilyl)oxy)propan-2-ol (1-4-10):ZOHTBSCI, imidazole / 0TBSHO DCMH01-4-10

[0434] To a solution of (R)-propane-l,2-diol (50.0 g, 657 mmol, 48.1 mL, 1 eq) in DCM (500 mL) was added TBSCI (99.0 g, 657 mmol, 80.9 mL, 1 eq) and imidazole (44.7 g, 657 mmol, 1 eq). The mixture was stirred at 25 °C for 16 hours. On completion, the reaction was filtered and concentrated under vacuum to give (R)-l-((tert-butyldimethylsilyl)oxy)propan-2-ol (125g, crude) as a yellow oil. Analytical data shown in the table below.

[0435] Intermediate Table 4(m / z)# SM1Meth. Structure ‘HNMR [M+l](400 MHz, CDCh) 5 = 3.75 - 3.65 (m, 1H), 1-4-1 I-4A 3.56 (br d, J = 5.6 Hz,NHBocNHBoc 1H), 1.45 (s, 9H), 1.21- 1.08 (m, 6H) 1-4-2 I-4BHe / ^IHBoc Msc / CiHBoc1-4-3 o-^ I-4C MsO / N—and TFAmethanamine(400 MHz, CDCh) 5 = 4.05 - 3.96 (m, 1H), 3.38 (d, 7 = 3.6 Hz, I-4-3a I-4C31H), 3.34 - 3.24 (m, andH00CF32H), 3.16 (d, 7=1.6 Hz, methanamine 3H), 1.12 (d, 7= 6.4 Hz, 3H)1-4-4 ""r^N'BocI-4B '"■^N'BOCHO H MsO HH NMR (400 MHz, CDCh) 5 = 3.67 - 3.49 1-4-5 I-4D ci / \l—BocZ(m, 4H), 2.95 (s, 3H),1.47 (s, 9H)1-4-6 HO^BocN— I-4B2MSC / BOCN —Commercially 1-4-7 B / DTBS available 1-4-8 I-4E. M.s ZO ^^OTBSCommercia 1-4-9 B r B S lly available (400 MHz, DMSO-A) 5 = 4.30 - 4.00 (m, 1H), 3.62 - 3.55 (m, 1H), <, OTBS1-4- yjDH3.47 (dd, 7= 5.2, 9.6 I-4F Hz, 1H), 3.30 - 3.24 10 HC) HOZ(m, 1H), 1.04 - 0.99 (m, 3H), 0.89 - 0.84 (m, 9H), 0.08 - -0.02 (m, 6H)1-4- Commercially11 B / \|HBOC available!SM: Starting Material(s)2TEA was used as the base3Step 3 was not used

[0436] Intermediate Method I-5A

[0437] Preparation of tert-butyl ((2R)-3-((4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl- 1 H-indazol-5-yl)- 1 -methyl- 1 H-pyrazol-5 -yl)oxy)butan-2-yl)carbamate (1-5- 1 ):

[0438] To a solution of 4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l-methyl-lH-pyrazol-5-ol (5.20 g, 15.2 mmol, 1 eq) in dioxane (80 mL) was added tert-butyl ((2R)-3-hydroxybutan-2-yl)carbamate (3.45 g, 18.2 mmol, 1.2 eq), PPh (5.98 g, 22.8 mmol, 1.5 eq) and DBAD (6.99 g, 30.4 mmol, 2 eq) and stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-60% Ethyl acetate / Petroleum ether) to give tertbutyl ((2R)-3-((4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l-methyl-lH-pyrazol-5-yl)oxy)butan-2-yl)carbamate (5.50 g, 10.7 mmol, 71% yield) as a yellow solid.

[0439] Intermediate Method 1-5B

[0440] Preparation of (2S)-2-((l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-5-yl)oxy)-N-methylpropan-l -amine (1-5-3):MsO N— TFA'K2CO3, DMF1-4-3

[0441] Step 1. A mixture of l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-5-ol (1.50 g, 4.24 mmol, 1 eq), (R)-l-(2,2,2-trifluoro-N-methylacetamido)propan-2-yl methanesulfonate (1.34 g, 5.09 mmol, 1.2 eq), K2CO3 (2.70 g, 19.5 mmol, 4.61 eq) in DMF (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 1 hour under N2 atmosphere. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOs, PE: EA = 1:1) to give N-((2S)-2-((l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-5-yl)oxy)propyl)-2,2,2-trifluoro-N-methylacetamide (2.00 g, 3.84 mmol, 90% yield) as a white solid. LCMS: m / z 521.3 (M+l).

[0442] Step 2. To a solution of N-((2S)-2-((l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-5-yl)oxy)propyl)-2,2,2-trifluoro-N-methylacetamide (2.00 g, 3.84 mmol, 1 eq) in THF (10 mL) was added LiOH·H₂O (322 mg, 7.68 mmol, 2 eq) and H2O (10 mL). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 0 / 1, DCM: MeOH= 10:1) to give (2S)-2-((l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-5-yl)oxy)-N-methylpropan-l-amine (1.50 g, 3.11 mmol, 80% yield) as a yellow oil. LCMS: m / z 425.3 (M+l).

[0443] Intermediate Method I-5C

[0444] Preparation of tert-butyl methyl(2-((4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-l -(methylsulfonyl)- lH-pyrazol-3-yl)oxy)ethyl)carbamate (1-5-4): / o \ NaH, ACN1-3-20 1-5-4

[0445] To a solution of tert-butyl methyl(2-((4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethyl)carbamate (500 mg, 1.04 mmol, 1 eq) in ACN (10 mL) was added methylsulfonyl methanesulfonate (451 mg, 2.59 mmol, 2.5 eq) and NaH (62.2 mg, 1.55 mmol, 60% purity, 1.5 eq) at 0 °C under Ns atmosphere. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched by addition of HsO (30 mL) at 0 °C under Ns atmosphere and extracted with EA (20 mL x 3).The combined organic layer was washed with brine (20 mL x 2), dried over NaiSCh filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-16% Ethyl acetate / Petroleum ether) to give tert-butyl methyl(2-((4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-l-(methylsulfonyl)-lH-pyrazol-3-yl)oxy)ethyl)carbamate (300 mg, 0.535 mmol, 52% yield) as a colorless oil. Analytical data shown in the table below.

[0446] Intermediate Method I-5D

[0447] Preparation of tert-butyl methyl(2-((4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl- 1 H-pyrazolo[3,4-c]pyri din-5 -yl)- 1 -((methylsulfonyl)methyl)- 1 H-pyrazol-3-yl)oxy)ethyl)carbamate (1-5-5):oxone, THF / H2O

[0448] Step 1. To a solution of tert-butyl methyl(2-((4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethyl)carbamate (660 mg, 1.37 mmol, 1 eq) in DMF (10.0 mL) was added NaH (82.1 mg, 2.05 mmol, 60% purity, 1.5 eq) at 0 °C under N2 atmosphere. Then was added chloro(methylsulfanyl)methane (660 mg, 6.84 mmol, 5 eq). The mixture was stirred at 60 °C for 1 hour. On completion, the reaction mixture was quenched by addition of H2O (40 mL) at 0 °C under N2 atmosphere and extracted with EA (25 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Hexanes: Ethyl acetate= 1:0 to 1:1) to give tert-butyl methyl(2-((4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-l-((methylthio)methyl)-lH-pyrazol-3-yl)oxy)ethyl)carbamate (350 mg, 0.645mmol, 47% yield) as a yellow solid.!H NMR (400 MHz, CDCh) 5 = 8.11 - 8.02 (m, 1H), 7.08 - 6.94 (m, 1H), 6.21 - 6.05 (m, 1H), 5.88 (dd, J = 2.4, 9.2 Hz, 1H), 5.56 (d, J= 11.6 Hz, 1H), 5.02 (s, 2H), 4.49 (s, 2H), 4.04 (d, J = 10.4 Hz, 1H), 3.82 - 3.65 (m, 3H), 2.97 (s,3H), 2.77 -2.66 (m, 1H), 2.23 (s, 3H), 2.16 (d, 7 = 13.6 Hz, 1H), 1.76 (t. 7= 8.8 Hz. 2H), 1.66 (d. 7 = 4.4 Hz, 1H), 1.59(s, 2H), 1.44 (s, 9H), 1.33 - 1.18 (m, 2H), 0.89 (t, 7 = 6.6 Hz, 1H); LCMS: m / z 543.7 (M+l).

[0449] Step 2. A mixture of tert-butyl methyl(2-((4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-l-((methylthio)methyl)-lH-pyrazol-3-yl)oxy)ethyl)carbamate (330 mg, 0.517 mmol, 1 eq) in THF (5 mL) and H2O (1 mL) was added oxone (478 mg, 2.84 mmol, 5.5 eq) at 0 °C under N2 atmosphere. The mixture was stirred at 25 °C for 0.5 hours under N2 atmosphere. On completion, the reaction mixture was quenched by addition of a Sodium sulfite solution (5 mL) at 0 °C and extracted with EA (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate= 1:0 to 1:1) to give tert-butyl methyl(2-((4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-l-((methylsulfonyl)methyl)-lH-pyrazol-3-yl)oxy)ethyl)carbamate (215 mg, 0.374 mmol, 72% yield) as a brown oil. LCMS: m / z 575.6 (M+l).

[0450] Intermediate Method I-5E

[0451] Preparation of (2S)-2-((l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-5-yl)oxy)-N-methylpropan-l -amine (1-5-6):N'NTHP 1.5-6

[0452] Step 1. A mixture of l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo|3,4-c|pyridin-5-yl)-lH-pyrazol-5-ol (9.80 g, 27.7 mmol, 1 eq), (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N-methylacetamide (7.70 g, 41.6 mmol, 1.5 eq), DBAD (14.1 g, 61.0 mmol, 2.2 eq, PPhs (16.0 g, 61.0 mmol, 2.2 eq) was degassed and purged with N2 for 3 times, then 2-MeTHF (120 mL) was added to the mixture, the mixture was degassed and purged with N2 for 3 times again, and then the mixture was stirred at 25 °C for 2 hours under N2 atmosphere. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:1 to 1:2) to give N-((2S)-2-((l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-5-yl)oxy)propyl)-2,2,2-trifluoro-N-methylacetamide (25.0 g, 24.0 mmol, 87% yield, 50% purity) as a yellow solid. LCMS: m / z 521.2 (M+l).

[0453] Step 2. To a solution of N-((2S)-2-((l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-5-yl)oxy)propyl)-2,2,2-trifluoro-N-methylacetamide (25.0 g, 24.0 mmol, 1 eq) in THF (100 mL) and H2O (20 mL) was added LiOH·H₂O (5.04 g, 120 mmol, 5 eq). The mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was diluted with water (100 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO, DCM / MeOH= 10:1 to 5:1) to give (2S)-2-((l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-5-yl)oxy)-N-methylpropan-l -amine (10.9 g, 23.0 mmol, 96% yield, 90% purity) as a yellow oil. LCMS: m / z 425.2 (M+l)

[0454] Intermediate Method I-5F

[0455] Preparation of tert-butyl (2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH- pyrazolo[3,4-c]pyridin-5-yl)-l,3-dimethyl-l H-pyrazol-5-yl)oxy)ethyl)(methyl)carbamate (I- 5-7):' 1 — 7 / / 2^zZE CD O O

[0456] To a solution of 4-(7 -fluoro- 1 -(tetrahydro-2H-pyran-2-y l)-3-vinyl-l H-indazol-5-yl)- l,3-dimethyl-lH-pyrazol-5-ol (1.79 g, 9.26 mmol, 1.5 eq) in DMF (22 mL) was added CS2CO3 (6.03 g, 18.5 mmol, 3 eq) and KI (512 mg, 3.09 mmol, 0.5 eq). The mixture was stirred at 80 °C for 12 hours. On completion, the mixture was filtered, the filtrate was diluted with H2O (50 mL) and extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, Hexanes: Ethyl acetate= 1 / 1 to give tert-butyl (2-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l,3- dimethyl-lH-pyrazol-5-yl)oxy)ethyl)(methyl)carbamate (1.20 g, 2.34 mmol, 37% yield) as a yellow oil. LCMS: m / z 536.3 (M+23).

[0457] Intermediate Table 5# SM1Meth. Structure (m / z) [M+l] 'H NMR1-3-1,-5-1 I-5A 514.31-4-1# SM1Meth. Structure (m / z) [M+l] ‘H NMR / \, BocU r;[i jr-o1-3-2,-5-2 I-5A 514.21-4-1F^UTHPJQ-oH1-3-10-5-3 I-5B 425.31-4-3 / / N-NTHP(400 MHz, CDCls) 5 = 8.54 (s, 1H), 8.27 - 8.04 (m, 1H), 7.14 - 6.89 (m, 1H), 6.14 (t, J = 17.2 Ox ZO Hz, 1H), 5.90 (d, 7= 9.4 X Hz, 1H), 5.59 (d, 7 = 11.4 A / "~O Boc Hz, 1H), 4.60 (t, 7= 5.2 -5-4 1-3-20 I-5C 561.4 Hz, 2H), 4.05 (d, 7= 10.6Hz, 1H), 3.78 -3.71 (m, / / N-N 2H), 3.29 (s, 3H), 3.00 (s, THP'6H), 2.78 - 2.65 (m, 1H), 2.27 - 2.13 (m, 2H), 2.06 (d, 7= 1.6 Hz, 1H), 1.77 (t, 7= 9.0Hz, 2H), 1.68 (s, 1H), 1.42 (s, 9H)O / \\ _ / A^N i ^Boc-5-5 1-3-20 I-5D 575.6N' T / A / AN-NTHP'# SM1Meth. Structure (m / z) [M+l] 'H NMR / \ / “AJI O HN—1-3-10-5-6 I-5E 425.2I-4-3aN'NTHP' 1 > 1 —1-3-27 536.3-5-7 1-5F1-4-5z o"'^ / (M+23)coz0\ \ 0'SM: Starting Material(s)

[0458] Intermediate Method I-6A

[0459] Preparation of ethyl 3-isopropoxy-lH-pyrazole-5-carboxylate (1-6-1):OOH

[0460] To a solution of ethyl 3-hydroxy-lH-pyrazole-5-carboxylate (10.0 g, 64.0 mmol, 1 eq) in DMF (100 mL) was added K2CO3 (26.5 g, 192 mmol, 3 eq) and 2-iodopropane (21.8 g, 128 mmol, 2 eq). The mixture was stirred at 120 °C for 12 h. On completion, the reaction mixture was partitioned between ethyl acetate (300 mL x 3) and water (300 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 10:1) to give ethyl 3-isopropoxy-lH-pyrazole-5-carboxylate (6.00 g, 30.3 mmol, 47% yield) as a white solid. LCMS: in / z 199.1 (M+l).

[0461] Intermediate Method I-6B

[0462] Preparation of (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-i sopropoxy- 1 H-pyrazole (1-6-2):TBSCI, Imidazole DIBAL-H OTBS THFLAH, THFNIS, ACN PPh3, NISDCM

[0463] Step 1. To a solution of ethyl (S)-2-hydroxypropanoate (5.00 g, 42.3 mmol, 1 eq) in DCM (50 mL) was added Imidazole (8.64 g, 127 mmol, 3 eq), and then TBSCI (9.57 g, 63.5 mmol, 1.5 eq) was added at 0°C. The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was partitioned between DCM (60 mL x 3) and water (50 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 (SiOs, PE / EA= 10:1) to give ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate (9.70 g, 41.7 mmol, 99% yield) as a brown solid.NMR (400 MHz, DMSO-&) d = 4.38 - 4.29 (m, 1H), 4.14 - 4.04 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H), 1.19 (t, J= 7.2 Hz, 3H), 0.87 - 0.85 (m, 9H), 0.05 (d, J = 3.2 Hz, 6H).

[0464] Step 2. To a solution of ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate (8.70 g, 37.4 mmol, 1 eq) in THF (87 mL) was added DIBAL-H (1 M in Tol., 74.8 mL, 2 eq) at 0°C under N2 atmosphere. The mixture was stirred 25 °C for 4 h. On completion, water (3 mL), 15% NaOH (3 mL) and water (7.5 mL) were added successively, and the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOj, Petroleum ether / Ethyl acetate= 10:1) to give (S)-2-((tert-butyldimethylsilyl)oxy)propan-l-ol (4.87 g, 25.6 mmol, 68% yield) as a white oil. H NMR (400 MHz, DMSO- e) S = 4.53 (t, J =5.6 Hz, 1H), 3.80 - 3.66 (m, 1H), 3.30 - 3.09 (m, 2H), 1.09 - 0.99 (m, 3H), 0.87 -0.84 (m, 8H), 0.04 (d, J= 0.8 Hz, 6H).

