BIS-bicycloheteroaryl macrocycles and their use

Abstract

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

Description

83573-422399 BIS-BICYCLOHETEROARYL MACROCYCLES AND THEIR USE RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 644,833, filed May 9, 2024, the entire disclosure of which is incorporated herein by reference. TECHNICAL FIELD

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

[0003] Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G, et al. The protein kinase complement of the human genome. Science. 2002, 298:1912–34). Dysregulation of kinase activity is associated with many diseases, including cancers, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. 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 rewiring83573-422399 mediated by chromatin remodeling and autocrine / paracrine communication among tumor cells and within the tumor microenvironment (Swayden M, et al. Tolerant / Persister Cancer Cells and the Path to Resistance to Targeted Therapy. Cells 2020, 9, 2601). Therefore, it is necessary to invent kinase inhibitors that can target not only the kinase oncogenic drivers, overcome most frequent resistance mutations, but also tolerant persister cancer cells for overcoming resistance, achieving better efficacy and longer disease control.

[0004] Therefore, it is desirable to develop a novel, multitargeted kinase inhibitors that are potent against oncogenic driver and point mutations, other emerging and established resistance mutations, and / or emerging resistance targets for tolerant / persistent cancer cells. SUMMARY

[0005] In one aspect, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,

[0006] wherein R1, A,Y2, Y3, Y4, Y5, Y6, Y7, m, n,and “ ” are as described herein.

[0007] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,83573-422399

[0008] wherein R1, A, X6, X7, Y1, Y2, Y3, Y4, Y5, 67Y , Y , n, p, and “ are as

[0009] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,

[0010] wherein R1, R10,X7, Y5, Y6, Y7, m, n, and “ ” are as described herein.

[0011] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,83573-422399

[0012] wherein R1, R10, X5, X6, X7, Y5, Y6, Y7, n, p,and “ ” are as described herein.

[0013] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,

[0014] wherein R1,X6, X7, Y5, Y6, Y7, m, n,and “ ” are as described herein.

[0015] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,83573-422399

[0016] wherein R1, X6, X7, Y5, Y6, Y7, n, p,and “ ” are as described herein

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

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

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

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

[0021] In further aspects, the disclosure relates to a method of inhibiting a kinase, comprising contacting a cell comprising one or more of aberrant kinases with an effective amount of at least one compound of Formula (I)-(VI), or a pharmaceutically acceptable salt thereof, and / or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.

[0022] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection83573-422399 with any other embodiments described herein to the extent that the embodiments do not contradict one another.

[0023] 1. A compound of the formula I

[0024] wherein

[0025] A is a 5- to 10-membered heteroarylene or C6-C10 arylene;

[0026] B / C is a 9-membered bicyclic heteroarylene, wherein

[0027] X1is C(R2), N(R3), or N;

[0028] X2is C(R4), N(R5), or N;

[0029] X3is C or N;

[0030] X4is C or N;

[0031] X5is C(R6) or N;

[0032] X6is C(R7) or N; and

[0033] X7is C(R8) or N; provided that at least one of X1to X7is a nitrogen atom;

[0034] D / E is a 9-membered bicyclic heteroarylene, wherein

[0035] Y1is C(R9), N(R10), or N;

[0036] Y2is C(R11), N(R12), or N;

[0037] Y3is C or N;

[0038] Y4is C or N;

[0039] Y5is C(R13) or N;

[0040] Y6is C(R14) or N; and

[0041] Y7is C(R15) or N; provided that at least one of Y1to Y7is a nitrogen atom;

[0042] each L is independently a bond, -C(R16)(R17)-, -O-, -N(R18)C(O)-, -C(O)N(R18)-, -N(R18)-, -N(R18)S(O)-, -S(O)N(R18)-, -N(R18)S(O)2-, -S(O)2N(R18)-, -S-, -S(O)-, or -S(O)2-, provided that (L)m does not comprise an -O-O-, -O-S-, -O-N-, -S-S-, or -N-N- bond;83573-422399

[0043] each R1, when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, and each R1, when present and bonded to a nitrogen atom, is independently deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2;

[0044] each of R2, R4, R6, R7, R8, R9, R11, R13, R14, or R15, when present, is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, ,83573-422399 -S(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, or -P(O)2ORc; wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by Re, Rf, -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;

[0046] each R10or R12, when present, is independently H, deuterium, halogen, C1-C6alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -OS(O)NRcRd, -OS(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=NRe)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, -N(C(O)Re)(C(O)Rf), -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NRcS(O)NReRf, -NRcS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -C(=NRf)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0047] each R16and R17, when present, is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or two of R12and R13, taken together with the carbon or carbons to which they are attached, combine to form C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re,83573-422399 -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;

[0048] each R18, when present, is independently H, deuterium, -C(O)Rc, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; or an R14and an R12or an R13, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2;

[0049] each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, C1-C6 alkylene-5- to 10-membered heteroaryl, and C1-C6 alkylene-3- to 7-membered heterocycloalkyl, or Raand Rbor Rcand Rdor Reand Rf, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, or C1-C6 alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6alkyl)2, -S(O)N(C2-C6alkylene), -S(O)2N(H or C1-C6alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)- (H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)O(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)2(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)N(H or83573-422399 C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)2N(C2-C6alkylene), -C(O)-(H or C1-C6alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6alkyl)2, -P(O)(C2-C6alkylene), -P(O)2(H or C1-C6alkyl)2, -P(O)2(C2-C6alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(O)O(H or C1-C6alkyl), -P(O)2O(H or C1-C6alkyl), -CN, or -NO2;

[0050] m is 3, 4, 5, 6, 7, or 8; and

[0051] n is 0, 1, 2, 3, or 4;

[0052] or a pharmaceutically acceptable salt thereof.

[0053] 2. The compound of clause 1, having the formula II

[0054] wherein

[0055] each of Z and Z1is independently a bond, -O-, -N(R18)C(O)-, -C(O)N(R18)-, -N(R18)-, -N(R18)S(O)-, -S(O)N(R18)-, -N(R18)S(O)2-, -S(O)2N(R18)-, -S-, -S(O)-, or -S(O)2-;

[0056] each L1is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, -C(R16)(R17)- C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-;

[0057] L2is a bond, -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)- C(R16)(R17)-; and

[0058] p is 1 or 2;

[0059] or a pharmaceutically acceptable salt thereof.

[0060] 3. The compound of clause 1, having the formula III83573-422399

[0061] or a

[0062] 4. The compound of any one of the preceding clauses, having the formula IV

[0063] wherein

[0064] each of Z and Z1is independently a bond, -O-, -N(R18)C(O)-, -C(O)N(R18)-, -N(R18)-, -N(R18)S(O)-, -S(O)N(R18)-, -N(R18)S(O)2-, -S(O)2N(R18)-, -S-, -S(O)-, or -S(O)2-;

[0065] each L1is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, -C(R16)(R17)- C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-;

[0066] L2is a bond, -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)- C(R16)(R17)-; and

[0067] p is 1 or 2;83573-422399

[0068] or a pharmaceutically acceptable salt thereof.