[0465] Step 3. To a solution of (S)-2-((tert-butyldimethylsilyl)oxy)propan-l-ol (4.49 g, 23.6 mmol, 2 eq) and ethyl 3-isopropoxy-lH-pyrazole-5-carboxylate (2.34 g, 11.81 mmol, 1 eq) in 2-Me THF (4 mL) was added PPh; (6.81 g, 25.9 mmol, 2.2 eq) and DIAD (5.25 g, 25.9 mmol, 2.2 eq). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiOi, Petroleum ether / Ethyl acetate= 8:1) to give ethyl (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-isopropoxy-lH-pyrazole-5-carboxylate (4.43 g, crude) as a white solid. LCMS: m / z 371.1 (M+l)

[0466] Step 4. To a solution of ethyl (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-isopropoxy-lH-pyrazole-5-carboxylate (4.29 g, 11.6 mmol, 1 eq) in THF (40 mL) was added Li A ILL (2.5 M in THF, 6.95 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, water (0.6 mL), 15% NaOH (0.6 mL) and water (2.0 mL) was added successively, and the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: THF= 6:1) to give (S)-(l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-isopropoxy-lH-pyrazol-5-yl)methanol (2.26 g, 6.88 mmol, 59% yield) as a brown solid. LCMS: m / z 329.1 (M+l)

[0467] Step 5. To a solution of (S)-(l-(2-((tert-butyldimethylsilyl)oxy)propyl)-3-isopropoxy-lH-pyrazol-5-yl)methanol (2.06 g, 6.27 mmol, 1 eq) in ACN (20 mL) was added NIS (2.12 g, 9.41 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was partitioned between ethyl acetate (25 mL x 3) and water (25 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO:, PE: THF= 6:1) to give (S)-(l-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-lH-pyrazol-5-yl)methanol (2.79 g, 6.13 mmol, 98% yield) as a purple oil. LCMS: m / z 455.4 (M+l)

[0468] Step 6. To a solution of (S)-(l-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-lH-pyrazol-5-yl)methanol (15.0 g, 33.0 mmol, 1 eq) in DCM (150 mL) was added NIS (14.8 g, 66.0 mmol, 2 eq) and PPh (12.99 g, 49.51 mmol, 1.5 eq). The mixture was stirred at 0 °C for 2 h. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography LSiO \ Petroleum ether / THF= 40:1 to 30:1) to give (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-lH-pyrazole (14.5 g, 25.7 mmol, 78% yield) as a whitesolid. LCMS: m / z 565.2 (M+l).

[0469] Intermediate Method I-6C

[0470] Preparation of 5-(bromomethyl)-4-iodo-l -methyl- IH-pyrazole (1-6-5):LAH NIS, ACNTHFPBr3DCM1-6-5

[0471] Step 1. To a solution of methyl l-methyl-lH-pyrazole-5-carboxylate (10.0 g, 71.4 mmol, 1 eq) in THF (100 mL) was added LAH (2.5 M, 42.8 mL, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 6 hr. On completion, the reaction mixture was quenched with H2O (4 mL) dropwise at 0 °C and adjusted with 15% NaOH (4 mL). Then was added H2O (4 mL) and Na2SO4, and the mixture was stirred at 25 °C for 20 min and filtered. The filtrate was concentrated under reduced pressure to give (1 -methyl- lH-pyrazol-5-yl) methanol (7.88 g, crude) as a colorless oil. 'H NMR (400 MHz, DMSO-rfc) 5 = 7.31 (s, 1H), 6.17 (s, 1H), 5.31 (t, J = 5.2 Hz, 1H), 4.52 (d, J = 5.2 Hz, 2H), 3.79 (s, 3H).

[0472] Step 2. To a solution of (1 -methyl- lH-pyrazol-5-yl)methanol (7.30 g, 65.1 mmol, 1 eq) in ACN (50 mL) was added NIS (17.6 g, 78.1 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was quenched with a saturated solution of Na^SO? (30 mL), partitioned between water (300 mL) and ethyl acetate (100 mL x 7), the combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (4-iodo-l-methyl-lH-pyrazol-5-yl)methanol (13.0 g, 54.6 mmol, 84% yield) as a white solid.!H NMR (400 MHz, DMSO-cfe) § = 7.43 (s, 1H), 5.32 (s, 1H), 4.48 (s, 2H), 3.87 (s, 3H); LCMS: ni / z 238.9 (M+l)

[0473] Step 3. To a solution of (4-iodo-l-methyl-lH-pyrazol-5-yl)methanol (5.00 g, 21.0 mmol, 1 eq) in DCM (50 mL) was added tribromophosphane (6.82 g, 25.2 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 6 h. On completion, the mixture was quenched with sat. NaHCOs (100 mL), and extracted with DCM (100 mL). The organic layer was washed with water (100 mL), brine (2x200 mL). The organic layer was dried over sodium sulfate, and concentrated in vacuum to afford 5-(bromomethyl)-4-iodo-l-methyl-lH-pyrazole (4.50 g, 15.0mmol, 71% yield) as a white solid. LCMS: m / z 300.8 (M+l)

[0474] Intermediate Method I-6D

[0475] Preparation of 5-(bromomethyl)-4-iodo-l,3-dimethyl-lH-pyrazole (1-6-6):

[0476] Step 1. To a solution of ethyl l,3-dimethyl-lH-pyrazole-5-carboxylate (10.0 g, 59.5 mmol, 1.0 eq) in ACN (100 mL) was added NTS ( 14.7 g, 65.4 mmol, 1.1 eq). The mixture was stirred at 60 °C for 16 hr. On completion, the mixture was quenched with sat. NazSOs (500 mL) and extracted with ethyl acetate (250 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 4-iodo-l,3-dimethyl-lH-pyrazole-5 -carboxylate (17 g, crude) as a colorless oil. LCMS: m / z 295.2 (M+l).

[0477] Step 2. To a solution of ethyl 4-iodo-l,3-dimethyl-lH-pyrazole-5-carboxylate (8.00 g, 27.2 mmol, 1.0 eq) in MeOH (150 mL) was added LiBPL (14.8 g, 680 mmol, 25 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hr. The mixture was quenched with water (200 mL) and concentrated in vacuum to give a residue. Then, to the residue was added water (100 mL) and was extracted with ethyl acetate (60 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was triturated with PE / EA = (10:1) at 25 °C for 10 min to give (4-iodo-l,3-dimethyl-lH-pyrazol-5-yl)methanol (6.30 g, 22.5 mmol, 83% yield) as a white solid. LCMS: / z 252.9 (M+l).

[0478] Step 3. To a solution of (4-iodo-l,3-dimethyl-lH-pyrazol-5-yl)methanol (4 g, 15.9 mmol, 1.0 eq in DCM (40 mL) was added PBr (4.73 g, 17.5 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. On completion, the mixture was adjusted to pH = 7~8 with Sat. NaHCOs, water (100 mL) was added, and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 5 / 1 to 1 / 1) to give 5-(bromomethyl)-4-iodo-l,3-dimethyl-lH-pyrazole (2.70 g, 8.57 mmol, 54% yield) as a white solid. Analyticaldata shown in the table below.

[0479] Intermediate Method I-6E

[0480] Preparation of 5-(bromomethyl)-3-ethoxy-4-iodo-l-methyl-lH-pyrazole (1-6-7):

[0481] Step 1. To a solution of methyl 3-hydroxy-l-methyl-lH-pyrazole-5-carboxylate (9 g, 57.6 mmol, 1 eq), EtI (8.99 g, 57.6 mmol, 4.61 mL, 1 eq) in DMF (90 mL) was added K2CO3 (23.9 g, 172 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hr. On completion, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with water (200 mLx2) and 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 1:1) to give methyl 3-ethoxy-l-methyl-lH-pyrazole-5-carboxylate (10 mg, 54.3 mmol, 94% yield) as a white oil.NMR (400 MHz, CDCL) 5 = 6.15 - 6.12 (m, 1H), 4.17 - 4.09 (m, 2H), 4.01 - 3.98 (m, 3H), 3.84 -3.81 (m, 3H), 1.37 - 1.32 (m, 3H); LCMS: m / z 185.2 (M+l).

[0482] Step 2. To a solution of methyl 3-ethoxy-l-methyl-lH-pyrazole-5-carboxylate (9 g, 48.8 mmol, 1 eq) in THF (90 mL) was added LiAlH4 (1.85 g, 48.8 mmol, 1 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. On completion, the mixture was quenched with MeOH (200 mL) at 0 °C, and the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH= 1:0 to 1:1) to give (3-ethoxy-l-methyl-lH-pyrazol-5-yl)methanol (7.9 g, 48.05 mmol, 98% yield) as a white solid. LCMS: m / z 157.4 (M+l)

[0483] Step 3. To a solution of (3-ethoxy-l-methyl-lH-pyrazol-5-yl)methanol (6.9 g, 44.1 mmol, 1 eq) in ACN (70 mL) was added NIS (8.95 g, 39.7 mmol, 0.9 eq) at 0°C. The mixture was stirred at 0 °C for 2 h. On completion, the mixture was quenched with a saturated aqueoussolution of Na2SOs (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated togive a residue. The residue was purified by column chromatography (SiOi, Petroleum ether / Ethyl acetate= 1:0 to 1:1) to give (3-ethoxy-4-iodo-l -methyl- lH-pyrazol-5-yl)methanol (14.5 g, 43.6 mmol, 99% yield) as a white solid. LCMS: m / z 283.0 (M+l)

[0484] Step 4. To a solution of (3-ethoxy-4-iodo-l -methyl- lH-pyrazol-5-yl)methanol (12.5 g, 44.3 mmol, 1 eq), PPh (13.9 g, 53.1 mmol, 1.2 eq) in DCM (120 mL) was added CBr4 (17.6 g, 53.1 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. On completion, the mixture was diluted with water (200 mL) and extracted with DCM (50 mL x 3). The combined organic phase was dried over NaaSCU, 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 65:35) to give 5-(bromomethyl)-3-ethoxy-4-iodo-l -methyl- IH-pyrazole (8.6 g, 24.9 mmol, 56% yield) as a yellow solid. Analytical data shown in the table below.

[0485] Intermediate Method I-6F

[0486] Preparation of (S)-(l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methanol (1-6-8):TBSCI, imidazole OTBS HO PPh3, DIAD, THFPPh3, NIS DCM

[0487] Step 1. To a solution of (2R)-propane-l,2-diol (50.0 g, 657 mmol, 1 eq) in DCM (500 mL) was added TBSCI (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 heated to 25 °C for 10 hr. On completion, themixture was filtered and concentrated to give (2R)-1 -[tert-butyl (dimethyl) silyl] oxypropan-2-ol (120 g, 630 mmol, 95% yield) as a colorless oil.1H NMR (400 MHz, DMSO-&) 6 = 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).

[0488] Step 2. A mixture of ethyl 3-ethoxy-lH-pyrazole-5-carboxylate (22.0 g, 129 mmol, 1 eq), (2R)-l-[tert-butyl(dimethyl)silyl]oxypropan-2-ol (49.2 g, 258 mmol, 2 eq), PPh (74.6 g, 284 mmol, 2.2 eq) in THF (250 mL) was degassed and purged with Ni 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 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 (SiCL, Petroleum ether / Ethyl acetate= 1:0 to 5:1) to give ethyl 2-[(lS)-2-[tert-butyl (dimethyl) silyl] oxy-1-methyl-ethyl]-5-ethoxy-pyrazole-3-carboxylate (36.0 g, 105 mmol, 81 % yield) as a transparent oil.!H NMR (400 MHz, CDC13) 5 = 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).

[0489] Steps 3-5 were performed following the procedure described in steps 4-6 of Intermediate Method I-6B to obtain (S)-(l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methanol (25.6 g, 58.1 mmol, 61.9% yield) as a white solid. Analytical data shown in the example table below.

[0490] Intermediate Method I-6G

[0491] Preparation of l-((3S,4R)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-lH-pyrazole (1-6-9):LiAIH4, THF NIS, ACNNIS, PPh3, DCM

[0492] Step 1. To a solution of 3,6-dioxabicyclo[3.1.0]hexane (6.50 g, 75.5 mmol, 1 eq) in EtOH (260 mL) was added N2H4. H2O (188 mmol, 9.5 mL, 98% purity, 2.5 eq at 0 °C. The reaction was stirred at 25 °C for 10 minutes, and then heated at 60 °C and stirred for 16 hours. On completion, the mixture was concentrated to give a residue. The residue was diluted with EA (1 L), filtered, the filter cake was washed with water (500 mL), and then the filter cake was concentrated in vacuum to give (3R,4S)-4-hydrazinotetrahydrofuran-3-ol (8.90 g, 75.3 mmol, 99% yield) as a yellow oil. H NMR (400 MHz, DMSO-de) 5 = 4.05 - 4.02 (m, 1H), 3.79 -3.71 (m, 3H), 3.49 (d, J = 2.4 Hz, 1H), 3.47 - 3.45 (m, 2H), 3.44 (d, J = 1.6 Hz, 1H), 3.06 -3.02 (m, 1H).

[0493] Step 2. To a solution of (3R,4S)-4-hydrazinotetrahydrofuran-3-ol (6.00 g, 50.7 mmol, 1 eq) in toluene (25 mL) was added AcOH (15 mL) and dimethyl but-2-ynedioate (7.22 g, 50.7 mmol, 1 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was poured into ice-cooled water. The resulting precipitate was collected, washed with waterand hexane, and the filter liquor was concentrated under reduced pressure to give methyl 5-hydroxy-2-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]pyrazole-3-carboxylate (11.5 g, 30.4 mmol, 60% yield) as a yellow oil. LCMS: m / z 251.0 (M+23).

[0494] Step 3. To a solution of methyl 5-hydroxy-2-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]pyrazole-3-carboxylate(l 1.5 g, 50.7 mmol,1 in DMF (lOOmL) was added K2CO3 (14.0 g, 101 mmol, 2 eq) and EtI (8.71 g, 55.8 mmol, 1.1 eq). The mixture was stirred at 100 °C for 7 hours. On completion, the reaction mixture was quenched by H2O (100 mb), and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with saturated brine, dried with anhydrous Na2SO4, and concentrated under reduced pressure to give methyl 5-ethoxy-2-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]pyrazole-3-carboxylate (8.00 g, 22.7 mmol, 44% yield) as a yellow oil.

[0495] Step 4. To a solution of methyl 5-ethoxy-2-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]pyrazole-3-carboxylate (8.00 g, 31.2 mmol, 1 eq) in DCM (40 mL) was added TBSC1 (5.65 g, 37.4 mmol, 1.2 eq) and imidazole (4.25 g, 62.4 mmol, 2 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 100 / 1 to 88 / 12) to give methyl 2-[(3S,4R)-4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-3-yl]-5-ethoxy-pyrazole-3-carboxylate (3.10 g, 8.20 mmol, 26% yield) as a yellow oil.!H NMR (400 MHz, DMSO-rfo) 5 = 6.22 (s, 1H). 4.71 - 4.65 (m, 1H), 4.56 - 4.49 (m, 1H), 4.23 - 4.15 (m, 3H), 4.02 - 3.97 (m, 1H), 3.93 - 3.88 (m, 1H), 3.77 (s, 3H), 3.60 - 3.56 (m. 1H), 1.34 (t, J = 7.2 Hz. 3H), 0.81 (s, 9H), -0.05 (d, 7= 11.8 Hz, 6H); LCMS: m / z 371.4 (M+l)

[0496] Steps 5-7 were performed following a similar procedure as shown in steps 4-6 of Intermediate Method I-6B to give l-((3S,4R)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-lH-pyrazole (2.80 g, 4.60 mmol, 71% yield) as a yellow oil. LCMS: m / z 579.0 (M+l)

[0497] Intermediate Method I-6H

[0498] Preparation of l-(2-((tert-butyldimethylsilyl)oxy)cyclobutyl)-3-ethoxy-4-iodo-5-(iodomethyl)- 1 H-pyrazole (1-6-10):TMSOTMSO2 M HCI / dioxane DCMEtl, K2CO3Pd / C, H2DMF MeOHTBSCI, imidazole DCM

[0499] Step 1. To a solution of l,2-bis((trimethylsilyl)oxy)cyclobut-l-ene (12.0 g, 52.0 mmol, 1 eq) in HCI / dioxane (2 M, 100 mL, 3.84 eq) was added phenylmethanol (6.76 g, 62.4 mmol, 1.2 eq). The mixture was stirred at 80 °C for 4 hours. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOi, Petroleum ether / Ethyl acetate = 1:0 to 0:1) to give 2-benzyloxycyclobutanone (4.00 g, 22.7 mmol, 43% yield) as a yellow oil. H NMR (400 MHz, CDCh) 5 = 7.36 - 7.16 (m, 5H), 4.72 -4.61 (m, 2H), 4.58 - 4.49 (m, 1H), 2.75 - 2.58 (m, 2H), 2.30 - 2.14(m, 1H), 1.87 (dq, J = 8.0,10.4 Hz, 1H).