[0069] 5. The compound of any clause 1, having the formula V

[0070] or a pharmaceutically acceptable salt thereof.

[0071] 6. The compound of any one of clauses 1, 2, or 5, having the formula VI

[0072] wherein

[0073] each of Z and Z1is independently a bond, -O-, -N(R18)C(O)-, -C(O)N(R18)-, -N(R18)-, -N(R18)S(O)-, -S(O)N(R18)-, -N(R18)S(O)2-, -S(O)2N(R18)-, -S-, -S(O)-, or -S(O)2-;

[0074] each L1is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, -C(R16)(R17)- C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-;

[0075] L2is a bond, -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)- C(R16)(R17)-; and

[0076] p is 1 or 2;

[0077] or a pharmaceutically acceptable salt thereof.83573-422399

[0078] 7. The compound of any one of the preceding clauses, wherein ring B / C is of the formula ,,

[0080] or a pharmaceutically acceptable salt thereof.

[0081] 8. The compound of any one of the preceding clauses, wherein ring A in the portion

[0082] is a 5- or 6-memberedand each “ ” represents a pointof covalent attachment;

[0083] or a pharmaceutically acceptable salt thereof.

[0084] 9. The compound of any one of the preceding clauses, wherein ring A in the portion

[0085] is a 5- or 6-memberedthe group consisting of ,83573-422399 ,

[0086] wherein attachment;

[0087] or a

[0088] 10. The compound of any one clauses, wherein each R1, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, or methoxymethyl;

[0089] or a pharmaceutically acceptable salt thereof.

[0090] 11. The compound of any one of the preceding clauses, wherein each R1, when present and bonded to nitrogen, is independently methyl or ethyl;

[0091] or a pharmaceutically acceptable salt thereof.

[0092] 12. The compound of any one of the preceding clauses, wherein ring A in the portion is selected from the group,

[0094] or aacceptable salt thereof.

[0095] 13. The compound of any one of clauses 1 to 10, wherein ring A in the portion

[0096] is C6-C10 arylene, n is 0,” represents a point of covalentattachment;83573-422399

[0097] or a pharmaceutically acceptable salt thereof.

[0098] 14. The compound of any one of clauses 1 to 10, or 13, wherein ring A in the portion

[0099] is phenylene, n is 0, 1, ” represents a point of covalentattachment;

[0100] or a pharmaceutically acceptable salt thereof.

[0101] 15. The compound of any one of clauses 2, 4, or 6 to 14, wherein each L1, when present, is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)- C(R16)(R17)-;

[0102] or a pharmaceutically acceptable salt thereof.

[0103] 16. The compound of any one of clauses 2, 4, or 6 to 15, wherein each L1, when present, is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)- C(R16)(R17)-, wherein one or two of R16is a C1-C6alkyl;

[0104] or a pharmaceutically acceptable salt thereof.

[0105] 17. The compound of any one of clauses 2, 4, or 6 to 16, wherein each L1, when present, is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)- C(R16)(R17)-, wherein one or two of R16is a C1-C6alkyl, and the remaining R16and R17are H or deuterium;

[0106] or a pharmaceutically acceptable salt thereof.

[0107] 18. The compound of any one of clauses 2, 4, or 6 to 17, wherein p is 1;

[0108] or a pharmaceutically acceptable salt thereof.

[0109] 19. The compound of any one of clauses 2, 4, or 6 to 18, wherein L1, when present, is - C(R16)(R17)-C(R16)(R17)-;

[0110] or a pharmaceutically acceptable salt thereof.

[0111] 20. The compound of any one of clauses 2, 4, or 6 to 19, wherein p is 2;

[0112] or a pharmaceutically acceptable salt thereof.

[0113] 21. The compound of any one of clauses 2, 4, or 6 to 17, or 20, wherein one instance of L1, when present, is -C(R16)(R17)- and another instance of L1, when present, is -C(R16)(R17)- C(R16)(R17)-;

[0114] or a pharmaceutically acceptable salt thereof.

[0115] 22. The compound of any one of clauses 2, 4, or 6 to 21, wherein Z, when present, is -O- ;83573-422399

[0116] or a pharmaceutically acceptable salt thereof.

[0117] 23. The compound of any one of clauses 2, 4, or 6 to 21, wherein Z, when present, is - N(R18)C(O)-;

[0118] or a pharmaceutically acceptable salt thereof.

[0119] 24. The compound of any one of clauses 2, 4, or 6 to 21, wherein Z, when present, is a bond;

[0120] or a pharmaceutically acceptable salt thereof.

[0121] 25. The compound of any one of clauses 2, 4, or 6 to 24, wherein each Z1, when present, is independently -O- or -N(R18)-;

[0122] or a pharmaceutically acceptable salt thereof.

[0123] 26. The compound of any one of clauses 2, 4, or 6 to 25, wherein L2, when present, is a bond;

[0124] or a pharmaceutically acceptable salt thereof.

[0125] 27. The compound of any one of the preceding clauses, wherein -(L)p- or -L2-(Z1-L1)p-Z- is of the formula , , , ,83573-422399

[0127] or a pharmaceutically acceptable salt thereof.

[0128] 28. The compound of any one of the preceding clauses, wherein R2, when present, is H or deuterium;

[0129] or a pharmaceutically acceptable salt thereof.

[0130] 29. The compound of any one of the preceding clauses, wherein R3, when present, is H, deuterium, or C1-C6alkyl;

[0131] or a pharmaceutically acceptable salt thereof.

[0132] 30. The compound of any one of the preceding clauses, wherein R4, when present, is H or deuterium;

[0133] or a pharmaceutically acceptable salt thereof.

[0134] 31. The compound of any one of the preceding clauses, wherein R5, when present, is H, deuterium, or C1-C6 alkyl;

[0135] or a pharmaceutically acceptable salt thereof.

[0136] 32. The compound of any one of the preceding clauses, wherein R6, when present, is H or deuterium;

[0137] or a pharmaceutically acceptable salt thereof.

[0138] 33. The compound of any one of the preceding clauses, wherein R7, when present, is H or deuterium;

[0139] or a pharmaceutically acceptable salt thereof.

[0140] 34. The compound of any one of the preceding clauses, wherein R8, when present, is H, deuterium, halogen, C1-C6 alkyl, or -NRaRb;

[0141] or a pharmaceutically acceptable salt thereof.

[0142] 35. The compound of any one of the preceding clauses, wherein R9, when present, is H or deuterium; or a pharmaceutically acceptable salt thereof.

[0143] 36. The compound of any one of the preceding clauses, wherein R10, when present, is H, deuterium, C1-C6 alkyl, or -S(O)2Rc; wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by Re, Rf, -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;

[0144] or a pharmaceutically acceptable salt thereof.

[0145] 37. The compound of any one of the preceding clauses, wherein R10, when present, is H, deuterium, methyl, ethyl, or propyl, wherein each hydrogen atom in methyl, ethyl, and propyl is independently optionally substituted by OH.83573-422399

[0146] 38. The compound of any one of the preceding clauses, wherein R10, when present, is

[0147] , , , , or , wherein the “ ” denotes apresent, is H or deuterium;

[0149] or a pharmaceutically acceptable salt thereof.

[0150] 40. The compound of any one of the preceding clauses, wherein R12, when present, is H, deuterium, C1-C6alkyl, or -S(O)2Rc; wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by Re, Rf, -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;

[0151] or a pharmaceutically acceptable salt thereof.

[0152] 41. The compound of any one of the preceding clauses, wherein R12, when present, is H, deuterium, methyl, ethyl, propyl, or -S(O)2Re, wherein each hydrogen atom in methyl, ethyl, and propyl is independently optionally substituted by OH;

[0153] or a pharmaceutically acceptable salt thereof.

[0154] 42. The compound of any one of the preceding clauses, wherein R12, when present, is “

[0155] 43. The compound of any one of the preceding clauses, wherein R14, when present, is H or deuterium;

[0156] or a pharmaceutically acceptable salt thereof.

[0157] 44. The compound of any one of the preceding clauses, wherein R15, when present, is H, deuterium, halogen, C1-C6alkyl, or -NRaRb;

[0158] or a pharmaceutically acceptable salt thereof.

[0159] 45. The compound of any one of the preceding clauses, wherein R18, when present, is H or C1-C6 alkyl;

[0160] or a pharmaceutically acceptable salt thereof.

[0161] 46. The compound of clause 1, selected from the group consisting of

[0162] 15-(methanesulfonyl)-8-methyl-2,11,12,15-tetrahydro-8H,10H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole;83573-422399

[0163] 8-methyl-2,11,12,15-tetrahydro-8H,10H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole;

[0164] 2-(8-methyl-2,8,11,12-tetrahydro-10H,15H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazol-15-yl)ethan-1-ol;

[0165] 2-(8-methyl-2,8,11,12-tetrahydro-10H,14H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazol-14-yl)ethan-1-ol;

[0166] (2S)-1-[(10S)-12-ethyl-22-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13- hexahydro-14H-3,5:16,18-diethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin- 14-yl]propan-2-ol; and

[0167] (10S)-12-ethyl-22-fluoro-14-[(2S)-2-hydroxypropyl]-6-(methoxymethyl)-8,10-dimethyl- 2,11,12,14-tetrahydro-8H-3,5:16,18-diethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-13(10H)-one;

[0168] or a pharmaceutically acceptable salt thereof.

[0169] 47. The compound of clause 1, selected from the group consisting of

[0170] (2S)-2-[(10S)-20-methoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-15H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15- yl]propan-1-ol;

[0171] 2-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0172] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-15H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15- yl]propan-1-ol;

[0173] (2S)-2-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-15H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15- yl]propan-1-ol;

[0174] 2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0175] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0176] (2S)-1-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol;

[0177] (2S)-2-[(10S)-12-ethyl-6,8,10,22-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-83573-422399 (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0178] (2S)-2-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0179] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:16,18- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0180] (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol;

[0181] (2S)-2-[(10S)-19-fluoro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0182] (2S)-2-[(10S)-20-methoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0183] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:18,16- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0184] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4,8]oxadiazacyclopentadecin- 14-yl]propan-1-ol;

[0185] (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:18,16- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0186] (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:16,18- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0187] (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4,8]oxadiazacyclopentadecin- 14-yl]propan-2-ol;

[0188] (2S)-2-[(10S)-20-fluoro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0189] (2S)-2-[(10S)-20-chloro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0190] (2S)-2-[(10S)-19-chloro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-83573-422399 (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0191] (10S)-6,8,10,12,15,22-hexamethyl-2,10,11,12,13,15-hexahydro-8H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine;

[0192] (2S)-2-[(10S)-20-chloro-12-ethyl-6-(methoxymethyl)-8,10,22-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0193] (2S)-2-[(10S)-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10,22-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0194] (2S)-2-[(10S)-20-methoxy-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0195] (2S)-2-[(10S)-6,8,10,12,20,22-hexamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0196] (2S)-2-[(10S)-20-ethyl-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0197] (2S)-2-[(10S)-20-cyclopropyl-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0198] (2S)-2-[(10S)-20-(difluoromethoxy)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0199] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-20-(trifluoromethoxy)-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0200] (2S)-2-[(10S)-20-(dimethylamino)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; and

[0201] (2S)-1-[(5S)-32,35,5,7-tetramethyl-11H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4- c]pyridina-1(5,3)-indazola-3(4,3)-pyrazolacyclooctaphan-11-yl]propan-2-ol;

[0202] or a pharmaceutically acceptable salt thereof.

[0203] 48. The compound of clause 1, selected from the group consisting of83573-422399

[0204] 2-[(10S)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-(azenometheno)-16,18- ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0205] (2S)-1-[(10S)-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol;

[0206] (2S)-1-[(10S)-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol;

[0207] (2S)-1-[(10S)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro- 14H-3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0208] (2S)-2-[(10S)-6-(methoxymethyl)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H- 3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0209] (2S)-1-[(10S)-12-ethyl-8,10-dimethyl-20-(propan-2-yl)-2,8,10,11,12,13-hexahydro- 14H-3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol; and

[0210] 2-[(5S)-32,5-dimethyl-12H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-b]pyridina-1(5,3)- indazola-3(4,3)-pyrazolacyclooctaphan-12-yl]ethan-1-ol;

[0211] or a pharmaceutically acceptable salt thereof.

[0212] 49. The compound of clause 1, selected from the group consisting of

[0213] (2S)-2-[(11S)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0214] (2S)-2-[(11S)-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0215] (11S)-7,9,11,13,16-pentamethyl-12,13,14,16-tetrahydro-9H,11H-6,3-(azenometheno)- 17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine;

[0216] (2S)-2-[(11S)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0217] (2S)-1-[(11S)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;83573-422399

[0218] (2S)-2-[(11S)-7,9,11,13,23-pentamethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; and

[0219] (2S)-1-[(11S)-7,9,11,13,23-pentamethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0220] or a pharmaceutically acceptable salt thereof.

[0221] 50. The compound of clause 1, selected from the group consisting of

[0222] (2S)-2-[(10S)-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)-16,18- ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)-yl]propan-1-ol;

[0223] (2S)-1-[(10S)-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)-16,18- ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)-yl]propan-2-ol;

[0224] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)- 16,18-ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)- yl]propan-1-ol; and

[0225] (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)- 16,18-ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)- yl]propan-2-ol

[0226] or a pharmaceutically acceptable salt thereof.

[0227] 51. A pharmaceutical composition comprising a compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, and optionally one or more excipients.

[0228] 52. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of clauses 1 to 50, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of clause 51.

[0229] 53. A compound according to any one of clauses 1 to 50, or a pharmaceutically acceptable salt thereof, for use in a method of treating disease in a subject.

[0230] 54. Use of a compound according to any one of clauses 1 to 50, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease in a subject. DETAILED DESCRIPTION

[0231] 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 particular83573-422399 embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0232] 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.

[0233] 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.

[0234] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0235] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and / or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.

[0236] 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.83573-422399

[0237] 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.