[0500] Step 2. To a solution of 2-benzyloxycyclobutanone (3.80 g, 21.5 mmol, 1 eq) and tertbutyl N-aminocarbamate (3.42 g, 25.8 mmol, 1.2 eq in MeOH (40 mL) was added AcOH (1.30 g, 21.5 mmol, 1 eq) to adjust to pH=6. The mixture was stirred at 25 °C for 0.2 hours. Then NaBHgCN (4.07 g, 64.7 mmol, 3 eq) was added to the mixture. The mixture was stirred at 25 °C for 12 hours. On completion, the mixture was quenched with water (3 mL) and extracted with ethyl acetate (2 mL x 3), and the combined organic phase was dried over- anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether / Ethyl acetate = 1:0 to 0: 1) to give tert-butyl N-[(2-benzyloxycyclobutyl)amino]carbamate (4.60 g, 15.7 mmol, 72% yield) as a yellow oil. LCMS: m / z 237.2 (M+l)

[0501] Step 3. To a solution of tert-butyl N-[(2-benzyloxycyclobutyl)amino]carbamate (4.60 g, 15.7 mmol, 1 eq) in DCM (40 mL) was added HCl / dioxane (2 M, 7.87 mL, 1 eq). The mixture was stirred at 25 °C for 12 hours. On completion, the mixture was filtered and concentrated to give (2-benzyloxycyclobutyl)hydrazine (3.00 g, 15.6 mmol, 99% yield) as a yellow oil. LCMS: m / z 193.2 (M+l)

[0502] Step 4. To a solution of (2-benzyloxycyclobutyl)hydrazine (3.00 g, 15.6 mmol, 1 eq) in EtOH (40 mL) was added NaOAc (3.84 g, 46.8 mmol, 3 eq) and dimethyl but-2-ynedioate (2.44 g, 17.1 mmol, 1.1 eq). The mixture was stirred at 80 °C for 1 hour. On completion, the reaction mixture was partitioned between ethyl acetate (5 mL x 3) and water (5 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether / THF = 1:1 to 4:1) to give methyl 2-(2-benzyloxycyclobutyl)-5-hydroxy-pyrazole-3-carboxylate (3.32 g, 10.9 mmol, 70% yield) as a yellow oil. LCMS: m / z 303.1 (M+l)

[0503] Step 5. To a solution of methyl 2-(2-benzyloxycyclobutyl)-5-hydroxy-pyrazole-3-carboxylate (3.30 g, 10.9 mmol, 1 eq) in DMF (40 mL) was added K2CO3 (4.53 g, 32.7 mmol, 3 eq) and iodoethane (2.55 g, 16.3 mmol, 1.5 eq). The mixture was stirred at 100 °C for 1 hour. On completion, the reaction mixture was partitioned between ethyl acetate (150 mL x 3) and water (50 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOz, Petroleum ether / THF = 1:0 to 0:1) to give methyl 2-(2-benzyloxycyclobutyl)-5-ethoxy-pyrazole-3-carboxylate (2.00 g, 6.05 mmol, 55% yield) as a colorless oil. LCMS: m / z 331.3 (M+l)

[0504] Step 6. A mixture of methyl 2-(2-benzyloxycyclobutyl)-5-ethoxy-pyrazole-3-carboxylate (1.80 g, 5.45 mmol, 1 eq), Pd / C (579 mg, 0.544 mmol, 10% purity, 0.1 eq) inMeOH (20 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 12 hours under H2 atmosphere. On completion, 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 0:1) to give methyl 5-ethoxy-2-(2-hydroxycyclobutyl) pyrazole-3-carboxylate (570 mg, 2.37 mmol, 43% yield) as a yellow oil. LCMS: m / z 241.2 (M+1)

[0505] Step 7. To a solution of methyl 5-ethoxy-2-(2-hydroxycyclobutyl)pyrazole-3-carboxylate (530 mg, 2.21 mmol, 1 eq) in DCM (10 mL) was added TBSC1 (498 mg, 3.31 mmol, 1.5 eq) and imidazole (225 mg, 3.31 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was partitioned between dichloromethane (10 mL x 3) and water (10 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 methyl 2-[2-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-5-ethoxy-pyrazole-3-carboxylate (700 mg, 1.97 mmol, 89% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) 5 = 6.38 - 6.16 (m, 1H), 5.68 - 5.43 (m. 1H), 4.84 - 4.52 (m, 1H), 4.32 - 4.21 (m, 2H), 3.98 - 3.82(m, 3H), 2.27 - 2.17 (m, 2H), 2.04 - 1.70 (m, 2H), 1.51 - 1.43 (m, 3H), 0.89 - 0.76 (m, 9H), 0.02 - -0.04 (m, 3H), -0.06 - -0.10(m, 3H).

[0506] Steps 8-10 were performed following the procedure shown for steps 4-6 in Intermediate Method I-6B to obtain l-(2-((tert-butyldimethylsilyl)oxy)cyclobutyl)-3-ethoxy-4-iodo-5-(iodomethyl)-lH-pyrazole (200 mg, 0.355 mmol, 25% yield) as a yellow oil. LCMS: m / z 563.1 (M+l).

[0507] Intermediate Method I-6I

[0508] Preparation of 4-bromo-5-(bromomethyl)-l-methyl-lH-l,2,3-triazole (1-6-12):CBr4, PPh3DCM1-6-12

[0509] Step 1. To a solution of methyl l-methyl-lH-l,2,3-triazole-5-carboxylate (2.50 g, 16.1 mmol, 1 eq) in THF (25 mL) was added LiAlIL (2.5 M in THF, 7.73 mL, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was quenched with water (20 mL) andextracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (l-methyl-lH-l,2,3-triazol-5-yl)methanol (1.20 g, 10.6 mmol, 66% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) 5 = 7.59 (s, 1H), 5.42 (t. J = 5.6 Hz. 1H), 4.57 (d, J= 5.6 Hz. 2H), 3.97 (s, 3H).

[0510] Step 2. To a solution of (l-methyl-lH-l,2,3-triazol-5-yl)methanol (870 mg, 7.69 mmol, 1 eq) in ACN (9 mL) was added NBS (1.64 g, 9.23 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the mixture was quenched with sat. Na₂SO₄ (20 mL) and extracted with ethyl acetate (15 mLx3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH= 1:0 to 10: 1) to give (4-bromo- 1 -methyl- 1H- 1.2.3-triazol-5-yl)methanol (1.00 g, 5.21 mmol, 68% yield) as a white solid. LCMS: m / z 191.9 (M+l)

[0511] Step 3. A mixture of (4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)methanol (900 mg, 4.69 mmol, 1 eq) and PPh3(1.84 g, 7.03 mmol, 1.5 eq) in DCM (9 mL) was degassed and purged with N for 3 times, and then was added CBr4 (1.87 g, 5.62 mmol, 1.2 eq) in DCM (1 mL). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF= 1:0 to 3:1) to give 4-bromo-5 -(bromomethyl)- 1 -methyl- 1H- 1.2.3-triazole (1.00 g, 3.92 mmol, 84% yield) as a white solid. LCMS: m / z 255.9 (M+l).

[0512] Intermediate Method I-6J

[0513] Preparation of 4-bromo-l-methyl-lH-l,2,3-triazol-5-ol (1-6-13):KHSO5NaOH THFBr nBuLi, THF1-6-13

[0514] Step 1. A mixture of 4,5-dibromo-l-methyl-triazole (3.00 g, 12.4 mmol, 1 eq) in dry THF (30 mL) was cooled to -78 °C then degassed and purged with N2 for 3 times. Then to the mixture was added n-BuLi (2.5 M in THF, 10 mL, 2 eq) dropwise at -78 °C, and then added 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.63 g, 24.9 mmol, 2 eq). The mixture was stirred at -78 °C for 2 hours under N2 atmosphere. On completion, the mixture was added to a saturated solution of NH4CI (500 mL) slowly, filtered and the filter cake was dried to give 4-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)triazole (3.50 g, 12.1 mmol, 97.6% yield) as a white solid. LCMS: m / z 287.8 (M+l)

[0515] Step 2. To a solution of 4-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)triazole (3.50 g, 12.1 mmol, 1 eq) in THF (35 mL) was added potassium oxidooxy hydrogen sulfate (5.11 g, 30.4 mmol, 2.5 eq) and NaOH (1 M, 30 mL, 2.5 eq). The mixture was stirred at 0 °C for 2 hours. On completion, the reaction mixture was filtered, and the filtrate was adjusted to pH=3 with citric acid, and then extracted with solvent 2-MeTHF (30 mL x 5). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (neutral condition) to give 5-bromo-3-methyl-triazol-4-ol (560 mg, 3.15 mmol, 25% yield) as a white solid. Analytical data shown in the example table below.

[0516] Intermediate Table 6# SM1Meth. Structure (mJz) H NMR [M+l]0OEt0^ \— NHEt0'' y-NH1-6-1 I-6A 199.1OH o^zOTBS11 / 1-6-2 / — 0 * I-6B 565.2and1-6-10 OE‘0" VNHEt0' y-NH1-6-3 I-6A / / . N 185.1OH°'AOTBS1l / 1-6-4 / T-0 * I-6B 551.0Land1-6-3°'A / U 11-6-5 0^^ I-6C 300.8? UNr(m / z) # SM1Meth. Structure H NMR [M+l](400 MHz. op° CDCh-J) 5 = 1-6-6 I-6D 316.8 4.46 (s, 2H), 3.91V 1 (s, 3H), 2.23 (s,3H)(400 MHz, CDCh) 5 = 4.40Br^v / / / Z' (s, 2H), 4.28 - 1-6-7 I-6ENTN 346.8 4.20 (m, 2H),3.80 (s, 3H), 1.40 OH °~A (t, J = 7.2 Hz,3H)(400 MHz,? T DMSO-de) 6 =5.28 (dd, 7 = 4.8,! A _ / 6.0 Hz, 1H), 4.56 Z Z ^-O\TBS- 4.43 (m, 2H), 1 OH N 4.34 (dd, 7 = 4.4, HO 13.2 Hz, 1H), 1-6-8 I-6F JCz'N440.9and 4.20 - 4.09 (m, 1-6-3 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)O1-6-9 N2H4H2O 1-6G T N 579.0—0 00 0— °~ATMSO. _P' \, / 0TBSTMSO-6-10 H2N- NHBOC I-6H 563.1—0 00 o—0^ °--\-6-11 0ZN I-6G l-Jf "0TBS2H4H2O T N 593.1—0 0|Z\0 o— °~A(m / z) # SM1Meth. Structure H NMR [M+l]O1-6-12 O'Ar-N / I-6I / / , N 255.91r? NN' BC V / / N-N N'N (400 MHz,N^ DMSO-rfc) 8 = 1-6-13 N^-Br 1-6J?-OH12.75 - 11.19 (m, Br Br 1H), 3.69 (s, 3H) OEt Br1-6-14 r N— I-6C 314.8C N—OHCommercially 1-6-15°v JI. N availableXSM: Starting Material(s)2Steps 4-6 only

[0517] General Method A

[0518] Preparation of (2S)-l-{(105, 111?, 17E -19-fluoro-8, 10,1 l,12-tetramethyl-16-[(propan- 2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3’,4'-j:4",3"- n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (Ex. 1) and (2S)-l-{(10 / ?,ll / ?,17£’)-19- fluoro-8,10, 11, 12-tetramethyl-16-[(propan-2-yl)oxy]-2,8,10, 11, 12,13-hexahydro- 14 / / -3.5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [1,4]oxazacyclopentadecin- 14-yl }propan-2-ol (Ex. 2):

[0519] Step 1. To a solution of tert-butyl ((2R)-3-((4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l-methyl-lH-pyrazol-5-yl)oxy)butan-2-yl)carbamate (2.70 g, 5.26 mmol, 1 eq) in DMF (30 mL) was added (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-lH-pyrazole (3.26g, 5.78 mmol, 1.1 eq) andNaH (421 mg, 10.5 mmol, 60% purity, 2 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was quenched by addition of satd. aq. NH4CI (50 mL) at 25 °C. diluted with H2O (100 mL), and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressureto give a residue. The residue was purified by flash silica gel chromatography (0-50% Ethyl acetate / Petroleum ether) to give tert-butyl ((2R)-3-((4-(6-fluoro-l -(tetrahydro- 2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l-methyl-lH-pyrazol-5-yl)oxy)butan-2-yl)carbamate (3.86 g, 4.06 mmol, 77% yield) as a yellow solid. LCMS: m / z 972.4 (M+23).

[0520] Step 2. To a solution of tert-butyl ((2R)-3-((4-(6-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l-methyl-lH-pyrazol-5-yl)oxy)butan-2-yl)carbamate (3.60 g, 3.79 mmol, 1 eq) in DMF (40 mL) was added TBAC (1.05 g, 3.79 mmol, 1 eq), Pd(OAc)2 (170 mg, 0.758 mmol, 0.2 eq) and NaHCO (955 mg, 11.4 mmol, 3 eq), and the mixture was stirred at 130 °C for 1 h. On completion, the reaction mixture was diluted with H2O (100 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-50% Ethyl acetate / Petroleum ether) to afford tert-butyl (HR,17£')-14-[(25)-2-{[tert-butyldi(methyl)silylJoxy}propylJ-19-fluoro-8, 10,11 -trimethyl-2-(oxan-2-yl)- 16- [(propan-2-yl)oxy] -2, 8, 10, 11, 13,14-hexahydro-1277-3, 5-ethenotripyrazolo[3,4- / :3',4'-j:4",3”-n][l,4]oxazacyclopentadecine-12-carboxylate (3.00 g, 3.65 mmol, 96% yield) as a yellow solid. LCMS: m / z 822.5 (M+l).

[0521] Step 3. To a solution of tert-butyl (117?, 17E)-14-[(2S)-2-{ [tert-butyldi(methyl)silyl]oxy [propyl]- 19-fluoro-8, 10, 11 -trimethyl-2-(oxan-2-yl)- 16-[(propan-2-yl)oxy]-2,8,10,ll,13,14-hexahydro-12H-3,5-ethenotripyrazolo[3,4- / :3',4’-j:4”,3"-n][l,4]oxazacyclopentadecine-12-carboxylate (1.50 g, 1.82 mmol, 1 eq) in DMSO (15 mL) was added CsF (1.94 g, 13 mmol, 7 eq) and stirred at 50 °C for4h. On completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-80% THF / Petroleum ether) to afford tert-butyl (HR,17£’)-19-fluoro-14-[(25)-2-hydroxypropyl]-8,10,l l-trimethyl-2-(oxan-2-yl)-16-[(propan-2-yl)oxy]-2,8,10,ll,13,14-hexahydro-12 / / -3,5-ethenotripyrazolo[3,4- / :3',4’ / :4”,3"-n][l,4]oxazacyclopentadecine-12-carboxylate (800 mg, 1.13 mmol, 62% yield) as a yellow solid. LCMS: m / z 708.5 (M+l).

[0522] Step 4. To a solution of tert-butyl (ll / ?,177?)-19-fluoro-14-[(25)-2-hydroxypropyl]-8, 10, 11 -trimethyl-2-(oxan-2-yl)- 16- [(propan-2-yl)oxy ] -2,8, 10, 11, 13, 14-hexahydro- 1277-3,5 -ethenotripyrazolo[3,4- / :3',4'-j:4",3"-ra][l,4]oxazacyclopentadecine-12-carboxylate (50.0 mg, 0.0706 mmol, 1 eq) in DCM (1 mL) was added TFA (2.69 mmol, 0.2 mL, 38 eq), and the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give (25)- 1 -{ ( 11R, 1 IE)- 19-fluoro-8, 10, 11 -trimethyl- 16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4’-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (50.0 mg, crude) as a yellow solid. LCMS: rn / z 524.2 (M+l).

[0523] Step 5. To a solution of (2S)-l-{(HA,17 / 7)-19-fluoro-8,10,l l-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,l2,l3-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3’,4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (50.0 mg, 0.0955 mmol, 1 eq) in MeOH (1 mL) was added NaBH₃CN (12.0 mg, 0.191 mmol, 2 eq), (HCHO)n (5.79 mg, 0.191 mmol, 2 eq) and AcOK (65.6 mg, 0.668 mmol, 7 eq), and the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give (2S)-l-{(10S,117?,17E)-19-fluoro-8,10,ll,12-tetramethyl- 16-[(propan-2-y l)oxy] -2,8, 10, 11, 12, 13-hexahydro- 1477-3,5-ethenotripyrazolo|3,4- / :3',4’; / :4".3"- / / || 1.4|oxazacyclopentadecin- 14-yl }propan-2-ol (1.63 mg, 0.00303 mmol, 3.26% yield) as a white solid (Ex. 1) and (25')-l-{(107i’,llA,17£')-19-fluoro-8, 10, 11, 12-tetramethyl- 16-[(propan-2-yl)oxy ]-2,8, 10, 11, 12, 13-hexahydro- 1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (3.56 mg, 0.00662 mmol, 7.12% yield) as a white solid (Ex. 2). Analytical data for Ex. 1 and Ex. 2 can be found in the table below.

[0524] General Method B

[0525] Preparation of (2S)-l-{(10S,117?,17 / 7)-12-ethyl-19-fluoro-8,10,ll-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,ll,12,13-hexahydro-147 / -3,5-ethenotripyrazolo[3,4- / :3',4'- / :4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (Ex. 5) and (25 l-{(107?,ll / ?,17£)-12-ethyl-19-fluoro-8,10,l l-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,l 1,12,13-hexahydro- 1477-3, 5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n] [1,4]oxazacyclopentadecin- 14-yl }propan-2-ol (Ex. 6):

[0526] To a solution of (2S)-l-{(Tl / ?;17E)-19-fluoro-8 / 10Jl-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l, l 2, l3-hexahydro-l47 / -3,5-ethenotripyra7olo|3.4- / ':3’,4’- / ':4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (350 mg, 0.668 mmol, 1 eq) in MeOH (3 mL) was added NaBH₃CN (84.0 mg, 1.34 mmol, 2 eq), acetaldehyde (147 mg, 1.34 mmol, 40% purity, 2 eq) and stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to afford (25)-l-{(10S,ll / ?,17£)-12-ethyl-19-fluoro-8,10,ll-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,11, 12, 13 -hexahydro- 1477-3, 5-ethenotripyrazolo[3,4 / :3',4'-j:4", 3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (15.74 mg, 0.0285 mmol, 5.25% yield as a white solid (Ex. 5) and (25)-l-{(10A,l l / ?,17£')-12-ethyl-19-fluoro-8,10,ll-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4: / :3',4’-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (15.41 mg, 0.0279 mmol, 5.14% yield) as a white solid (Ex. 6). Analytical data for Ex. 5 and Ex. 6 can be found in the table below.

[0527] General Method C

[0528] Preparation of (2 )-l-[(10 / ?,l l / ?,17E)-16-ethoxy-12-ethyl-19-fluoro-8,10,ll-trimethyl-2,8,10,1 l,12,13-hexahydro-14 / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol (Ex. 7) and (2S)-1-[(1OS,11 / ?,17£)-16-ethoxy-12-ethyl-l 9-fluoro-8, 10, 11 -trimethyl-2,8, 10, 11, 12, 13-hexahydro- 1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol (Ex. 12):Pd(OAc)2, TBAC NaHCO3, DMFTFA DCMEx. 12 Ex 7

[0529] Steps 1 -4 were performed in a similar manner to steps 1 -4 of General Method A, using intermediate 1-6-4 in Step 1.