[0238] 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.).

[0239] 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

[0240] 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 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 atom covalently attached to ring A, where the atoms counted in the macrocycle includes the shortest path through ring A, followed by the shortest path of atoms through ring B / C, followed by the shortest path of atoms through ring D / E, 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 atom in ring A that served as the starting point.83573-422399

[0241] 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-C20alkyl or C1-C20alkylene, C1-C12alkyl or C1-C12alkylene, or C1-C6 alkyl or C1-C6 alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n-propylene ((-CH2-)3), iso- propylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0242] The term “alkenyl” refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. The term “alkenylene” refers to a straight- or branched- chain di-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” or “alkenylene” to a specific range of atoms, such as C2-C20 alkenyl or C2-C20 alkenylene, C2-C12 alkenyl or C2-C12 alkenylene, or C2-C6 alkenyl or C2-C6 alkenylene. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Examples of alkenylene groups include ethenylene (or vinylene) (- CH=CH-), n-propenylene (-CH=CHCH2-), iso-propenylene (-CH=CH(CH3)-), and the like. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl or alkenylene group can be unsubstituted or substituted as described herein. An alkenyl or alkenylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0243] The term “alkynyl” refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. The term “alkynylene” refers to a straight- or branched-chain divalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” or “alkynylene” to a specific range of atoms, such as C2-C20 alkynyl or C2-C20 alkynylene, C2-C12 alkynyl or C2-C12 alkynylene, or C2-C6alkynyl or C2-C6alkynylene. Examples of alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), and the like. It will be appreciated that an alkynyl or alkynylene group can be unsubstituted or substituted as described herein. An alkynyl or alkynylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.83573-422399

[0244] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle. The term “cycloalkylene” refers to a saturated or partially saturated, monocyclic or polycyclic divalent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” or “cycloalkylene” to a specific range of atoms, such as having 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include monovalent radicals of the following entities, while cycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties: ,In particular, a cyclopropyl moiety can be depicted by the structural Inparticular, a cyclopropylene moiety can be depicted by the structural It will be appreciated that a cycloalkyl or cycloalkylene group can beas described herein. A cycloalkyl or cycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0245] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.

[0246] The term “haloalkyl” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include –CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F. The term “haloalkylene” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include -CF2-, -C(H)(F)-, -C(H)(Br)-, -CH2CF2-, and -CH2C(H)(F)-.

[0247] The term “aryl” refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. The term “arylene” refers to a divalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. In some embodiments, it can be advantageous to limit the number of atoms in an “aryl” or “arylene” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused-83573-422399 ring polycyclic groups of 6 to 14 carbon atoms (C6-C14 aryl), monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-C10aryl), divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6-C14 arylene), divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-C10arylene). Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. Examples, without limitation, of arylene groups are phenylene, naphthalenylene and anthracenylene. It will be appreciated that an aryl or arylene group can be unsubstituted or substituted as described herein. An aryl or arylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0248] The term “heterocycloalkyl” refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. The term “heterocycloalkylene” refers to a divalent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. In some embodiments, it can be advantageous to limit the number of atoms in a “heterocycloalkyl” or “heterocycloalkylene” to a specific range of ring atoms, such as from 3 to 12 ring atoms (3- to 12-membered), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 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 “heterocycloalkylene” to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Polycyclic ring systems include fused, bridged, and spiro systems. The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities, while heterocycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:83573-422399

[0249] Awhere the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of three-membered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane. A five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-1H- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro- 1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2- one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2-one, and oxazolidin-2-one. A six-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocycle groups include mono-valent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring.

[0250] It will be appreciated that a heterocycloalkyl or heterocycloalkylene group can be unsubstituted or substituted as described herein. A heterocycloalkyl or heterocycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0251] 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 some83573-422399 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:

[0252] or six- membered heterocycle. A five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include mono- valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-limiting examples of five- membered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of six-83573-422399 membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole. Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8- naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H- benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole. In particular, a pyrazolyl moiety can be depicted by the structural formula . In particular,an example of a pyrazolylene moiety can be depicted by the structural .

[0253] It will be appreciated that a heteroaryl or heteroarylene group canor 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.

[0254] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.

[0255] 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.

[0256] 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.

[0257] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures83573-422399 depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,15N,18O,17O,31P,32P,35S,18F,36Cl, and125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0258] Certain chemical entities of Formula (I)-(VI) may be depicted in two or more tautomeric forms. Any and all alternative tautomers are included within the scope of these formulas, and no inference should be made as to whether the chemical entity exists as the tautomeric form in which it is drawn. It will be understood that certain chemical entities described herein can exist in different tautomeric forms. It will be readily appreciated by one of skill in the art that because of rapid interconversion, tautomers can generally be considered to be the same chemical compound. Examples of tautomers include but are not limited to enol-keto tautomers, amine-imine tautomers, and the like.

[0259] Theto a class of substituents, is meant to refer to embodiments of this disclosure for which each and every one of the number of atom members, from i to j including i and j, is independently realized. By way of example, the term C1-C3 refers independently to embodiments that have one carbon member (C1),83573-422399 embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3).

[0260] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent –J-K-, where J ≠ K, refers herein to such disubstituent with J attached to a first substituted member and K attached to a second substituted member, and it also refers to such disubstituent with J attached to the second substituted member and K attached to the first substituted member.

[0261] It will be appreciated that certain of the compounds described herein include one or more position that can exists as stereoisomers. For example, certain of the compounds described herein include one or more carbon atoms that can exist in one or more stereoisomeric arrangements. It will be appreciated that a carbon atom that can exist in stereoisomeric arrangements that is depicted without showing any stereoisomeric arrangement includes as a disclosure each of eh possible stereoisomeric arrangements. For example a carbon atom having four groups that can be prioritized according to the Cahn-Ingold Prelog Rules known to one of skill in the art will be understood herein as describing no particular stereochemical definition as in the structure on the left below, and also as describing both possible stereoisomers (S) and (R) as shown belowwhere Ra> Rb> Rc> Rdaccording to the Cahn-Ingold Prelog Rules.

[0262] As used herein and in connection with chemical structures depicting the variousembodiments described herein, “*”, “**”, and “ ”, each represent a point of covalentattachment of the chemical group or chemicalin 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 , , or,where “ ” represents a bond to A and the point ofcovalent bondembodiments, the portion of A-B defined by the group or chemical structure B can be represented83573-422399, where each of “-*”, “-**”, and “ ” represents a bond to B and the point of covalent bondattachment to

[0263] As used with chemical structures depicting the variousembodiments described herein “ ” represents a σ-bond with an optional π-bond either notpresent, in the case of “̶̶ ̶̶ ̶̶̶ ̶ ̶ “, or present, in the case of “====”. It will be appreciated that the“ ” symbol can be used in the context of a chain of atoms or a cyclic group. It will beunderstood that a " ” used in connection with a cyclic structure indicates that the bondsbetween the atoms within which the “ ” symbol is located can be either “̶ ̶ ̶̶ ̶̶̶ ̶ ̶ “ or“====” bonds, and the “ ” represents the delocalized electrons of π-bonds within the ringstructure. In particular,heteroarylene described by the structure

[0264] where X1is a carbon, X2are all carbons, can be depicted as either

[0265]

[0266] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(VI), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

[0267] 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 biologically83573-422399 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.

[0268] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0269] For a compound of Formula (I)-(VI) 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.

[0270] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(VI), and treatment methods employing such pharmaceutically acceptable prodrugs.83573-422399 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)-(VI)). 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.

[0271] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(VI), 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)-(VI) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem.1997, 40, 2011-2016; Shan et al., J. Pharm. Sci.1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255- 331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991). REPRESENTATIVE EMBODIMENTS

[0272] 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, or a pharmaceutically acceptable salt thereof,83573-422399

[0273] wherein R1, A, B, C, D, E, L, X1, X2, X3, X4, X5, X6, X7, Y1, Y2, Y3, Y4, Y5, Y6, Y7, m, n,and “ ” are as described herein.

[0274] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,

[0275] wherein R1, A,6 7 1 2 3 4 5X, X, Y, Y, Y, Y, Y,Y6, Y7, n, p, and “ ” are as described herein.

[0276] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,

[0277] wherein R1, R10,X7, Y5, Y6, Y7, m, n, and “ ” are as described herein.83573-422399

[0278] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,

[0279] wherein R1, R10, A, B, C, D, E, L1, L2, Z1, Z, X1, X2, X3, X4, X5, X6, X7, Y5, Y6, Y7, n, p,and “ ” are as described herein.

[0280] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,

[0281] wherein R1, R12, A, B, C, D, E, L1, L2, Z1, Z, X1, X2, X3, X4, X5, X6, X7, Y5, Y6, Y7, m, n,and “ ” are as described herein.

[0282] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,83573-422399

[0283] wherein R1, X6, X7, Y5, Y6, Y7, n, p,and “ ” are as described herein

[0284] In some embodiments, ring A is 5- to 10-membered heteroarylene.

[0285] In some embodiments, ring A is a 5- to 10-membered heteroarylene, wherein each R2, when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)NRaRb, -OS(O)Ra, Rb,is independently deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0286] In some embodiments, ring A is a 5- or 6-membered heteroarylene, wherein each R2, when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6 alkyl, C2-83573-422399 C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or each R2, when present and bonded to a nitrogen atom, is independently deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0287] In some embodiments, ring A in the portion

[0288] is a 5- or 6-memberedand each “ ” represents a pointof covalent attachment.

[0289] In some embodiments, ring A is of the formula

[0290] wherein “ ” isbond or a carbon-carbon doublebond, each “ ” represents a point of covalent attachment, and R1 and n are as describedherein.

[0291] In some embodiments, ring A is of the formula83573-422399

[0292] wherein “ ” is bond or a carbon-carbon doublebond, each “ ” representsring A is a 5-memberedheteroarylene, and R1and n are as described herein.

[0293] In some embodiments, ring A is of the formula

[0294] wherein each “ ” attachment, Z1 2 3, Z , and Z are eachindependently -O-, -S-, =C(H)-, =C(R1)-, -N(H)-, -N(R1)- or =N- and ring A is a 5-membered heteroarylene, provided that at least one of Z1, Z2, and Z3is not =C(H)-, or =C(R1)-.

[0295] In some embodiments, ring A is of the formula

[0296] wherein each “ ” 2 1 3attachment, Z is =N-, Z and Zare eachS-, =C(H)-, =C(R1)-, -N(H)-, or -N(R1)-, and ring A is a 5-membered heteroarylene.

[0297] In some embodiments, ring A is pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene wherein each is optionally substituted with 1, 2, 3, or 4 R1(n of R1), wherein each R1, when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or each R1, when present and bonded to a nitrogen atom, is independently deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to83573-422399 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0298] In some embodiments, ring A in the portion is a 5- or 6-membered consisting of,

[0300] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0301] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of ,83573-422399 ,isindependently as described herein.

[0303] In some embodiments, ring A is a 5-membered heteroarylene selected from the group consisting of ,,83573-422399 ,a point of covalent attachment.when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, - - - - - - Rb, toor optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, each R1, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, or methoxymethyl.

[0306] In some embodiments, each R1, when present and bonded to a nitrogen atom, is independently deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, each R1, when present and bonded to nitrogen, is independently methyl or83573-422399 ethyl. In some embodiments, each R1is independently C1-C6 alkyl, for example methyl, wherein one hydrogen atom in each C1-C6alkyl is optionally substituted with an -ORa. In some embodiments, n is 1 and R1is C1-C6 alkyl, for example methyl. In some embodiments, n is 2, and each R1is independently C1-C6alkyl, for example methyl. In some embodiments, n is 2, one R1is C1-C6 alkyl, for example methyl, wherein one hydrogen atom in C1-C6 alkyl is optionally substituted by -ORa, for example Rais C1-C6alkyl such that R1is C1-C6alkyl-O-C1-C6alkyl (e.g., -CH2OCH3), and one R1is methyl.

[0307] In some embodiments, ring A in the portion is selected from the group,

[0309] In somering A is a 5-membered heteroarylene selected from the group consisting of ,

[0311] In somering A is a 5-membered heteroarylene selected from the group83573-422399 consisting of

[0313] is a C6-C10 arylene, n is 0,” represents a point of covalentattachment.

[0314] In some embodiments, ring A in the portion

[0315] is a phenylene, n is 0, 1,” represents a point of covalentattachment.

[0316] In some embodiments, ring B / C is a 9-membered bicyclic heteroarylene, wherein X1is C(R2), N(R3), or N; X2is C(R4), N(R5), or N; X3is C or N; X4is C or N; X5is C(R6) or N; X6is C(R7) or N; and X7is C(R8) or N; provided that at least one of X1to X7is a nitrogen atom (e.g., N or NR3or NR5). In some embodiments, ring B / C is a 9-membered bicyclic heteroarylene, wherein X1is N(R3) or N; X2is N(R5) or N; X3is C or N; X4is C or N; X5is C(R6) or N; X6is C(R7) or N; and X7is C(R8) or N. In some embodiments, ring B / C is a 9-membered bicyclic heteroarylene, wherein X1is N; X2is N(R5), X3is C or N; X4is C or N; X5is C(R6) or N; X6is C(R7) or N; and X7is C(R8) or N. In some embodiments, ring B / C is a 9-membered bicyclic heteroarylene, wherein X1is C(R2), N(R3), or N; X2is C(R4), N(R5), or N; X3is C or N; X4is C or N; X5is C(R6) or N; X6is C(R7) or N; and X7is C(R8) or N; provided that at least one of X1to X7is a nitrogen atom (e.g., N or NR3or NR5) and one of X1or X2is a carbon atom (e.g., CR2or CR4).83573-422399

[0317] In some embodiments, X1is C(R2). In some embodiments, X2is C(R4). In some embodiments, X1is N(R3) or N. In some embodiments, X1is N. In some embodiments, X2is N(R5) or N. In some embodiments, X2is N. In some embodiments, one of X1or X2is N. In some embodiments, X1is C(R2), and X2is N(R5) or N. In some embodiments, X1is C(R2) and X2is N. In some embodiments, X1is N(R3) or N, and X2is C(R4). In some embodiments, X1is N and X2is C(R4).