[0530] Step 5 was performed as shown in General Method B to give (2. S')-I-|( I(). S, I I / < I7A)-16-ethoxy-12-ethyl-19-fluoro-8,10, 1 l-trimethyl-2,8,10, 11,12, 13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3',4'; / :4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol (1.09 mg,2.03 pmol, 1.09% yield) as a white solid (Ex. 12) and (2S)-l-[(10 / ?,ll / ?,17E)-16-ethoxy-12-ethyl- 19-fluoro-8, 10, 11 -trimethyl-2,8, 10, 11, 12, 13-hexahydro- 1477-3.5-ethenotripyrazolo[3,4:3',4'-j:4",3"- / / ][l,4]oxazacyclopentadecin-14-yl]propan-2-ol (15.28 mg, 0.0284 mmol, 15.28% yield) as a white solid (Ex. 7). Analytical data for Ex. 12 and Ex. 7 can be found in the example table below.

[0531] General Method D

[0532] Preparation of (2S)-l-{(10T?,ll / ?,17E)-20-fluoro-8,10,ll,12-tetramethyl-16-[(propan-2-yl)oxy]-2,8,10,ll,12,13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4,-j':4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (Ex. 10) and (2S)-l-{ (105,1 l / ?,17E)-20-fluoro-8,10,ll,12-tetramethyl-16-[(propan-2-yl)oxy]-2,8,10,l 1.1243-hexahydro- 14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (Ex. 11):

[0533] Step 1. To a solution of tert-butyl N-[(lR)-2-[4-(7-fluoro-l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)-2-methyl-pyrazol-3-yl]oxy-l-methyl-propyl]carbamate (1.40 g, 2.73 mmol, 1 eq) in DMF (14 mL) was added NaH (163 mg, 4.09 mmol, 60% purity, 1.5 eq) at 0°C. The mixture was stirred at 0 °C for 0.5 hour. Then was added Mel (580 mg, 4.09 mmol, 1.5eq) at 0 °C, and the mixture was stirred at 25°C for 2.5 hours. On completion, the reaction mixture was quenched by addition of NH4CI (30 mL) at 0 °C, and then diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOa, Petroleum ether / Ethyl acetate= 1:0 to 3:1), to give tert-butyl N-[(lR)-2-[4-(7-fluoro-l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)-2-methyl-pyrazol-3-yl]oxy-l-methyl-propyl]-N-methyl -carbamate (1.27 g, 2.41 mmol, 88% yield) as a yellow oil. LCMS: m / z 550.2 (M+l).

[0534] Step 2. To a solution of tert-butyl N-[(lR)-2-[4-(7-fluoro-l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)-2-methyl-pyrazol-3-yl]oxy-l-methyl-propyl]-N-methyl-carbamate (0.60 g, 1.14 mmol, 1 eq) in DCM (6 mL) was added TMSOTf (328 mg, 1.48 mmol, 1.3 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was quenched with water (20 mL) and extracted with DCM (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, to give (2R)-3-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l-methyl-lH-pyrazol-5-yl)oxy)-N-methylbutan-2-amine (545 mg, 1.02 mmol, 90% yield, 80% purity) as a yellow oil. LCMS: m / z 428.2 (M+l).

[0535] Step 3. To a solution of (2R)-3-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l-methyl-lH-pyrazol-5-yl)oxy)-N-methylbutan-2-amine (258 mg, 0.605 mmol, 1 eq) in DMF (5 mL) was added K2CO3 (251 mg, 1.81 mmol, 3 eq) and (S)-l-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-5-(iodomethyl)-3-isopropoxy-lH-pyrazole (375 mg, 0.665 mmol, 1.1 eq). The mixture was stirred at 80 °C for 1 hour. On completion, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOj, Petroleum ether / THF= 1:0 to 3:1), to give (2R)-N-((l-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-lH-pyrazol-5-yl)methyl)-3-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl- 1 H-indazol-5 -yl)- 1 -methyl- 1 H-pyrazol-5 -yl)oxy)-N-methylbutan-2-amine (250 mg, 0.289 mmol, 48% yield) as an off-white oil. LCMS: m / z 864.3 (M+l).

[0536] Step 4. A mixture of (2R)-N-((l-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-4-iodo-3-isopropoxy-lH-pyrazol-5-yl)methyl)-3-((4-(7-fluoro-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-indazol-5-yl)-l-methyl-lH-pyrazol-5-yl)oxy)-N-methylbutan-2-amine (220 mg, 0.255 mmol, 1 eq), NaHCCh (53.5 mg, 0.637 mmol, 2.5 eq), Pd(OAc)2 (11.4 mg, 0.0509 mmol, 0.2 eq) and TBAC (70.8 mg, 0.255 mmol, 1 eq) in DMF (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 130 °C for 1 hour under N2 atmosphere. Oncompletion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue to give (ll / ?,17 )-14-[(2S)-2-{[tert-butyldi(methyl)silyl]oxy}propyl]-20-fluoro-8,10,ll,12-tetramethyl-2-(oxan-2-yl)-16-[(propan-2-yl)oxy]-2,10,l l,12,13,14-hexahydro-877-3,5-ethenotripyrazolo[3,4: / :3',4’-j:4",3"-n][l,4]oxazacyclopentadecine (200 mg, 0.217 mmol, 85% yield, 80% purity) as a brown solid. LCMS: m / z 736.4 (M+l).

[0537] Step 5. To a solution of (11 / ?, 17E)-14-[(2S)-2-{[tert-butyldi(methyl)silyl]oxy}propyl]-20-fluoro-8, 10, 11, 12-tetramethy l-2-(oxan-2-y 1)- 16-[(propan-2-yl)oxy ] -2, 10,11,12,13,14-hexahydro-8H-3,5-ethenotripyrazolo[3,4- / :3',4' / :4",3"-n][ 1,4]oxazacyclopentadecine (200 mg, 0.272 mmol, 1 eq) in MeOH (1 mL) was added cone. HCI / H2O (12.0 M, 0.2 mL, 32.5 eq). The mixture was stirred at 25 °C for Ih. On completion, the mixture was quenched with NaHCO? (50 mL) and extracted with water (30 mL) and DCM (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC to give (2S)-l-{(10 / ?,ll / ?,17£)-20-fluoro-8,10,ll,12-tetramethyl-16-[(propan-2-yl)oxy]-2,8,10,ll,12,13-hexahydro-147 / -3,5-ethenotripyrazolo|3,4; / :3’, 4’; / :4".3"- / z|| l.4|oxazacyclopentadecin- 14-yl }propan-2-ol (2.71 mg, 4.45 pmol, 1.64% yield, 95.91% purity, FA) as a white solid (Ex. 10), and to give (25)-l-{ 110. S, I 1 / 17 / 7)-2O-fl uoro-8, 10, 1 1, 12-tetraniethyl- 16-| (propan-2-y 1 fox y |-2,8, 10, 1 1, 12.13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (12.11 mg, 0.0204 mmol, 7.51% yield, 98.34% purity, FA) as white solid (Ex.11). Analytical data for Ex. 10 and Ex. 11 can be found in the example table below.

[0538] General Method E

[0539] Preparation of (2S)-l-{(10 / ?,ll / ?,17E)-12-ethyl-20-fluoro-8,10,ll-trimethyl-16-[(propan-2-yl)oxy]-2,8,10,l l,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3',4' / :4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (Ex. 13) and (2S)-l-{ (10S, 11R, 17E)-12-ethyl-20-fluoro-8, 10, 11 -trimethyl- 16-[(propan-2-yl)oxy]-2,8, 10, 11, 12, 13-hexahydro-l4 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl}propan-2-ol (Ex.14):General NaH, Etl, DMF Method D Steps 2-5

[0540] Step 1. To a solution of teit-butyl N-[(lR)-2-[4-(7-fluoro-l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)-2-methyl-pyrazol-3-yl]oxy-l-methyl-propyl]carbamate (1.30 g, 2.53 mmol, 1 eq) in DMF (13 mL) was added NaH (202 mg, 5.06 mmol, 60% purity, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. CH3CH2I (592 mg, 3.80 mmol, 0.304 mL, 1.5 eq) was added into the mixture. The mixture was stirred at 25 °C for 1.5 hours. On completion, the mixture was poured into a NH4CI (100 mL) aqueous solution, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1 / 0 to 80 / 20) to give tert-butyl N-ethyl-N-[(lR)-2-[4-(7-fluoro-l-tetrahydropyran-2-yl-3-vinyl-indazol-5-yl)-2-methyl-pyrazol-3-yl]oxy-l-methyl-propyllcarbamate (900 mg, 1.66 mmol, 66% yield) as a yellow oil.

[0541] Ex. 13 and Ex. 14 were obtained using the above intermediate following steps 2-5 as outlined in General Method D. Analytical data is shown in the example table below.

[0542] General Method F

[0543] Preparation of ( 17E)-7, 12, 14-trimethyl-2, 10, 11, 12, 13, 14-hexahydro-7 H-5, -(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-72][l,4]oxazacyclopentadecine (Ex. 17):TMSOTf, DCM

[0544] Step 1. To a solution of tert-butyl methyl(2-((l-methyl-4-(l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethyl)carbamate (420 mg, 0.870 mmol, 1 eq) in DCM (4 mL) was added TMSOTf (290. mg, 1.31 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the mixture the was adjusted to pH~7 with a saturated solution of NaHCO. and extracted with water (20 mL) and DCM (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound N-methyl-2-((l-methyl-4-(l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethan-l-amine (285 mg, 0.745 mmol, 86% yield) as a yellow oil. LCMS: m / z 383.3 (M+l).

[0545] Step 2. To a solution of N-methyl-2-((l-methyl-4-(l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethan-l-amine (285 mg, 0.745 mmol, 1 eq) in DMF (4 mL) was added K3PO4 (474 mg, 2.24 mmol, 3 eq) and 5-(bromomethyl)-4-iodo-l-methyl-lH-pyrazole (224 mg, 0.745 mmol, 1 eq). The mixture wasstirred at 60 °C for 1 hour. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2, Petroleum ether / THF= 1:0 to 0: 1 ) to give compound N-((4-iodo-1 -methyl-1 H-pyrazol-5-yl)methyl)-N-methyl-2-((l -methyl-4-(l -(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethan-l-amine (370 mg, 0.614 mmol, 82% yield) as a yellow oil. ’H NMR (400 MHz, CDCh) 3 = 8.31 (s, 1H), 8.00 -7.80 (m, 1H), 7.40 (s, 1H), 7.03 - 6.96 (m, 1H), 6.11 (dd, J = 0.8, 18.0 Hz, 1H), 5.78 (dd, J = 2.4, 8.8 Hz, 1H), 5.55 (d, J = 11.6 Hz, 1H), 4.50 (t, 7= 5.6 Hz, 2H), 4.11 - 3.98 (m, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.67 (s, 2H), 2.97 (t, 7 = 5.6 Hz, 2H), 2.34 (s, 3H), 1.84 - 1.67 (m, 4H), 1.44 (s, 4H); LCMS: m / z 603.0 (M+l).

[0546] Step 3. A mixture of N-((4-iodo-l-methyl-lH-pyrazol-5-yl)methyl)-N-methyl-2-((l-methyl-4-(l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethan-l -amine (100 mg, 0.166 mmol, 1 eq), TBAC (46.1 mg, 0.166 mmol, 1 eq), NaHCOs (34.9 mg, 0.415 mmol, 2.5 eq) and Pd(OAc)2 (7.45 mg, 0.0332 mmol, 0.2 eq) in DMF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 130 °C for 16 hours under N2 atmosphere. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:0 to 0:1) to give compound (17£)-7,12,14-trimethyl-2-(oxan-2-yl)-2,10,l l,12,13,14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-zz][l,4]oxazacyclopentadecine (45.0 mg, 0.0948 mmol, 57% yield) as a yellow oil. LCMS: m / z 475.2 (M+l).

[0547] Step 4. To a solution of (17E)-7,12,14-trimethyl-2-(oxan-2-yl)-2,10,l l,12,13,14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-n][l,4]oxazacyclopentadecine (40.0 mg, 0.0842 mmol, 1 eq) in DCM (0.3 mL) was added TFA (153 mg, 1.35 mmol, 0.1 mL, 16 eq). The mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was adjusted to pH~7 with a saturated solution of NaHCOs, followed by extraction with water (20 mL) and DCM (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate filtered and concentrated to give a residue. The residue was purified by prep-HPLC to give compound (17E)-7,12,14-trimethyl-2,10,ll,12,13,14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-zi][l,4]oxazacyclopentadecine (1.82 mg, 0.00446 mmol, 5.29% yield, 95.6% purity) as a whitesolid. Analytical data shown in the example table below.

[0548] General Method G

[0549] Preparation of (17£')-6,7,12,14,20-pentamethyl-2,10,ll,12,13,14-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine (Ex. 18):

[0550] Step 1. To a solution of tert-butyl (2-((l,5-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (450 mg, 0.881 mmol, 1 eq) in DCM (10 mL) was added ZnBi'2 (1.19 g, 5.29 mmol, 6 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was partitioned between dichloromethane (5 mL x 3) and water (5 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 2-((l,5-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)-N-methylethan-l-amine (360 mg, 0.876 mmol, 99% yield) as a yellow oil. LCMS: m / z 411.2 (M+l).

[0551] Step 2 was performed following the procedure outlined Step 2 of General Method F, with a reaction time of 2 hours.

[0552] Step 3 was performed following the procedure outlined Step 2 of General Method F,with a reaction time of 1 hour.

[0553] Step 4. To a solution of (17£)-6,7,12,14,20-pentamethyl-2-(oxan-2-yl)-2,10,1 l,12,13,14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4:3',4'-j:4",3"-n][l,4]oxazacyclopentadecine (20.0 mg, 0.0397 mmol, 1 eq) in DCM (2 mL) was added HCl / dioxane (2 M, 60 pL, 3 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by prep-HPLC to give (17£')-6,7,12,14,20-pentamethyl-2,10,ll,12,13,14-hexahydro-7 / / -5,3-(azenometheno)tripyrazolo[3,4: / :3',4' / :4",3"-n][l,4]oxazacyclopentadecine (1.82 mg, 0.00392 mmol, 9.85% yield, FA) as a white solid. Analytical data shown in the example table below.

[0554] General Method H

[0555] Preparation of (ll / ?,17E)-6,7,ll,12,14,20-hexamethyl-2,10,ll,12,13,14-hexahydro-7 / / -5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-nJ[l,4Joxazacyclopentadecine (Ex. 19):TMSOTf, 2,6-lutidine - ► DCMPd(OAc)2, TBAC1-6-5NaHCO3, DMF K3PO4, DMF

[0556] Step 1. To a solution of tert-butyl N- [( 1 R)-2 - [ 1, 5-di methyl-4-(7 -methyl- 1 -tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl] oxy-l-methyl-ethyl]-N-methyl-carbamate (750 mg, 1.43 mmol, 1 eq) in DCM (7 mL) was added TMSOTf (2.86 mmol, 516 pL, 2 eq and 2,6-lutidine (2.86 mmol, 332 pL, 2 eq). The mixture was stirred at 0 °C for 10 minutes. On completion, the reaction mixture was quenched by addition of H2O (50 mL) at 25 °C, and then extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (2R)-l-[l,5-dimethyl-4-(7-methyl-l-tetrahydropyran-2-yl-3-vinyl-pyrazolo [3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-2-amine (600 mg, 1.41 mmol, 98% yield) as a yellow solid. LCMS: m / z 425.1 (M+l).

[0557] Steps 2-4 were performed following a similar procedure as outlined in steps 2-4 in General Method G to afford (117?,17E)-6,7,ll,12,14,20-hexamethyl-2,10,ll,12,13,14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4' / ':4",3"-n][l,4]oxazacyclopentadecine (13.7 mg, 0.0301 mmol, 22% yield, 95% purity) as a white solid. Analytical data shown in the example table below.

[0558] General Method I

[0559] Preparation of (llR,17£)-20-methoxy-7,ll,12,14-tetramethyl-2,10,l l,12,13,14-hexahydro-7H-3,5-ethenodipyrazolo[3,4; / :3',4' / ][L2,3]triazolo[4,5-n][l,4]oxazacyclopentadecine (Ex. 22):cone. HCI / H2O, MeOHHN-N EX. 22

[0560] Steps 1-3 were performed following the procedure described in steps 1-3 for General Method F, using intermediate 1-3-8 as the staring material in Step 1.

[0561] Step 4. To a solution of (ll / ?,17E)-20-methoxy-7,ll,12,14-tetramethyl-2-(oxan-2-yl)-2,10,ll,12,13,14-hexahydro-7H-3,5-ethenodipyrazolo[3,4;:3',4'- / ][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecine(100 mg, 0.193 mmol, 1 eq) in MeOH (2.1 mL) was added cone. HCl / HsO (12 M, 500 pL, 31.1 eq). 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 prep-HPLC to give ( 11 / ?, 17£’)-20-methoxy-7, 11, 12, 14-tetramethyl-2, 10, 11, 12, 13, 14-hexahydro-7 / 7-3,5-ethenodipyrazolo[3,4: / :3',4' / ][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecine (6.14 mg, 0.0137 mmol, 7.12% yield, 97.18% purity) as a yellow solid. Analytical data shown in the example table below.