[0318] In some embodiments, X3is C or N. In some embodiments, X3is C. In some embodiments, X3is N. In some embodiments, X4is C or N. In some embodiments, X4is C. In some embodiments, X4is N. In some embodiments, X5is C(R6) or N. In some embodiments, X5is C(R6). In some embodiments, X5is N. In some embodiments, X6is C(R7) or N. In some embodiments, X6is C(R7). In some embodiments, X6is N. In some embodiments, X7is C(R8) or N. In some embodiments, X7is C(R8). In some embodiments, X7is N.

[0319] In some embodiments, X3is N, X4is C, X5is C(R6), X6is C(R7), and X7is C(R8). In some embodiments, X3is N, X4is C, X5is N, X6is C(R7), and X7is C(R8). In some embodiments, X3is N, X4is C, X5is C(R6), X6is C(R7), and X7is N. In some embodiments, X3is N, X4is C, X5is C(R6), X6is N, and X7is C(R8). In some embodiments, X3is C, X4is N, X5is C(R6), X6is C(R7), and X7is C(R8). In some embodiments, X3is C, X4is N, X5is C(R6), X6is N, and X7is C(R8). In some embodiments, X3is C, X4is C, X5is C(R6), X6is C(R7), and X7is C(R8). In some embodiments, X3is C, X4is C, X5is C(R6), X6is C(R7), and X7is N. In some embodiments, X3is C, X4is C, X5is C(R6), X6is N, and X7is C(R8).

[0320] In some embodiments, ring B / C is of the formula ,,,83573-422399 ,

[0322] In some ring D / E is a 9-membered bicyclic heteroarylene, wherein Y1isC(R9), N(R10), or N; Y2is C(R11), N(R12), or N; Y3is C or N; Y4is C or N; Y5is C(R13) or N; Y6is C(R14) or N; and Y7is C(R15) or N; provided that at least one of Y1to Y7is a nitrogen atom (e.g., N or NR10or NR12). In some embodiments, ring D / E is a 9-membered bicyclic heteroarylene, wherein Y1is C(R9), N(R10), or N; Y2is C(R11), N(R12), or N; Y3is C or N; Y4is C or N; Y5is C(R13) or N; Y6is C(R14) or N; and Y7is C(R15) or N; provided that one of Y1or Y2is a carbon atom (e.g., CR9or CR11). In some embodiments, ring D / E is a 9-membered bicyclic heteroarylene, wherein Y1is N(R10) or N; Y2is N(R12) or N; Y3is C or N; Y4is C or N; Y5is C(R13) or N; Y6is C(R14) or N; and Y7is C(R15) or N. In some embodiments, ring D / E is a 9- membered bicyclic heteroarylene, wherein Y1is N; Y2is N(R12); Y3is C or N; Y4is C or N; Y5is C(R13) or N; Y6is C(R14) or N; and Y7is C(R15) or N. In some embodiments, ring D / E is a 9- membered bicyclic heteroarylene, wherein Y1is C(R9), N(R10), or N; Y2is C(R11), N(R12), or N; Y3is C or N; Y4is C or N; Y5is C(R13) or N; Y6is C(R14) or N; and Y7is C(R15) or N provided that at least one of Y1to Y7is a nitrogen atom (e.g., N or NR10or NR12) and one of Y1or Y2is a carbon atom (e.g., CR9or CR11).

[0323] In some embodiments, Y1is C(R9). In some embodiments, Y2is C(R11). In some embodiments, Y1is N(R10) or N. In some embodiments, Y1is N. In some embodiments, Y2is N(R12) or N. In some embodiments, Y2is N. In some embodiments, one of Y1or Y2is N. In some embodiments, Y1is C(R9), and Y2is N(R12) or N. In some embodiments, Y1is C(R9) and Y2is N. In some embodiments, Y1is N(R10) or N, and Y2is C(R11). In some embodiments, Y1is N and Y2is C(R11).

[0324] In some embodiments, Y3is C or N. In some embodiments, Y3is C. In some embodiments, Y3is N. In some embodiments, Y4is C or N. In some embodiments, Y4is C. In some embodiments, Y4is N. In some embodiments, Y5is C(R13) or N. In some embodiments, Y5is C(R13). In some embodiments, Y5is N. In some embodiments, Y6is C(R14) or N. In some83573-422399 embodiments, Y6is C(R14). In some embodiments, Y6is N. In some embodiments, Y7is C(R15) or N. In some embodiments, Y7is C(R15). In some embodiments, Y7is N.

[0325] In some embodiments, Y3is N, Y4is C, Y5is C(R13), Y6is C(R14), and Y7is C(R15). In some embodiments, Y3is N, Y4is C, Y5is N, Y6is C(R14), and Y7is C(R15). In some embodiments, Y3is N, Y4is C, Y5is C(R13), Y6is C(R14), and Y7is N. In some embodiments, Y3is N, Y4is C, Y5is C(R13), Y6is N, and Y7is C(R15). In some embodiments, Y3is C, Y4is N, Y5is C(R13), Y6is C(R14), and Y7is C(R15). In some embodiments, Y3is C, Y4is N, Y5is C(R13), Y6is N, and Y7is C(R15). In some embodiments, Y3is C, Y4is C, Y5is C(R13), Y6is C(R14), and Y7is C(R15). In some embodiments, Y3is C, Y4is C, Y5is C(R13), Y6is C(R14), and Y7is N. In some embodiments, Y3is C, Y4is C, Y5is C(R13), Y6is N, and Y7is C(R15).

[0326] In some embodiments, ring D / E is of the formula , , , ,83573-422399 ,some or is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, ,C6 alkyl, -S(O)2Rc, -S(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, or -P(O)2ORc; wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by Re, Rf, -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 -NO2.83573-422399

[0330] In some embodiments, R2, when present, is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R2, when present, is H, deuterium, halogen, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R2, when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R2, when present, is H or deuterium. In some embodiments, R2, when present, is H. In some embodiments, R2, when present, is deuterium.

[0331] In some embodiments, R3, when present, is H, deuterium, C1-C6 alkyl, -S(O)2Rc, -S(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, or -P(O)2ORc; wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by Re, Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, R3, when present, is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by83573-422399 deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R3, when present, is H, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R3, when present, is H or C1-C6alkyl. In some embodiments, R3, when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, cyclopropyl, and the like. In some embodiments, R3, when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and the like. In some embodiments, R3, when present, is H or deuterium. In some embodiments, R3, when present, is H. In some embodiments, R3, when present, is deuterium.

[0332] In some embodiments, R4, when present, is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, Rc,is H, deuterium, halogen, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc,83573-422399 -P(O)2ORc, -CN, or -NO2. In some embodiments, R4, when present, is H, deuterium, halogen, or C1-C6alkyl. In some embodiments, R4, when present, is H or deuterium. In some embodiments, R4, when present, is H. In some embodiments, R4, when present, is deuterium.

[0333] In some embodiments, R5, when present, is H, deuterium, C1-C6alkyl, -S(O)2Rc, -S(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, or -P(O)2ORc; wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by Re, Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, R5, when present, is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R5, when present, is H, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R5, when present, is H or C1-C6 alkyl. In some embodiments, R5, when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, cyclopropyl, and the like. In some embodiments, R5, when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and the like. In some embodiments, R5, when present, is H or deuterium. In some embodiments, R5, when present, is H. In some embodiments, R5, when present, is deuterium.

[0334] In some embodiments, R6, when present, is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc,83573-422399 -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R6, when present, is H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R6, when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R6, when present, is H or deuterium. In some embodiments, R6, when present, is H. In some embodiments, R6, when present, is deuterium.

[0335] In some embodiments, R7, when present, is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R7, when present, is H, deuterium, halogen, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd,83573-422399 -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R7, when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R7, when present, is H or deuterium. In some embodiments, R7, when present, is H. In some embodiments, R7, when present, is deuterium.

[0336] In some embodiments, R8, when present, is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R8, when present, is H, deuterium, halogen, C1-C6 alkyl, or -NRaRb, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R8, when present, is H, deuterium, halogen, C1-C6alkyl, -NRaRb. In some embodiments, R8, when present, is H or deuterium. In some embodiments, R8, when present, is H. In some embodiments, R8, when present, is deuterium. In some embodiments, R8, when present, is halogen, for example fluoro. In some embodiments, R8, when present, is C1-C6 alkyl, for example methyl. In some embodiments, R8, when present, is -NRaRb.83573-422399

[0337] In some embodiments, R9, when present, is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, - - - - - - - - Rc, isH, deuterium, halogen, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R9, when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R9, when present, is H or deuterium. In some embodiments, R9, when present, is H. In some embodiments, R9, when present, is deuterium.

[0338] In some embodiments, each R10or R12, when present, is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -OS(O)NRcRd, -OS(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=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 C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl,83573-422399 and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=NRe)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, -N(C(O)Re)(C(O)Rf), -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NRcS(O)NReRf, -NRcS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -C(=NRf)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0339] In some embodiments, R10, when present, is independently H, deuterium, halogen, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -OS(O)NRcRd, -OS(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=NRe)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, -N(C(O)Re)(C(O)Rf), -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NRcS(O)NReRf, -NRcS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -C(=NRf)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, R10, when present is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=NRe)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, -N(C(O)Re)(C(O)Rf), -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NRcS(O)NReRf, -NRcS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -C(=NRf)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, R10is C1-C6alkyl, for example ethyl or propyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted by -ORe, wherein Reis H such that R10is a C1-C6 alkanol (e.g., ethanol or propanol such as 2-hydroxy-propan-1-yl or 1-hydroxy-propan-2-yl). In some embodiments, R10, when present, is H, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R10, when present, is H or C1-C6alkyl. In some embodiments, R10, when present,83573-422399 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, cyclopropyl, and the like. In some embodiments, R10, when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and the like. In some embodiments, R10, when present, is H or deuterium. In some embodiments, R10, when present, is H. In some embodiments, wherein R10, when present, is H, deuterium, methyl, ethyl, or propyl, wherein each hydrogen atom in methyl, ethyl, and propyl is independently optionally substituted by OH. In some embodiments, R10, when present, is deuterium. In some embodiments, R10, when present, is or, wherein the “ ” denotes a point

[0340] In embodiments, R11, when present, is H, deuterium, halogen, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R11, when present, is H, deuterium, halogen, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R11, when present, is H, deuterium, halogen, or C1-C6alkyl. In some embodiments, R11, when present, is H or deuterium. In some embodiments, R11, when present, is83573-422399 H. In some embodiments, R11, when present, is deuterium. In some embodiments, R12, when present independently H, deuterium, halogen, C1-C6alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -OS(O)NRcRd, -OS(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=NRe)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, -N(C(O)Re)(C(O)Rf), -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NRcS(O)NReRf, -NRcS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -C(=NRf)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, R12, when present is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=NRe)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, -N(C(O)Re)(C(O)Rf), -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NRcS(O)NReRf, -NRcS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -C(=NRf)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, R12is -S(O)2Rc, for example where Rcis C1-C6 alkyl, for example methyl. In some embodiments, R12is C1-C6 alkyl, for example ethyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted by -ORe, wherein Reis H such that R12is a C1-C6 alkanol (e.g., ethanol or propanol). In some embodiments, R12is C1-C6 alkyl, for example methyl. In some embodiments, R12, when present, is H, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R12, when present, is H or C1-C6 alkyl. In some embodiments, R12, when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, cyclopropyl, and the like. In some embodiments, R12, when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and the like. In some embodiments, R12, when present, is H or deuterium. In some embodiments, R12, when present, is H. In some embodiments, R12, when present, is deuterium. In some embodiments, R12, when present, is methyl or -S(O)2Re, for example -S(O)2C1-C6alkyl such as83573-422399 -S(O)2CH3. In some embodiments, R12, when present, is H, deuterium, methyl, ethyl, propyl, or -S(O)2Re, wherein each hydrogen atom in methyl, ethyl, and propyl is independently optionally substituted by OH. In some embodiments, R12, when present, is -CH3, -S(O)2CH3, , ,, , or , wherein the “ ” denotes asome when present, is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R13, when present, is H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R13, when present, is H, deuterium, halogen, or C1-C6alkyl. In some embodiments, R13, when present, is H or deuterium. In some embodiments, R13, when present, is H. In some embodiments, R13, when present, is deuterium.

[0342] In some embodiments, R14, when present, is H, deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to83573-422399 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R14, when present, is H, deuterium, halogen, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R14, when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R14, when present, is H or deuterium. In some embodiments, R14, when present, is H. In some embodiments, R14, when present, is deuterium. In some embodiments, R14, when present, is halogen, for example fluoro or chloro. In some embodiments, R15, when present, is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc,83573-422399 -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R15, when present, is H, deuterium, halogen, or C1-C6alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1- C6alkyl, C1-C6haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2. In some embodiments, R15, when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R15, when present, is H or deuterium. In some embodiments, R15, when present, is H. In some embodiments, R15, when present, is deuterium. In some embodiments, R15, when present, is -NRaRb, where each of Raand Rbis independently C1-C6 alkyl such as methyl. In some embodiments, R15, when present, is C3-C6 cycloalkyl, for example cyclopropyl. In some embodiments, R15, when present, is halogen, for example chloro or fluoro. In some embodiments, R15, when present, is C1-C6 alkyl, for example methyl, ethyl, or propyl (e.g., isopropyl), optionally substituted by halogen (e.g., fluoro such as difluoromethyl or trifluoromethyl). In some embodiments, R15, when present is -ORc, wherein Rcis C1-C6 alkyl, for example methyl.