[0562] General Method J

[0563] Preparation of (3 / ?,4S)-4-[(10S,17E’)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4", 3"- 7i][l,4]oxazacyclopentadecin-14-yl]oxolan-3-ol (Ex. 29) and (3S,42?)-4-[(10S,17. E)-16-ethoxy-6,8, 10, 12,20-pentamethyl-2,8, 10, 11, 12, 13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]oxolan-3-ol (Ex. 30):Pd(OAc)2, TBAC, NaHCO3DMFHN-NEx. 29

[0564] Step 1. To a solution of (2S)-2-((l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-5-yl)oxy)-N-methylpropan-l-amine (1.20 g, 2.83 mmol, 1 eq) in DMF (20 mL) was added K3PO4 (1.80 g, 8.49 mmol, 3 eq) and 1-((3S,4R)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-lH-pyrazole (1.80 g, 3.11 mmol, 1.1 eq). The mixture was stirred at 60 °C for 2 hours. On completion, the reaction mixture was partitioned between ethyl acetate (60 mL x 3) and water (80 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by columnchromatography (SiCL, Petroleum ether / Ethyl acetate= 1:0 to 0:1) to give (2S)-N-((1-((3S,4R)- 4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-2-((l,3-dimethyl-4-(7 -methyl- l-(tetrahydro-2H-pyran-2-yl)-3- vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-5-yl)oxy)-N-methylpropan-l-amine (1.60 g, 1.43 mmol, 50% yield, 78% purity) as a yellow oil. LCMS: m z 875.5 (M+l).

[0565] Step 2. A mixture of (2S)-N-((l-((3S,4R)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-2-((l,3-dimethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin- 5-yl)-lH-pyrazol-5-yl)oxy)-N-methylpropan-l-amine (900 mg, 1.03 mmol, 1 eq), Pd(OAc)2 (23.0 mg, 0.102 mmol, 0.1 eq), NaHCCh (259 mg, 3.09 mmol, 3 eq) and TBAC (285 mg, 1.03 mmol, 1 eq) in DMF (9 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hours under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 100 / 1 to 0 / 1) to give (10S,17E -14-(4-{[tert-butyldi(methyl)silyl]oxy}oxolan-3-yl)-16-ethoxy-6,8,10,12,20-pentamethyl-2-(oxan-2-yl)-2,10, 11, 12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-n][l,4]oxazacyclopentadecine (550 mg, 0.544 mmol, 52% yield) as a yellow oil. LCMS: m / z 747.7 (M+l)

[0566] Step 3. To a solution of (10S,17£ -14-(4-{[tert-butyldi(methyl)silyl]oxy}oxolan-3-yl)-16-ethoxy-6,8, 10, 12,20-pentamethyl-2-(oxan-2-yl)-2, 10, 11, 12, 13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4: / :3',4' / :4",3"- / z][l,4]oxazacyclopentadecine (550 mg, 0.736 mmol, 1 eq) in DCM (1 mL) was added HCl / MeOH (2 M, 368 pL, 1 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give a mixture of diastereomers (350 mg, 0.586 mmol, 79% yield, 92% purity) as a white solid. LCMS: m / z 549.3 (M+l). The mixture was further purified by reversed-phase SFC to give (3R,45)-4-[(105,17£)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-7z][l,4]oxazacyclopentadecin-14-yl]oxolan-3-ol (23.53 mg, 0.0418 mmol, 6.56% yield, 97.56% purity) as a white solid (Ex. 29) and (35,47?)-4-[(105,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro- 14 / 7-5, 3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]oxolan-3-ol (29.68 mg, 0.0538 mmol, 8.37% yield, 98.68% purity) as a white solid (Ex. 30). Analytical data shown in the example table below.

[0567] General Method K

[0568] Preparation of (25)-2-[(105,17 / y)-16-ethoxy-7, 10, 12, 20-tetramethyl-2, 7,10,11,12,13-hexahydro-14 / 7-5,3-(azenometheno)dipyrazolo[3,4- / :3',4’-j][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (Ex. 41):THP

[0569] Step 1. To a solution of tert-butyl methyl((2S)-2-((2-methyl-5-(7-methyl-l- (tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-2H-l,2,3-triazol-4-yl)oxy)propyl)carbamate (260 mg, 0.508 mmol, 1 eq) in DCM (4 mL) was added TMSOTf (158 mg, 0.711 mmol, 1.4 eq) and 2,6-dimethylpyridine (65.3 mg, 0.609 mmol, 1.2 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was filtered and concentrated to give (S)-N-methyl-2-((2-methyl-5-(7-methyl-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-2H-l,2,3-triazol-4-yl)oxy)propan-l-amine (160 mg, 0.488 mmol, 96% yield)as a yellow solid. LCMS: m / z 747.7 (M+l).

[0570] Step 2. To a solution of (S)-N-methyl-2-((2-methyl-5-(7-methyl-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-2H-l,2,3-triazol-4-yl)oxy)propan-l-amine (160 mg, 0.488 mmol, 1 eq) in THF (5 mL) was added DIEA (189 mg, 1.47 mmol, 3 eq) and (S)-l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-5-(iodomethyl)-l H-pyrazole (295 mg, 0.537 mmol, 1.1 eq). The mixture was stirred at 25 °C for 12 hours. On completion, the mixture was 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 (S)-N-((l-((S)-l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-N-methyl-2-((2-methyl-5-(7 -methyl-3-vinyl- 1 H-pyrazolo [3,4-c]pyridin-5 -yl)-2H- 1,2,3-triazol-4-yl)oxy)propan-l -amine (260 mg, 0.346 mmol, 71% yield) as a yellow solid.!H NMR (400 MHz, CDCE) 5 = 10.92 - 10.34 (m. 1H), 8.52 (s, 1H), 7.33 - 7.14 (m, 1H), 6.33 (d, J = 18.0 Hz, 1H), 5.84 (d, J= 11.6 Hz, 1H), 5.27 - 5.13 (m, 1H), 4.86 - 4.74 (m, 1H), 4.50 - 4.39 (m, 2H), 4.31 (s, 3H), 3.88 (t, 7 = 9.6 Hz, 1H), 3.76 - 3.57(m, 2H), 3.07 (s, 3H), 2.51 (s, 3H), 1.62 (d, 7= 2.4 Hz, 3H), 1.61 - 1.58 (m, 3H), 1.58 - 1.54 (m, 3H), 1.42 (d, 7= 6.8 Hz, 3H),0.94 (s, 9H), 0.08 (s, 3H), 0.00 (s, 3H).

[0571] Step 3. To a solution of (S)-N-((l-((S)-l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-N-methyl-2-((2-methyl-5-(7-methyl-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-2H-l,2,3-triazol-4-yl)oxy)propan-l-amine (260 mg, 0.346 mmol, 1 eq) in DCM (4 mL) was added DHP (87.5 mg, 1.04 mmol, 3 eq) and PPTS (17.4 mg, 0.0693 mmol, 0.2 eq). The mixture was stirred at 40 °C for 12 hours. On completion, the mixture was 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 (2S)-N-((l-((S)-l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-N-methyl-2-((2-methyl-5-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-2H-l,2,3-triazol-4-yl)oxy)propan-l -amine (260 mg, 0.311 mmol, 89% yield) as a yellow oil. LCMS: m / z 834.4 (M+l).

[0572] Step 4. A mixture of (2S)-N-((l-((S)-l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-N-methyl-2-((2-methyl-5-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-2H-l,2,3-triazol-4-yl)oxy)propan-l-amine (240 mg, 0.287 mmol, 1 eq), Pd(OAc)2 (6.46 mg, 0.0287 mmol, 0.1 eq), TBAC (119 mg, 0.431 mmol, 1.5 eq) and NaHCOg (60.4 mg, 0.719 mmol, 2.5 eq) in DMF (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 130 °C for 1 hour under N2 atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (5 mL x 3) and water (5 mL), and the combined organic phase was dried over anhydroussodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / THF= 1:0 to 0:1) to give ( l()1S’,l7,)-l4-|(2. S’)-l-{| / tj / 7-butyldi(methyl)silyl]oxy}propan-2-yl]-16-ethoxy-7,10,12,20-tetramethyl-2-(oxan-2-yl)- 2, 10, 11, 12,13,14-hexahydro-7H-5,3-(azenometheno)dipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecine (115 mg, 0.162 mmol, 56% yield) as a yellow oil. LCMS: m / z 706.5 (M+l)

[0573] Step 5. To a solution of (10S,17E)-14-[(25)-l-{[te / 't-butyldi(methyl)silyl]oxy}propan- 2-yl] - 16-ethoxy-7, 10, 12,20-tetramethyl-2-(oxan-2-yl)-2, 10, 11,12, 13, 14-hexahydro-7H-5,3- (azenometheno)dipyrazolo[3,4- / :3',4'-j] [ 1,2,3]triazolo[4,5-n] [ 1,4]oxazacyclopentadecine ( 100 mg, 0.141 mmol, 1 eq) in DCM (3 mL) was added HCl / dioxane (2 M, 0.566 mL, 10 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by prep-HPLC to give (25)-2- [(105, 17£)- 16-ethoxy-7, 10, 12,20-tetramethyl-2,7, 10, 11, 12, 13-hexahydro- 14H-5,3- (azenometheno)dipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (34.43 mg, 0.0638 mmol, 45.01% yield, 94% purity, FA) as a yellow solid. Analytical data shown in the example table below.

[0574] General Method L

[0575] Preparation of (25)-2-[(105,17E)-16-ethoxy-8,10,12,20-tetramethyl-2,8,10,ll,12,13-hexahydro-14 / 7-5,3-(azenometheno)dipyrazolo[3,4- / :3',4’-j][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (Ex. 43):HN'NEx. 43

[0576] Step 1. A mixture of tert-butyl methyl((2S)-2-((l-methyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-l,2,3-triazol-5-yl)oxy)propyl)carbamate (350 mg, 0.684 mmol, 1 eq) in DCM (4 mL) at 0 °C was added TFA (2.69 g, 23.5 mmol, 1.75 mL, 34.4 eq) and then the mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was concentrated under reduced pressure to give (2S)-N-methyl-2-((l-methyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-l,2,3-triazol-5-yl)oxy)propan-l-amine (300 mg, 0.509 mmol, crude, TFA) as a yellow oil.

[0577] Step 2. To a mixture of (2S)-N-methyl-2-((l-methyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-l,2,3-triazol-5-yl)oxy)propan-l-amine (250 mg, 0.424 mmol, 1 eq, TFA) in DMF (5 mL) was added K3PO4 (270 mg, 1.27 mmol, 3 eq), (S)-l-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-5-(iodomethyl) -IH-pyrazole (350 mg, 0.637 mmol, 1.5 eq,) at 25 °C, and then the mixture was stirred at 60 °C for 0.5 hour. On completion, to the mixture was added water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried with anhydrous NaaSOzi, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiOa, THF / DCM: 0% to 100%) to give (2S)-N-((1-((S)-l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-N-methyl-2-((l-methyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-l,2,3-triazol-5-yl)oxy)propan-l-amine (110 mg, 0.0989 mmol, 23% yield, 75% purity) as a yellow oil. H NMR (400 MHz, CDCh) 5 = 8.45 (s, 1H), 7.20 (dd, 7= 11.2, 17.6 Hz, 1H), 6.30 (d, 7= 17.6 Hz, 1H), 5.98 (dd, 7= 2.4, 9.2 Hz, 1H), 5.78 (d, 7 = 11.6 Hz, 1H), 4.78 - 4.62 (m, 2H), 4.33 - 4.19 (m, 2H), 4.09 - 4.03 (m, 5H), 3.61 - 3.48 (m, 2H), 3.22 (s, 3H), 3.11 (s, 3H), 2.79 - 2.69 (m. 2H), 2.29 (d, 7 = 4.8 Hz. 3H), 1.98 - 1.84 (m, 5H), 1.48 -1.45 (m, 9H), 0.94 (s, 9H), 0.09 (s, 3H), 0.00 (s, 3H); LCMS: m / z 834.5 (M+l).

[0578] Step 3. To a solution of (2S)-N-((l-((S)-l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-ethoxy-4-iodo-lH-pyrazol-5-yl)methyl)-N-methyl-2-((l-methyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-viny 1- 1 H-pyrazolo [3,4-c]pyridin-5 -yl)- 1 H- 1,2,3-triazol-5 -yl)oxy)propan- 1 -amine (60.0 mg, 0.0719 mmol, 1 eq) in DMF (1 mL) was added NaaCCL (30.5 mg, 0.287 mmol, 4 eq), and Pd(dppf)Ch (10.5 mg, 0.0143 mmol, 0.2 eq) at 25 °C under N2. The mixture was stirred at 85 °C for 16 hours. On completion, to the mixture was added water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give ( 105, 1 IE)- 14-[(25)- 1 -{ [terLbutyldi(methyl)silyl]oxy}propan-2-yl]-16-ethoxy- 8.10.12.20-tetramethyl-2-(oxan-2-yl)-2,10,ll,12,13,14-hexahydro-8 / 7-5,3-(azenometheno)dipyrazolo[3,4-:3',4'-j][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecine (60.0 mg, 0.0229 mmol, 32% yield, 27% purity) as a yellow oil. LCMS: m / z 706.5 (M+l).

[0579] Step 4. ( 105, 17E)-14-[(25)-l-{[tert-butyldi(methyl)silyl]oxy }propan-2-yl ]-16-ethoxy- 8.10.12.20-tetramethyl-2-(oxan-2-yl)-2, 10, 11, 12, 13,14-hexahydro-877-5,3-(azenometheno)dipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5- / i][l,4]oxazacyclopentadecine (60.0 mg, 0.0229 mmol, 1 eq) in DCM (3 mL) was added TFA (414 mg, 3.63 mmol, 0.27 mL, 158 eq) at 25 °C. The mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was quenched by addition of saturated sodium bicarbonate solution (50 mL) at 25 °C, and then diluted with DCM (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over NaiSO-t, filtered and concentrated under reduced pressure to give a residue. The product was purified by Prep-HPLC to give (25) -2- [( 105, 17E)- 16-ethoxy-8, 10, 12,20-tetramethyl-2,8, 10, 11, 12, 13-hexahydro- 14H-5.3-(azenometheno)dipyrazolo [3,4- / : 3',4'-j] [ 1,2,3]triazolo 14, 5 - / / ] 1 1,4]oxazacyclopentadecin-14-yl]propan-l-ol (5.03 mg, 0.00899 mmol, 39.20% yield, 99% purity, FA) as a yellow solid. Analytical data shown in the example table below.

[0580] General Method M

[0581] Preparation of (11S,17E)-7,1 l,12,14,20-pentamethyl-2,10,l l,12,13,14-hexahydro-7H- 5.3-(azenometheno)dipyrazolo[3,4-j:4',3'-n][l,2,3]triazolo[4,5- / ][l,4]oxazacyclopentadecine (Ex. 45):K2CO3Pd(dtbpf)CI2CPME

[0582] Step 1. To a solution of tert-butyl methyl((2S)-l-((l-methyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)propan-2-yl)carbamate (55.0 mg, 0.108 mmol, 1 eq) in DCM (0.5 mL) was added HCl / dioxane (2 M, 0.0539 mL, 1 eq) and stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give (S)-N-methyl-l-((l-methyl-4-(7-methyl-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)propan-2-amine (35.0 mg, 0.107 mmol, 100% yield) as ayellow oil. LCMS: m / z 327.2 (M+l).

[0583] Step 2. To a solution of (S)-N-methyl-l-((l-methyl-4-(7-methyl-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)propan-2-anrine (35.0 mg, 0.0965 mmol, 1 eq, HC1) in THF (1 mL) was added DIEA (49.9 mg, 0.386 mmol, 4 eq), 4-bromo-5-(bromomethyl)-l-methyl-lH-l,2,3-triazole (24.6 mg, 0.0965 mmol, 1 eq) and Nal (14.5 mg, 0.0965 mmol, 1 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiOj, PE: THF = 1:1) to give (S)-N-((4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)methyl)-N-methyl-l-((l-methyl-4-(7-methyl-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)propan-2-amine (40.0 mg, 0.0799 mmol, 83% yield) as a blue oil. LCMS: m / z 500.3 (M+l).

[0584] Step 3. To a solution of (S)-N-((4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)methyl)-N-methyl-l-((l-methyl-4-(7-methyl-3-vinyl-lH-pyrazolo[3,4-cJpyridin-5-yl)-lH-pyrazol-3-yl)oxy)propan-2-amine (35.0 mg, 0.0699 mmol, 1 eq) in DCM (0.5 mL) was added DHP (17.7 mg, 0.210 mmol, 3 eq) and PPTS (1.76 mg, 0.00699 mmol, 0.1 eq). The mixture was stirred at 40 °C for 24 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: THF = 1:1) to give (2S)-N-((4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)methyl)-N-methyl-l-((l-methyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)propan-2-amine (20.0 mg, 0.0342 mmol, 49% yield) as a brown oil. LCMS: m / z 584.1 (M+l).

[0585] Step 4. A mixture of (2S)-N-((4-bromo-l -methyl- 1H- 1,2, 3-triazol-5-yl)methyl)-N-methyl- 1 -(( 1 -methyl-4-(7 -methyl- 1 -(tetrahydro-2H-pyran-2-yl)-3-vinyl- 1 H-py razolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)propan-2-amine (15.0 mg, 0.0257 mmol, 1 eq), K2CO3 (31.9 mg, 0.231 mmol, 9 eq), Pd(dtbpf)Cl2(3.35 mg, 0.00513 mmol, 0.2 eq) in CPME (0.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 16 h under N2 atmosphere. On completion, the mixture was quenched with water (2 mL) and extracted with EA (2 mLx3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give (115,17E)-7,ll,12,14,20-pentamethyl-2-(oxan-2-yl)-2,10,ll,12,13,14-hexahydro-7 / 7-5,3-(azenometheno)dipyrazolo[3,4 / :4',3'-n][l,2,3]triazolo[4,5- / ][l,4]oxazacyclopentadecine (12.0 mg, 0.0238 mmol, 93% yield) as a black solid. LCMS: m / z 504.3 (M+l).

[0586] Step 5. To a solution of (HS,17£)-7,ll,12,14,20-pentamethyl-2-(oxan-2-yl)-2,10,ll,12,13,14-hexahydro-7H-5,3-(azenometheno)dipyrazolo[3,4-j:4',3'-n][l,2,3]triazolo[4,5- / |[l,4]oxazacyclopentadecine (7.00 mg, 0.0139 mmol, 1 eq) in DCM (0.5 mL) was added TFA (0.1 mL, 1.35 mmol, 97 eq). The mixture was stirred at 25 °C for 1 h. Oncompletion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC to give (llS,17E)-7,ll,12,14,20-pentamethyl-2,10,ll,12,13,14-hexahydro-7H-5,3-iazenoiiietheno)dipyrazolo|3,4 / ':4',3'-n|| l.2.3|triazolo|4,5 ]| l,4|oxazacyclopentadecine (0.31 mg, 0.74 pmol, 5.32% yield) as a white solid. Analytical data shown in the example table below.

[0587] General Method N

[0588] Preparation of (17E)-7-ethyl-12,14,20-trimethyl-2,10,ll,12,13,14-hexahydro-7 / / -5,3-(azenometheno)tripyrazolo[3,4 / :3',4' / :4",3"-n][l,4]oxazacyclopentadecine (Ex. 46):

[0589] Step 1. To a solution of tert-butyl (2-((l-ethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethyl)(methyl)carbamate (360 mg, 0.705 mmol, 1 eq) in DCM (2.1 mL) was added HCl / dioxane (2 M, 4.32 mL, 12.2 eq) and stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated to give 2-((l-ethyl-4-(7 -methy 1-3-vinyl- 1 H-pyrazolo [3,4-c]pyridin-5 -yl)- 1 H-pyrazol-3-y l)oxy)-N -methylethan-1 -amine (255 mg, 0.703 mmol, 99% yield, HC1) as a yellow solid. LCMS: m / z327.2 (M+l).

[0590] Step 2. To a solution of 2-((l-ethyl-4-(7-methyl-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)-N-methylethan-l-amine (255 mg, 0.702 mmol, 1 eq, HC1) in THF (4 mL) was added DIEA (272 mg, 2.11 mmol, 3 eq) and 5-(bromomethyl)-4-iodo-l-methyl-IH-pyrazole (232 mg, 0.773 mmol, 1.1 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 (SiO;, PE: THF= 1:0 to 2:1) to give 2-((l-ethyl-4-(7-methyl-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)-N-((4-iodo-l-methyl-lH-pyrazol-5-yl)methyl)-N-methylethan-l -amine (200 mg, 0.366 mmol, 52% yield) as a white solid. LCMS: wz / z 547.1 (M+l).

[0591] Step 3. To a solution of 2-((l-ethyl-4-(7-methyl-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)-N-((4-iodo-l-methyl-lH-pyrazol-5-yl)methyl)-N-methylethan-l-amine (200 mg, 0.366 mmol, 1 eq) in DCM (2 mL) was added DHP (154 mg, 1.83 mmol, 5 eq) and PPTS (18.4 mg, 0.0732 mmol, 0.2 eq). The mixture was stirred at 40 °C for 48 h. On completion, the mixture was purified by column chromatography f SiOj, PE: THF=l:0 to 2:1) to give 2-((l-ethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)-N-((4-iodo-l-methyl-lH-pyrazol-5-yl)methyl)-N-methylethan-1 -amine (130 mg, 0.206 mmol, 56 % yield) as a colorless oil. LCMS: m / z 631.2 (M+l).

[0592] Step 4. A mixture of 2-((l-ethyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)-N-((4-iodo-l-methyl-lH-pyrazol-5-yl)methyl)-N-methylethan-l -amine (112 mg, 0.177 mmol, 1 eq), NaHCOa (37.3 mg, 0.444 mmol, 2.5 eq), TBAC (49.4 mg, 0.177 mmol, 1 eq) and Pd(OAc)2 (3.99 mg, 0.0177 mmol, 0.1 eq) in DMF (2.2 mL) 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 mixture was quenched with water (20 mL) and extracted with EA (15 mL x 3), and the combined organic layers were washed with brine (15 mLx 2), dried over Na2SO4, filtered and concentrated to give (17E)-7-ethyl- 12, 14,20-trimethyl-2-(oxan-2-yl)-2, 10, 11, 12, 13,14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-n][l,4]oxazacyclopentadecine (100 mg, crude) as a brown oil. LCMS: m / z 503.4 (M+l).

[0593] Step 5. To a solution of (17E')-7-ethyl-12,14,20-trimethyl-2-(oxan-2-yl)-2, 10, 11, 12, 13, 14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-zz][l,4]oxazacyclopentadecine (80.0 mg, 0.159 mmol, 1 eq in DCM (0.5 mL) was added TFA (5.38 mmol, 0.4 mL, 33.8 eq. 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 prep-HPLC to give(17E’)-7-ethyl-12,14,20-trimethyl-2,10,ll,12,13,14-hexahydro-77 / -5,3- (azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"- / i][l,4]oxazacyclopentadecine (13.95 mg, 0.0331 mmol, 20.81% yield, 99.38% purity) as a yellow solid. Analytical data shown in the example table below.

[0594] General Method O

[0595] Preparation of (17E)-7-cyclobutyl-12,14,20-trimethyl-2,10,ll,12,13,14-hexahydro- 7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-n][l,4]oxazacyclopentadecine (Ex. 49):ZnBr2, DCM✓ N-NTHPK2CO3Pd(dtbpf)CI2CPMEK3PO4, DMFTFA DCM

[0596] Steps 1 and 2 were performed following the procedure outlined in steps 1 and 2 of General Method G, using intermediate 1-3-19 as the starting material in Step 1.

[0597] Step 3. A mixture of 2-((l-cyclobutyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl- 1 H-pyrazolo[3,4-c]pyridin-5 -yl)- 1 H-pyrazol-3-yl)oxy)-N-((4-iodo- 1 -methyl- 1 H-pyrazol-5-yl)methyl)-N-methylethan-l-amine (50.0mg, 0.0761 mmol, 1 eq), K2CO (94.7 mg, 0.685 mmol, 9 eq), Pd(dtbpf)Cl2(9.93 mg, 0.0152 mmol, 0.2 eq) in CPME (2.5 mL) wasdegassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 16 hours under N2 atmosphere. On completion, the mixture was diluted with water (8 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was washed with a saturated sodium chloride solution (3 mL x 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 (2 g silica gel, EA in Petroleum ether from 0% to 100%) to give (17E)-7-cyclobutyl-12,14,20-trimethyl-2-(oxan-2-yl)-2, 10, 11, 12, 13, 14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4; / :3',4' / :4",3"- / z][l,4]oxazacyclopentadecine (15.0 mg, 0.0204 mmol, 27% yield, 72% purity) as a brown solid. LCMS: m / z 529.3 (M+l).

[0598] Step 4. To a solution of (17£)-7-cyclobutyl-12,14,20-trimethyl-2-(oxan-2-yl)-2,10,ll,12,13,14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine (10.0 mg, 0.0189 mmol, 1 eq) in DCM (1 mL) was added TFA (307 mg, 2.69 mmol, 0.2 mL, 142 eq). The mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was purified by Prep-HPLC to give (17£’)-7-cyclobutyl-12,14,20-trimethyl-2,10,11, 12, 13, 14-hexahydro-7H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine (4.91 mg, 0.00998 mmol, 52.7% yield, 90.3% purity) as a yellow solid. Analytical data shown in the example table below.

[0599] General Method P

[0600] Preparation of (nEl^Jd^O-trimethyl^ JOJhlSJd-hexahydro-S^-(azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,4]dioxacyclopentadecino[6,7-c?][l,2,3]triazole (Ex. 52):TFA, DCM

[0601] Step 1. To a solution of 5-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-l-methyl-lH-pyrazol-4-yl)-7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridine (2.00 g, 4.02 mmol, 1 eq) in DMSO (20 mL) was added CsF (3.05 g, 20.1 mmol, 5 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 2-((l-methyl-4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethan-l-ol (1.50 g, 3.91 mmol, 97.3% yield) as a white solid, which was used in the next step without further purification. LCMS: m / z 384.2 (M+l).

[0602] Step 2. To a solution of 2-((l-methyL4-(7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridin-5-yl)-lH-pyrazol-3-yl)oxy)ethan-l-ol (500 mg, 1.30 mmol, 1 eq) in THF (5 mL) was added dropwise NaH (78.2 mg, 1.96 mmol, 60% purity, 1.5 eq) at 0 °C. After addition, the mixture was stirred at this temperature for 30 mins, and then 4-bromo-5-(bromomethyl)-l-methyl-lH-l,2,3-triazole (399 mg, 1.56 mmol, 1.2 eq) in THF (1 mL) wasadded dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was triturated with EA (2 mL) at 25 °C for 5 mins. The mixture was filtered and concentrated to give a residue. The erode product was triturated with H2O (50 mL) at 30 °C for 25 mins to give 5-(3-(2-((4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)methoxy)ethoxy)-l-methyl-lH-pyrazol-4-yl)-7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridine (330 mg, 0.591 mmol, 45% yield) as a white solid. LCMS: m / z 559.1 (M+l).

[0603] Step 3. To a solution of 5-(3-(2-((4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)methoxy)ethoxy)-l-methyl-lH-pyrazol-4-yl)-7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-vinyl-lH-pyrazolo[3,4-c]pyridine (200 mg, 0.358 mmol, 1 eq) in methoxycyclopentane (10 mL) was added Pd(dtbpf)Ch (46.7 mg, 0.0717 mmol, 0.2 eq) and K3PO4 (456 mg, 2.15 mmol, 6 eq). The mixture was stirred at 130 °C for 2 hours. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOa, DCM / MeOH= 1:0 to 10: 1) to give ( 17£)-7, 14,20-trimethyl-2-(oxan-2-yl)-2,7, 10, 11, 13, 14-hexahydro-5,3-(azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,4]dioxacyclopentadecino[6,7-ri][l,2,3]triazole (38.0 mg, 0.0797 m mol, 22% yield) as a brown solid. LCMS: in / z 477.3 (M+l).

[0604] Step 4. To a solution of (17£)-7,14,20-trimethyl-2-(oxan-2-yl)-2,7,10.11,13,14-hexahydro-5,3-(azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,4]dioxacyclopentadecino[6,7-ri][l,2,3]triazole (38.0 mg, 0.0797 mmol, 1 eq) in DCM (2 mL) was added TEA (5.38 mmol, 0.4 mL, 67.5 eq). The mixture was stirred at 25 °C for 0.1 h. On completion, the mixture was filtered and concentrated to give a residue. The crude product was purified by reversed-phase HPLC to give (17£')-7,14,20-trimethyl-2,7,10,ll,13,14-hexahydro-5,3-(azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,4]dioxacyclopentadecino[6,7-ri][l,2,3]triazole (11.08 mg, 0.02824 mmol, 35.41% yield) as an off-white solid. Analytical data shown in the example table below.

[0605] General Method Q

[0606] Preparation of (10S,17E)-7,10,14,20-tetramethyl-2,ll,12,14-tetrahydro-77 / ,10H-5,3-(azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,5]dioxacyclopentadecino[6,7-c?][l,2,3]triazole (Ex. 53):

[0607] Step 1. To a solution of 5-(3-(((S)-4-((tert-butyldimethylsilyl)oxy)butan-2-yl)oxy)-l-methyl-lH-pyrazol-4-yl)-7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3- ((triisopropylsilyl)ethynyl)-lH-pyrazolo[3,4-c]pyridine (1.90 g, 2.79 mmol, 1 eq) in DMSO (35 mL) was added CsF (1.27 g, 8.38 mmol, 3 eq). The mixture was stirred at 25 °C for 12 hours. On completion, the mixture was poured into H2O (100 mL), and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (40 mL x 2), 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 give (3S)-3-((4-(3-ethynyl-7-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4-c]pyridin-5-yl)-l-methyl-lH-pyrazol-3-yl)oxy)butan-l-ol (825 mg, 2.01 mmol, 72% yield) as a brown solid. LCMS: m / z 410.3 (M+l).

[0608] Step 2. A mixture of (3S)-3-((4-(3-ethynyl-7 -methyl- l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4-c]pyridin-5-yl)-l-methyl-lH-pyrazol-3-yl)oxy)butan-l-ol (520 mg, 1.27 mmol, 1 eq), 4-bromo-l-methyl-lH-l,2,3-triazol-5-ol (248 mg, 1.40 mmol, 1.1 eq), PPh (666 mg, 2.54 mmol, 2 eq) in THF (5 mb) was added DBAD (584 mg, 2.54 mmol, 2 eq) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 0.5 hours. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 5 / 1 to 0 / 1) to give 5-(3-(((S)-4-((4-bromo- 1 -methyl- 1 H- 1,2, 3-triazol-5-yl)oxy)butan-2-yl)oxy)- 1 -methyl- 1 H-py razol-4-yl)-3-ethynyl-7-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4-c]pyridine (245 mg, 0.430 mmol, 33% yield) as a brown solid. LCMS: m / z 569.1 (M+l)

[0609] Step 3. To a solution of 5-(3-(((S)-4-((4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)oxy)butan-2-y l)oxy)-l -methyl- 1 H-pyrazol-4-yl)-3-ethynyl-7 -methyl- l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4-c]pyridine (110 mg, 0.434 mmol, 1.1 eq) in dioxane (5 inL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (200 mg, 0.790 mmol, 2 eq), CU2O (28.3 mg, 0.197 mmol, 0.5 eq) and PPI13 (103 mg, 0.395 mmol, 1 eq). The mixture was stirred at 70 °C for 12 hours. On completion, the mixture was poured into H2O (20 mL), and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 5 / 1 to 0 / 1) to give 5-(3-(((S)-4-((4-bromo- 1 -methyl- 1 H- 1,2, 3-triazol-5-yl)oxy)butan-2-yl)oxy)- 1 -methyl- 1 H-py razol-4-yl)-7 -methyl-l-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)-lH-pyrazolo[3,4-c]pyridine (195 mg, 0.279 mmol, 70% yield) as a brown oil. LCMS: m / z 697.2 (M+l).

[0610] Step 4. To a solution of 5-(3-(((S)-4-((4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)oxy)butan-2-yl)oxy)-l-methyl-lH-pyrazol-4-yl)-7-methyl-l-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)-lH-pyrazolo[3,4-c]pyridine (175 mg, 0.250 mmol, 1 eq) in DMA (2 mL) was added Xphos Pd G4 (21.5 mg, 0.025 mmol 0.1 eq) and NajCO (79.8 mg, 0.752 mmol, 3 eq). The mixture was stirred at 80 °C for 1.5 hours. On completion, the mixture was quenched by H2O (100 mL), and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 10 / 1 to 1 / 1) to give ( 10S, 1 IE)-!, 10, 14,20-tetramethyl-2-(oxan-2-yl)-2, 11, 12, 14-tetrahydro-7H, 1077-5,3-(azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,5]dioxacyclopentadecino[6,7-c?][l,2,3]triazole (75.0 mg, 0.152 mmol, 60% yield) as a brown solid. LCMS: m / z 491.2 (M+l).

[0611] Step 5. To a solution of (10S, 17E)-7, 10,14, 20-tetramethyl-2-(oxan-2-yl)-2, 11, 12,14-tetrahydro-7H,10H-5,3-(azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,5]dioxacyclopentadecino[6,7- ][l,2,3]triazole (65.0 mg, 0.132 mmol, 1 eq) in DCM (1 mL) was added HCl / dioxane (2 M, 0.1 mL). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give (10S,17£)-7,10,14,20-tetramethyl-2,l l,12,14-tetrahydro-7H,10 / f-5,3-(azenometheno)dipyrazolo[3',4’:10,ll;4",3":14,15][l,5]dioxacyclopentadecino[6,7-z / ][ l,2,3]triazole (8.71 mg, 0.0189 mmol, 14.25% yield, 98.11% purity, FA) as an off-white solid. Analytical data shown in the example table below.

[0612] General Method R

[0613] Preparation of (17£')-20-methoxy-7,14-dimethyl-2,7,10,ll,13,14-hexahydro-3,5-ethenodipyrazolo[3',4': 10, 11;4",3": 14, 15] [1,4]dioxacyclopentadecino[6,7-rZ] [ 1,2,3]triazol-6-amine (Ex. 54):CsF, DMSO / H2O Cu2O, PPh3, B2pin2dioxane

[0614] Step 1. To a solution of methyl 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-3-((triisopropylsilyl)ethynyl)-lH-indazol-5-yl)-l-methyl- lH-pyrazole-5-carboxylate (1.00 g, 1.38 mmol, 1 eq) in DMSO (10 mL) was added CsF (1.05 g, 6.90 mmol, 5 eq) and H2O (24.9 mg, 1.38 mmol, 1 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mLx3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 4-(3-ethynyl-7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)-3-(2-hydroxyethoxy)-l-methyl-lH-pyrazole-5-carboxylate (680 mg, 1.38 mmol, 100% yield, 92% purity) as a brown oil. LCMS: m / z 491.2 (M+l).

[0615] Step 2. To a solution of methyl 4-(3-ethynyl -7 -methoxy- l-(tetrahy dro-2H-pyran-2-yl)-lH-indazol-5-yl)-3-(2-hydroxyethoxy)-l-methyl-lH-pyrazole-5-carboxylate (600 mg, 1.32 mmol, 1 eq) in DMF (6 mL) was added 4-bromo-5-(bromomethyl)-l-methyl-lH-l,2,3-triazole (404 mg, 1.58 mmol, 1.2 eq) and NaH (79.2 mg, 1.98 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched with sat. NH4CI (18 mL) and extracted with ethyl acetate (15 mLx3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH= 1:0 to 10:1) to give 3-(2-((4-bromo- l-methyl-lH-l,2,3-triazol-5-yl)methoxy)ethoxy)-4-(3-ethynyl-7 -methoxy- 1-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)-l-methyl-lH-pyrazole-5-carboxylic acid (330 mg, 0.537 mmol, 41% yield) as a yellow solid. LCMS: m / z 614.2 (M+l).

[0616] Step 3. Amixture of3-(2-((4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)methoxy)ethoxy)-4-(3-ethynyl-7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)-l-methyl-lH-pyrazole-5-carboxylic acid (280 mg, 0.456 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (231 mg, 0.911 mmol, 2 eq), CU2O (32.6 mg, 0.228 mmol, 0.5 eq) and PPh (131 mg, 0.501 mmol, 1.1 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 24 h under N2 atmosphere. 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 10:1) to give (E)-3-(2-((4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)methoxy)ethoxy)-4-(7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-3-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)-lH-indazol-5-yl)-l-methyl-lH-pyrazole-5-carboxylic acid (160 mg, 0.108 mmol, 24% yield, 50% purity) as a yellow oil. LCMS: m / z IMA (M+l).

[0617] Step 4. A mixture of (E)-3-(2-((4-bromo-l-methyl-lH-l,2,3-triazol-5-yl)methoxy)ethoxy)-4-(7-methoxy-l-(tetrahydro-2H-pyran-2-yl)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) vinyl)- 1 H-indazol-5-y 1)- 1 -methyl- 1 H-pyrazole-5 -carboxylic acid (145 mg, 0.0976 mmol, 1 eq), Xphos Pd G4 (8.40 mg, 0.00977 mmol, 0.1 eq), K3PO4 (62.2mg, 0.293 mmol, 3 eq) in DMA (2 mL) w...

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula IR2R2R2N-N N-Nring B iseach L is independently -O-, -S-, -S(O)-, -S(O)2-, -N(R5)C(0)-, -C(0)N(R5)-, -N(R5)-, -N(R5)S(O)-, -S(O)N(R5)-, -N(R5)S(O)2-, -S(O)2N(R5)-, or -C(R6)(R7)-, provided that (L)ndoes not comprise an 0-0, S-0, or N-N bond;X is N or CH;each R1and R2, when present and covalently attached to a nitrogen atom, is independently deuterium, Ci-Ce alkyl, Ci-Ce alkenyl, C2-C6 alkynyl, C3-C0 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cwaryl, 5- to 10-membered heteroaryl, -C(0)Ra, -C(0)0Ra, -C(0)NRaRb, or -C(=NRa)NRaRb, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C6alkyl, Ci-C6haloalkyl, -Rg, -Rh, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NR8Rh, -OS(O)2NRgRh, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NR8Rh, -S(O)2NRgRh, -NR8Rh, -NRgC(0)Rh, -NR8C(0)0Rh, -NR8C(0)NR8Rh, -NRgS(O)Rh, -NRgS(O)2Rh, -NR8S(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(0)NRgRh, -P(0)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; or, when present and covalently attached to a carbon atom, is independently deuterium, halogen, Ci-Cbalkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -ORa, -0C(0)Ra, -0C(0)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(0)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)0Rb, -NRaC(0)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(0)NRaRb, -NRaS(O)2NRaRb, -C(0)Ra, -C(O)ORa, -C(0)NRaRb, -PRaRb, -P(0)RaRb, -P(O)2RaRb, -P(0)NRaRb, -P(0)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in Ci-Ce alkyl, C2-Cbalkenyl, C2-Ce alkynyl, C2-Cbcycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -R8, -Rb, -OR8, -0C(0)R8, -0C(0)NR8Rh, -OS(O)RS, -OS(O)2RS, -0S(0)NR8Rh, -0S(0)2NRgRh, -SR8, -S(O)Rg, -S(O)2R8, -S(O)NRgRh, -S(0)2NR8Rh, -NRgRh, -NRgC(0)Rh, -NRgC(0)0Rh, -NRgC(0)NRgRh, -NRgS(0)Rh, -NRgS(O)2Rh, -NRgS(0)NRgRh, -NRgS(0)2NRgRh, -C(O)Rg, -C(0)0Rg, -C(0)NR8Rh, -PRgRh, -P(0)R8Rh, -P(O)2R8Rh, -P(0)NR8Rh, -P(O)2NR8Rh, -P(O)OR8, -P(O)2OR8, -CN, or -NO2;each R3, when present, is independently deuterium, halogen, Ci-Cg alkyl, C2-C, alkenyl, C2-Ce alkynyl, C2-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -0C(0)Ra, -0C(0)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(0)NRaRb, -S(0)2NRaRb. -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)0Rb, -NRaC(0)NRaRb, -NRaS(0)Rb, -NRaS(O)2Rb, -NRaS(0)NRaRb, -NRaS(O)2NRaRb, -C(0)Ra, -C(O)ORa, -C(0)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(0)NRaRb, -P(0)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in Ci-Ce alkyl, C2-Cbalkenyl, C2-Cbalkynyl, Ci-Cbcycloalkyl, Cb-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-C, haloalkyl, -Rg, -Rh, -ORg, -0C(0)Rg, -0C(0)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NRgRh, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(0)2NRgRh, -NRgRh, -NRgC(0)Rh, -NRgC(0)0Rh, -NRgC(0)NRgRh, -NRgS(0)Rh, -NRgS(O)2Rh, -NRgS(0)NRgRh, -NR8S(O)2NR8Rh, -C(O)R8, -C(0)0R8, -C(0)NRgRh, -PRgRh, -P(0)R8Rh, -P(0)2RgRh, -P(0)NR8Rh, -P(0)2NRgRh, -P(O)ORS,-P(O)2ORg, -CN, or -NO2;R4is H, deuterium, Ci-C6alkyl, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, -P(O)2ORC, or -S(O)2ORC;each R5, when present, is independently H, deuterium, Ci-Cs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cb-Cio aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -ORe, -0C(0)Re, -0C(0)NReRf, -OS(O)Re, -OS(O)2Re, -0S(0)NReRf, -0S(0)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(0)NReRf, -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(0)Re, -C(0)0Re, -C(0)NReRf, -PReRf, -P(0)ReRf, -P(0)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;each Rband R', is independently H, deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORC, -0C(0)Rc, -0C(0)NRcRd, -0C(=NRc)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(0)NRcRd, -S(0)2NRcRd, -NR Rd, -NRcC(0)Rd, -N(C(0)Re)(C(0)Rd), -NRcC(0)0Rd, -NRcC(0)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(0)Rd, -NR S(0)2Rd, -NRcS(0)NRcRd, -NRcS(0)2NRcRd, -C(O)RC, -C(0)0R°, -C(0)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(0)RcRd, -P(O)2RcRd, -P(0)NRcRd, -P(0)2NRcRd, -P(0)0Rc, -P(O)2ORC, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORe, -0C(0)Re, -0C(0)NReRf, -OS(O)Re, -OS(O)2Re, -0S(0)NReRf, -0S(0)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(0)NReRf, -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(0)Re, -C(0)0Re, -C(0)NReRf, -PReRf, -P(0)ReRf, -P(0)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;or two of R5, R6and R7, taken together with the atom or atoms to which they are attached, optionally combine to form a C -C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl formed when two of R5, R6and R7are taken together is independently optionally substituted by -ORe, -0C(0)Re, -0C(0)NReRf, -OS(O)Re, -OS(O)2Re. -OS(O)NReRf, -0S(0)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(0)NReRf. -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf,-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;R8and R9are each independently H, deuterium, halogen, Ci-Cs alkyl, Ci-C, haloalkyl. -ORa, -C(O)Ra, -C(O)ORa, or -C(O)NRaRb;each Ra, Rb, Rc, Rd, Re, Rf, R8, and Rhis independently selected from the group consisting of H, deuterium, Ci-Ce alkyl, C2-Cbalkenyl, C2-C& alkynyl, Cs-Ce cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, Ci-Ce alkylene-Ce-Cio aryl, 5- to 10-membered heteroaryl, and Ci-C, alkylene-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 Ci-Cbalkyl, C -C, alkenyl, C2-C, alkynyl, Cs-Cf, cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, Ci-Ce alkylene-Ce-Cio aryl, 5- to 10-membered heteroaryl, or Ci-Cs alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, Ci-Cg alkyl, Ci-Ce haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or Ci-C6alkyl), -0C(0)N(H or Ci-C6alkyl)2, -OC(O)N(C2-C6alkylene), -OS(O)-(H or Ci-C6alkyl), -OS(O)2-(H or Ci-C6alkyl), -OS(O)N(H or Ci-C6alkyl)2, -OS(O)N(C2-C6alkylene), -OS(O)2N(H or Ci-C6alkyl)2, -OS(O)2N(C2-C6alkylene), -S(H or Ci-C6alkyl), -S(O)(H or Ci-C6alkyl), -S(O)2(H or Ci-C6alkyl), -S(O)N(H or Ci-C6alkyl)2, -S(O)N(C2-C6alkylene), -S(O)2N(H or Ci-C6alkyl)2, -S(O)2N(C2-C6alkylene), -N(H or Ci-C6alkyl)2, -N(C2-C6alkylene), -N(H or Ci-C6alkyl)C(O)-(H or Ci-C6alkyl), -N(H or Ci-Cs alkyl)C(O)O(H or Ci-C6alkyl), -N(H or Ci-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)C(O)N(C2-C6alkylene), -N(H or Ci-C6alkyl)S(O)-(H or Ci-C6alkyl), -N(H or Ci-C6alkyl)S(O)2(H or Ci-C6alkyl), -N(H or Ci-C6alkyl)S(O)N(H or Ci-Ce alkyl)2, -N(H or Ci-C6alkyl)S(O)N(C2-C6alkylene), -N(H or Ci-C6alkyl)S(O)2N(H or Ci-Ce alkyl)2, -N(H or Ci-C alkyl)S(O)2N(C2-C6alkylene), -C(O)-(H or Ci-C6alkyl), -C(0)0(H or Ci-C6alkyl), -C(O)N(C2-C6alkylene), -P(H or Ci-C6alkyl)2, -P(C2-C6alkylene), -P(O)(H or Ci-C6alkyl)2, -P(O)(C2-C6alkylene), -P(O)2(H or Ci-C6alkyl)2, -P(O)2(C2-C6alkylene), -P(O)N(H or Ci-C6alkyl)2, -P(O)N(C2-Ce alkylene), -P(0)2N(H or Ci-Ce alkyl)2, -P(O)2N(C2-Ce alkylene), -P(O)O(H or Ci-Cbalkyl), -P(O)2O(H or Ci-C6alkyl), -CN, or -NO2;m is 0, 1, or 2;n is 4, 5, 6, 7, 8 or 9; andp is 0, 1, or 2;provided thatN-N7(i) when X is CH or CR3and ring Bis or -Jw, then(a) at least one of R8or R9is not H; or(b) (L)Pcomprises at least two consecutive -C(R6)(R7)-, wherein each Rbis independently selected from deuterium, halogen, Ci-Cbalkyl, C2-Cbalkenyl, G-G, alkynyl, G-G cycloalkyl, 3- to 7-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)0Rb, -NRaC(0)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(0)NRaRb, -NRaS(O)2NRaRb, -C(0)Ra, -C(O)ORa, -C(0)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(0)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, and -NO2, wherein each hydrogen atom in Ci-Cg alkyl, C2-Cs alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, Cc-Cio aryl, and 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, Ci-Cbalkyl, Ci-Ce haloalkyl, -ORe, -0C(0)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -0S(0)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(0)NReRf, -S(O)2NReRf, -NReRf, -NReC(0)Rf, -NReC(0)0Rf, -NReC(0)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(0)NReRf, -NReS(0)2NReRf, -C(0)Re, -C(0)0Re, -C(O)NReRf, -PReRf, -P(0)ReRf, -P(0)2ReRf, -P(0)NReRf, -P(0)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and / / 2^^(ii) when X is N and ring Bis or, then ring A is substituted by at least one R1, wherein R1is C3-C6 cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C3-C6 cycloalkyl and 3- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, G-G. haloalkyl. -Rg, -Rh, -ORg, -0C(0)Rg, -0C(0)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NR8Rh, -SR8, -S(O)R8, -S(O)2Rg, -S(0)NR8Rh, -S(O)2NR8Rh, -NR8Rh, -NRgC(0)Rh, -NR8C(0)0Rh, -NR8C(O)NR8Rh, -NR8S(O)Rh, -NR8S(O)2Rh, -NR8S(O)NR8Rh, -NR8S(O)2NR8Rh, -C(0)R8, -C(O)ORg, -C(0)NRgRh, -PRgRh, -P(0)RgRh, -P(0)2RgRh, -P(0)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; andprovided that the compound is not of the formulaan isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

2. The compound of claim 1, having the formula IIan isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof,.

3. The compound of claim 1 or 2, an isotopically labeled form thereof, or a hydrate, solvate,or pharmaceutically acceptable salt thereof, wherein ringB is4. The compound of claim 1 or 2, an isotopically labeled form thereof, or a hydrate, solvate,R2R2N-N 'N-Nor pharmaceutically acceptable salt thereof, wherein ringB is5. The compound of claim 1 or 2, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring B is6. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A is7. The compound of any one of the claims 1 to 5, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A is8. The compound of claim 1, having the formula IIIan isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

9. The compound of claim 1 or 8, an isotopically labeled form thereof, or a hydrate, solvate,R2R2N-N N-N7or pharmaceutically acceptable salt thereof, wherein ringB is10. The compound of claim 1 or 8, an isotopically labeled form thereof, or a hydrate, solvate,R2R2N-N N-Nor pharmaceutically acceptable salt thereof, wherein ringB is11. The compound of claim 1 or 8, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring B is12. The compound of any one of claims 1 or 8 to 11, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A is13. The compound of any one of the claims 1 or 8 to 11, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A is14. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A iswherein each “ WV\T ■’ represents a point of covalent attachment.

15. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring A is16. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring B is17. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein ring B iswherein each “ 'A / W' ” represents a point of covalent attachment.

18. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

19. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein each R3, when present, is independently halogen, Ci-Ce alkyl, or -ORa.

20. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R?, when present, is F, Cl, -CH3, or -OCH3.

21. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R4is H or methyl.

22. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein each L is independently -C(R6)(R')-, -C(O)-, -O-, or -N(R5)-, provided that (L)ndoes not comprise a -O-O- or a -0-N(R3)- bond, and the point of covalent attachment of (L)nto ring A or ring B does not form a -N-N- or a -O-N- bond.

23. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein -(L)n- is -CR6R7-O(CR6R7)2O-, -CR6R7-O(CR6R7)3O-, -(CR6R7)C(O)N(R5)-(CR6R7)2-, -(CR6R7)N(R5)C(O)-(CR6R7)2-, -O(CR6R7)3N(R5)C(O)-(CR6R7)O-,-N(R5)-C(O)(CR6R7)2O(CR6R7)2-, -CR6R7O(CR6R7)2O-(CR6R7)2, -O(CR6R7)2O(CR6R7)2O-, -CR6R7O-CR6R7-C(O)N(R5)-(CR6R7)2-, -(CR6R7)3O(CR6R7)2-, -(CR’R7)2O(CR6R7)3-, -CR6R7-N(R5)-(CR6R7)4O-, -CR6R7-N(R5)-(CR6R7)3O-, -CR6R7-N(R5)-(CR6R7)2O-, -CR6R7-N(R5)-(CR6R7)2-, -CR6R7-N(R5)-(CR6R7)3O-, -CR6R7-N(R5)-(CR6R7)3-, -O(CR6R7)2O-CR6R7-, -O(CR6R7)2O(CR6R7)2-, -O(CR6R7)2O(CR6R7)3-,-(CRbR7)2-N(R5)-(CR6R7)3-, -O(CR6R7)2-N(R5)-CRbR7-, -(CR6R7)2-N(R5)-(CRbR7)2-, -O-(CR6R7)2-, -O-(CR6R7)3-, -O-(CR6R7)4-, -O-(CR6R7)5-, -O-(CR6R7)2O-, -O-(CR6R7)3O-, -O-(CR6R7)4O-, or -O-(CR6R7)5O-.

24. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein -(L)n- is -O(CR6R7)2O-CR6R7-, -O(CR6R7)2-N(R5)-CR6R7-, or -O-(CR6R7)3O-.

25. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein each R5, when present, is independently H, deuterium, or Ci-Cg alkyl.

26. The compound of any one of the preceding claims, an isotopically labeled form thereof,or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein each R5, when present, is independently H, deuterium, methyl, or ethyl.

27. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein each Rband R, when present, is independently H, deuterium, or Ci-Cg alkyl.

28. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein 0, 1, or 2 of R6is methyl, and the remaining R6and R' are independently H or deuterium.

29. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein -(L)n- is -O-(CH2)2O-CH2-, -OC(H)(CH3)-CH2-O-CH2-, -CH2O-(CH2)2O-, -C(H)(CH3)-O-(CH2)2O-, -CH2N(H)-(CH2)2O-, -CH2N(CH3)-(CH2)2O-, -CH2N(CH2CH3)-(CH2)2O-, -O(CH2)2N(H)CH2-, -O(CH2)2N(CH3)CH2-, -OCH2-(C(H)(CH3))-N(CH3)CH2-, -OCH2-C(H)(CH2F)-N(CH3)CH2-, -OCH2-C(H)(CH2CH3)-N(CH3)CH2-, -O(CH2)2N(C(O)CH3)CH2-, -OC(H)(CH3)CH2N(H)CH2-, -OC(H)(CH3)CH2N(CH3)CH2-, -OC(H)(CH3)CH2N(CH2CH3)CH2-, -O(C(H)(CH3))-C((H)(CH3))N(CH3)CH2-, -O(C(H)(CH3))-C((H)(CH3))N(CH2CH3)CH2-, -OC(H)(CH2CN)CH2N(CH3)CH2-, -OC(H)(CH2CH3)CH2N(CH3)CH2-, -OC(H)(CH2F)CH2N(CH3)CH2-, -OC(H)(CHF2)CH2N(CH3)CH2-, -OC(H)(CH2OH)CH2N(CH3)CH2-, -OC(H)(CH3)C(O)N(CH3)CH2-, -OC(H)(cyclobutyl)CH2N(CH3)CH2-, -OC(H)(CH3)CH2N(CH2CH3)CH2-, -OC(H)(CH3)CH2N(CH(CH3)2)-CH2-, -OC(H)(CH3)CH2N(CH3)-C(H)(CH3)-, -OC(H)(CH3)CH2N(CH(oxetan-3-yl)-CH2-, -OC(H)(CH3)CH2N(cyclopropyl)-CH2-, -OCH2C(H)(CH3)N(cyclopropyl)-CH2-, -OC(H)(CH3)CH2N(C(O)CH3)CH2-, -O(C(H)(CH3))CH2N(C(O)CH2CH3)CH2-, -CH2N(H)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-C(H)(CH3)-CH2O-,-CH2N(CH3)-(CH2)2(C(H)CH3)CH2O-, -CH2N(CH3)-(CH2)-(C(H)CH3)O-, -O(CH2)2-, -O(CH2)3-. -O(CH2)4-, -O(CH2)3O-, -O(CH2)4O-, -O(CH2)5O-, -O-(C(H)(CH3)-(CH2)2O-, -O(CH2)2-C(H)(CH3)-O-, -O(CH2)2C(H)(CH3)CH2O-, -O(CH2)3C(H)(CH3)CH2O-, -O(CH2)2N(H)C(O)-(CH2)O-, -O(CH2)2N(CH3)C(O)-(CH2)O-, -O(CH2)2O(CH2)2O-, -OC(H)(CH3)CH2OCH2-, -O(CH2)2OCH2C(H)(CH3)O-, -O(CH2)2OC(H)(CH3)-CH2O-,30. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein -(L)n- is -O-(CH2)2O-CH2-, -O(CH2)2N(CH3)CH2-, -OCH2-(C(H)(CH3))-N(CH3)CH2-, -OC(H)(CH3)CH2N(CH3)CH2-, -OC(H)(CH3)CH2N(CH2CH3)CH2-, -0(C(H)(CH3))-C((H)(CH3))N(CH3)CH2-, -O(C(H)(CH3))-C((H)(CH3))N(CH2CH3)CH2-, -O(CH2)3O-, or -O-(C(H)(CH3)-(CH2)2O-.

31. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein -(L)n- is32. A compound selected from the group consisting of (2S)-l-{(10S,ll / ?,17£’)-19-fluoro- 8,10,ll,12-tetramethyl-16-[(propan-2-yl)oxy]-2,8,10,ll,12,13-hexahydro-14H-3,5- ethenotripyrazolo[3,4:3',4'-j:4",3"- / i][l,4]oxazacyclopentadecin-14-yl}propan-2-ol; (2S)-l-{(10 / ?,117?,17 / ?)-19-fluoro-8,10,ll,12-tetramethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3',4’ / :4”,3"- n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;(2S)-l-[(10S,112?,17E)-16-ethoxy-19-fluoro-8,10,ll,12-tetramethyl-2,8,10,ll,12,13- hexahydro-l4W-3,5-ethenotripyrazolo|3.4- / :3'.4' / :4",3"- / 7|| 1,4|oxazacyclopentadecin-l4- yl]propan-2-ol;(2S)-l-[(10 / ?,l l / ?,17E)-16-ethoxy-19-fluoro-8,10,l l,12-tetramethyl-2,8,10,ll,12,13- hexahydro-147 / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-«][l,4]oxazacyclopentadecin-14- yl]propan-2-ol;(2S)- 1 -{ ( 1 OS, 117?, 17E - 12-ethyl- 19-fluoro-8, 10, 11 -trimethyl- 16- [(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3',4’- / :4”,3"- n|| 1,4|oxazacyclopentadecin- 14-yl |propan-2-ol;(2S)-l-{(10Z?,ll / ?,17E)-12-ethyl-19-fluoro-8,10,ll-trimethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro-14H-3,5-ethenotripyrazolo[3,4; / :3', 4'- / :4", 3"- n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;(2S)-1 -[( 10 / ?, 1 l / ?,17E)-16-ethoxy-12-ethyl-19-fluoro-8,10,ll-trimethyl-2,8,10,ll,12,13- hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3,,4'-j:4",3"-n][l,4]oxazacyclopentadecin-14- yl]propan-2-ol;(2S)-l-[(10 / ?,l l / ?,177t -16-ethoxy-20-fhioro-8, 10,1 l,12-tetramethyl-2, 8, 10,11,12,13- hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14- yl]propan-2-ol;(2S)- 1 -[( 1 OS, 11R,17E)-16-ethoxy-20-fluoro-8, 10, 11, 12-tetramethyl-2,8, 10, 11,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-zz][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;(2S)-l-{(10 / ?,ll / ?,17E)-20-fluoro-8,10,ll,12-tetramethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro-l 477-3, 5-ethenotripyrazolo[3,4- / :3',4'-j:4", 3"-n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;(2S)- 1 - { ( 1 OS, 11 R, 17 A')-20-fl LK )n )-8, 10, 11.12-tetramethyl- 16-[(propan-2-yl)oxy] - 2.8.10.11.12.13-hexahydro-14H-3,5-ethenotripyrazolo[3,4 / :3',4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;(2S)-l-[(10S,llZ?,17E)-16-ethoxy-12-ethyl-19-fluoro-8,10,ll-trimethyl-2,8,10,ll,12,13-hexahydro-14 / / -3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-zz][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;(2S)- 1 -{ ( 1 OR, 117?, 17E)- 12-ethy l-20-fluoro-8, 10,11 -trimethyl- 16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro-14 / 7-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-zi][l,4]oxazacyclopentadecin-14-yl}propan-2-ol;(2S)-l-{(10S,ll / ?,17ZT)-12-ethyl-20-fluoro-8,10,ll-trimethyl-16-[(propan-2-yl)oxy]- 2.8.10.11.12.13-hexahydro- 1477-3, 5-ethenotripyrazolo[3,4;:3', 4'; / :4", 3"-n] [ 1,4]oxazacyclopentadecin- 14-yl }propan-2-ol;(2S)-l-[(10S,117?,17E)-16-ethoxy-12-ethyl-20-fluoro-8,10,ll-trimethyl-2,8,10,ll,12,13-hexahydro-14H-3,5-ethenotripyrazolo[3,4- / :3,,4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;(2S)-l-[(10 / ?,l l / ?,17E)-16-ethoxy-12-ethyl-20-fluoro-8,10,ll-trimethyl-2,8,10,l l,12,13-hexahydro-1477-3,5-ethenotripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-2-ol;( 117?, 17 A')-20-methoxy-7, 11, 12, 14-tetramethyl-2, 10, 11, 12, 13,14-hexahydro-777-3,5-ethenodipyrazolo[3,4: / :3',4' / ][l,2,3]triazolo[4,5-n][l,4]oxazacyclopentadecine;(11 / ?, 17E)-20-methoxy-7, 11, 12, 14, 16-pentamethyl-2, 10, 11, 12, 13, 14-hexahydro-777-3,5-ethenodipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-7z][l,4]oxazacyclopentadecine;( 11 R, 17E) - 16-ethoxy-20-methoxy-7, 11,12,14-tetramethy 1-2, 10, 11, 12, 13,14-hexahydro-777-3,5-ethenodipyrazolo[3,4:3',4'-j][l,2,3]triazolo[4,5-zz][l,4]oxazacyclopentadecme;( 11 / ?, 17E)-20-chloro-7, 11, 12, 14-tetramethyl-2, 10, 11, 12, 13, 14-hexahydro-777-3,5-ethenodipyrazolo[3,4-:3',4'-j][l,2,3]triazolo[4,5-7z][l,4]oxazacyclopentadecine;(1 l / ?,177?)-20-chloro-7,l l,12,14,16-pentamethyl-2,10,ll,12,13,14-hexahydro-777-3,5-ethenodipyrazolo[3,4- / :3',4' / ][l,2,3]triazolo[4,5-w][l,4]oxazacyclopentadecine;(ll / ?,17 / ?)-20-chloro-16-ethoxy-7,l l,12,14-tetramethyl-2,10,ll,12,13,14-hexahydro-777-3,5-ethenodipyrazolo[3,4-:3',4' / ][l,2,3]triazolo[4,5- / z][l,4]oxazacyclopentadecine;( 17E)-20-methoxy-7, 14-dimethyl-2,7, 10, 11, 13, 14-hexahydro-3,5-ethenodipyrazolo[3',4': 10, 11;4",3": 14, 15] [ 1,4]dioxacyclopentadecino[6,7-d] [ 1,2,3]triazol-6-amine; and(17 / i)-20-methoxy-7,14-dimethyl-2,ll,12,14-tetrahydro-77 / ,1077-3,5-ethenodipyrazolo[3',4':10,ll;4",3":14,15][l,5]dioxacyclopentadecino[6,7-d][l,2,3]triazol-6-amine;an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

33. A compound selected from the group consisting of (17E)-7,12,14-trimethyl-2, 10, 11, 12, 13, 14-hexahydro-7 / -5,3-(azenometheno)tripyrazoloL3,4- / :3',4'- / :4",3"-n] [ 1,4]oxazacyclopentadecine;(l7A,)-6,7, l2,l4,2()-pentaniethyl-2, l(),l l,l2, l3,l4-hexahydr<)-7A / -5,3- (azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-ra][l,4]oxazacyclopentadecine;( 11 R, 17E)-6,7, 11, 12, 14,20-hexamethy 1-2, 10, 11, 12, 13,14-hexahydro-777-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"- / j][l,4]oxazacyclopentadecine;(17E)-7,12,14,20-tetramethyl-2,10,ll,12,13,14-hexahydro-7 / 7-5,3- (azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-ra][l,4]oxazacyclopentadecine;( 117?, 17E)-7, 11, 12, 14,20-pentamethyl-2, 10.11, 12, 13, 14-hexahydro-777-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecine;(2Sy 2-[( 1 OS, 17E)- 16-ethoxy-7, 10, 12,20-tetramethyl-2,7, 10, 11, 12, 13-hexahydro- 1477-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'; / :4",3”-7i][l,4]oxazacyclopentadecin-14-yl]propan-l-ol; (37?,4S)-4-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-1477- 5.3-(azenometheno)tripyrazolo[3,4: / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]oxolan-3-ol;(3. S',4 / ?)-4-|( I0. S, I7 / A- l6-ethoxy-6,8, 10, l2,2O-pentaniethyl-2.8, 10, 1 1.12, 13-hexahydro- 14 / 7- 5.3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-n][l,4]oxazacyclopentadecin-14-yl]oxolan-3-ol;(2S)-2-[(105,17E)-16-ethoxy-12-ethyl-7,10,20-trimethyl-2,7,10,l l,12,13-hexahydro-1477- 5.3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol;(15,2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-147 / - 5.3-(azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-zz][l,4]oxazacyclopentadecin-14-y l]cyclobutan- 1 -ol;(l / ?,25)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-14H- 5.3-(azenometheno)tripyrazolo[3,4- / :3',4'- / :4",3"-zz.][l,4]oxazacyclopentadecin-14-y l]cyclobutan- 1 -ol;(lS,22?)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-14H- 5.3-(azenometheno)tripyrazolo[3,4; / ':3',4'-j:4",3"-zz][l,4]oxazacyclopentadecin-14-yl]cyclobutan-l-ol;(l / ?,2 / ?)-2-[(10S,17£')-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-14H- 5.3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]cyclobutan- 1 -ol;1.5-anhydro-2,4-dideoxy-2-L(10S,17£’)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-14Z / -5,3-(azenometheno)tripyrazolo[3,4- / :3’,4'-j:4",3"-zi][l,4]oxazacyclopentadecin-14-yl]-L-r / zreo-pentitol;1.5-anhydro-2,4-dideoxy-2-[(10S,17E')-16-ethoxy-6,8,10,12,20-pentamethyl-2.8,10,ll,12,13-hexahydro-147 / -5,3-(azenometheno)tripyrazolo[3,4: / ’:3',4'; / :4",3"-n][l,4]oxazacyclopentadecin-14-yl]-D-r / ireo-pentitol;1.5-anhydro-2,3-dideoxy-3-[(10S,17£’)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,ll,12,13-hexahydro-14 / / -5,3-(azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-n][l,4]oxazacyclopentadecin-14-yl]-L-z / zz-eo-pentitol;1.5-anhydro-2.3-dideoxy-3-|( I0. S'.17 / 7)- 16-ethoxy-6.8.

10. l2.2()-pentamethyl-2.8.10.1 1.12.1 -hexahydro-147 / -5,3-(azenometheno)tripyrazolo[3,4- / :3’,4'-j:4",3"-n] [ 1,4]oxazacyclopentadecin- 14-yl] -D-th reo-pen ti tol;( 11 S, 1 lEyi, 11, 12, 14,20-pentamethyl-2, 10, 11, 12, 13, 14-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4: / :3',4' / :4",3"-zz][l,4]oxazacyclopentadecine;(2S)-2-[(10S,17£')-16-ethoxy-7,l(),12,2()-tetramethyl-2,7,l(),ll,12,13-hexahydro-147 / -5,3- (azenometheno)dipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-zi][l,4]oxazacyclopentadecin-14-yl]propan-l-ol;( 105, 17E)-7, 10, 12, 14, 16, 20-hexamethy 1-2, 10, 11, 12, 13.14-hexahydro-7H-5,3- (azenometheno)dipyrazolo[3,4: / :3',4'-j][l,2,3]triazolo[4,5-M][l,4]oxazacyclopentadecine; (2S)-2-[(10S,17£)-16-ethoxy-8,10,12,20-tetramethyl-2,8,10,ll,12,13-hexahydro-147 / -5,3-(azenometheno)dipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-zz][l,4]oxazacyclopentadecin-14-yl]propan-l-ol;(2S)-2-[(10S,17£)-16-ethoxy-6,10,12,20-tetramethyl-2,6,10,ll,12,13-hexahydro-14 / 7-5,3- (azenometheno)dipyrazolo[3,4- / :3',4'-j][l,2,3]triazolo[4,5-zz][l,4]oxazacyclopentadecin-14-yl]propan-l-ol;( 115, 17E)-7, 11, 12, 14,20-pentamethyl-2, 10,11,12,13,14-hexahydro-7H-5,3- (azenometheno)dipyrazolo[3,4-j:4',3'-ra][l,2,3]triazolo[4,5- / ][l,4]oxazacyclopentadecine; (17E)-7-ethyl-12,14,20-trimethyl-2,10,ll,12,13,14-hexahydro-7 / 7-5,3- (azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-ra][l,4]oxazacyclopentadecine;(17E)-12,14,20-trimethyl-7-(propan-2-yl)-2,10,ll,12,13,14-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"- / j][l,4]oxazacyclopentadecine;( 17E)-7 -cyclopropyl- 12,14, 20-trimethy 1-2,10,11,12,13,14-hexahydro-7 H-5,3- (azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"-n][l,4]oxazacyclopentadecine;( 17E)-7-cyclobutyl- 12,14, 20-trimethy 1-2, 10, 11, 12, 13, 14-hexahydro-7H-5,3- (azenometheno)tripyrazolo|3,4- / :3',4'-j:4",3"-raJLl,4Joxazacyclopentadecine;(17E)-7-(methanesulfonyl)-12,14,20-trimethyl-2,10,l l,12,13,14-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4-:3',4'- / :4",3"-7i][l,4]oxazacyclopentadecine;( 17E)-7-[(methanesulfonyl)methyl]-l 2, 14,20-trimethyl-2, 10, 1 l,12,13,14-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4: / :3',4' / :4",3"-n][l,4]oxazacyclopentadecine;( 17E)-7, 14,20-trimethyl-2,7, 10, 11, 13, 14-hexahydro-5,3- (azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,4]dioxacyclopentadecino[6,7- <7][l,2,3]triazole;( 1 OS, 17E)-7, 10, 14,20-tetramethyl-2, 11,12, 14-tetrahy dro-7 / / , 10H-5,3- (azenometheno)dipyrazolo[3',4':10,ll;4",3":14,15][l,5]dioxacyclopentadecino[6,7-c / || l,2,3]triazole;( 10S, 17E)-7, 10, 12, 15, 16, 20-hexamethyl-2, 10, 11, 12, 13, 15-hexahydro-7H-5,3- (azenometheno)tripyrazolo[3,4- / :3',4' / :4",3"- / z][l,4]oxazacyclopentadecine; and(17E)-7,12,15,16,20-pentamethyl-2,10,l l,12,13,15-hexahydro-77 / -5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"- / j][l,4]oxazacyclopentadecine;an isotopically labeled form thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

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

35. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of claims 1 to 33, or a pharmaceuticalcomposition of claim 34.

36. A compound according to any one of claims 1 to 33, for use in a method of treating disease in a subject.

37. Use of a compound according to any one of claims 1 to 33 in the manufacture of a medicament for the treatment of disease in a subject.