[0343] In some embodiments, ring B / C is of the formula ,83573-422399

[0345] In some embodiments, ring D / E is of the formula , , ,or

[0347] In some embodiments, (L)m is -L2-(Z1-L1)p-Z-, where p 1 is or 2. In some embodiments, each of Z and Z1is independently a bond, -O-, -N(R18)C(O)-, -C(O)N(R18)-, -N(R18)-, - N(R18)S(O)-, S(O)N(R18)-, -N(R18)S(O)2-, -S(O)2N(R18)-, -S-, -S(O)-, or -S(O)2-.

[0348] In some embodiments, p 1 is or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[0349] In some embodiments, each L1is independently C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-, or C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-.

[0350] In some embodiments, L2is a bond, C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-. In some embodiments, each L1is independently83573-422399 -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17), or -C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-. In some embodiments, each L1is independently C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17), or -C(R16)(R17)- C(R16)(R17)-C(R16)(R17)-, wherein one or two of R16is a C1-C6 alkyl. In some embodiments, each L1is independently C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17), or -C(R16)(R17)-C(R16)(R17)- C(R16)(R17)-, wherein one or two of R16is a C1-C6 alkyl, and the remaining R16and R17are H or deuterium. In some embodiments wherein p is 1, L1is -C(R16)(R17)-C(R16)(R17). In some embodiments wherein p is 2, one instance of L1is C(R16)(R17)- and another instance of L1, when present, is C(R16)(R17)-C(R16)(R17)-.

[0351] In some embodiments, Z is a bond, -O-, -N(R18)C(O)-, -C(O)N(R18)-, -N(R18)-, -N(R18)S(O)-, S(O)N(R18)-, -N(R18)S(O)2-, -S(O)2N(R18)-, -S-, -S(O)-, or -S(O)2-. In some embodiments, Z is -O-. In some embodiments, Z is -N(R18)C(O)-. In some embodiments, Z is a bond.

[0352] In some embodiments, each Z1is independently a bond, -O-, -N(R18)C(O)-, -C(O)N(R18)- , -N(R18)-, N(R18)S(O)-, S(O)N(R18)-, -N(R18)S(O)2-, -S(O)2N(R18)-, -S-, -S(O)-, or -S(O)2-. In some embodiments, each Z1is independently -O- or -N(R18)-.

[0353] In some embodiments, L2is a bond, C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-. In some embodiments, L2is a bond.

[0354] In some embodiments, each R16and R17, when present, is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or two of R16and R17, taken together with the carbon or carbons to which they are attached, combine to form C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 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.

[0355] In some embodiments, one of R16or R17and an R18, taken together with the atoms to83573-422399 which each is attached, combine to form a 4- to 7-membered heterocycloalkyl; wherein each hydrogen atom in 4- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0356] In some embodiments, each R16and R17, when present, is independently H, deuterium, halogen, or C1-C6alkyl, or two of R16and R17, taken together with the carbon or carbons to which they are attached, combine to form C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1- C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or one of R16or R17and an R18, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl; wherein each hydrogen atom in 4- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0357] In some embodiments, each R16and R17, when present, is independently H, deuterium, halogen, or C1-C6 alkyl, or two of R16and R17, taken together with the carbon or carbons to which they are attached, combine to form C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, or -ORe,; or one of R16or R17and an R18, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl; wherein each hydrogen atom in 4- to 7- membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, or -ORc.83573-422399

[0358] In some embodiments, each R18, when present, is independently H, deuterium, -C(O)Rc, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; or R18and one of R16or R17, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 7-membered heterocycloalkyl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0359] In some embodiments, each R18, when present, is independently -C(O)Rc, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.

[0360] In some embodiments, each R18, when present, is independently C1-C6 alkyl or C3-C6 cycloalkyl, wherein each hydrogen atom in C1-C6 alkyl and C3-C6 cycloalkyl is independently optionally substituted by -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2.83573-422399

[0361] In some embodiments, each R18is independently H, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R18, when present, is independently H, C1-C6alkyl, or C3-C6 cycloalkyl. In some embodiments, an R18and an R16or R17, taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl. In some embodiments, each R18is independently H, deuterium, methyl, ethyl, propyl, iso-propyl, or cyclopropyl. In some embodiments, each R18, when present, is independently H, methyl, or ethyl.

[0362] In some embodiments, -(L)p- or -L2-(Z1-L1)p-Z- is of the formula

[0364] In some embodiments, each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, C1-C6alkylene-C6-C10aryl, 5- to 10-membered heteroaryl, C1-C6 alkylene-5- to 10-membered heteroaryl, and C1-C6 alkylene-3- to 7-membered heterocycloalkyl, or Raand Rbor Rcand Rdor Reand Rf, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6- C10 aryl, C1-C6 alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, or C1-C6 alkylene-5- to 10-83573-422399 membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6haloalkyl, -OH, -OC1-C6alkyl, -OC(O)-(H or C1-C6alkyl), -OC(O)N(H or C1-C6alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6alkyl)2, -OS(O)N(C2-C6alkylene), -OS(O)2N(H or C1-C6alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6alkyl)2, -S(O)N(C2-C6alkylene), -S(O)2N(H or C1-C6alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)- (H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)O(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)2(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2, -P(O)(C2-C6 alkylene), -P(O)2(H or C1-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6 alkyl), -CN, or -NO2.

[0365] 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 E are connected by a linker portion as described herein, wherein the linker portion comprises a chain of atoms, including but not limited to C, N, O, and S to provide a macrocycle.

[0366] In some embodiments, the disclosure provides a compound selected from the group consisting of 15-(methanesulfonyl)-8-methyl-2,11,12,15-tetrahydro-8H,10H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole;

[0367] 8-methyl-2,11,12,15-tetrahydro-8H,10H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole;

[0368] 2-(8-methyl-2,8,11,12-tetrahydro-10H,15H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazol-15-yl)ethan-1-ol;

[0369] 2-(8-methyl-2,8,11,12-tetrahydro-10H,14H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazol-14-yl)ethan-1-ol;

[0370] (2S)-1-[(10S)-12-ethyl-22-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13- hexahydro-14H-3,5:16,18-diethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin- 14-yl]propan-2-ol; and

[0371] (10S)-12-ethyl-22-fluoro-14-[(2S)-2-hydroxypropyl]-6-(methoxymethyl)-8,10-dimethyl- 2,11,12,14-tetrahydro-8H-3,5:16,18-diethenotripyrazolo[3,4-f:3',4'-j:4'',3''-83573-422399 n][1,4]oxazacyclopentadecin-13(10H)-one;

[0372] or a pharmaceutically acceptable salt thereof.

[0373] In some embodiments, the disclosure provides a compound selected from the group consisting of (2S)-2-[(10S)-20-methoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-15H- 5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15- yl]propan-1-ol;

[0374] 2-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0375] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-15H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15- yl]propan-1-ol;

[0376] (2S)-2-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-15H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15- yl]propan-1-ol;

[0377] 2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol;

[0378] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0379] (2S)-1-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol;

[0380] (2S)-2-[(10S)-12-ethyl-6,8,10,22-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0381] (2S)-2-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0382] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:16,18- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0383] (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol;

[0384] (2S)-2-[(10S)-19-fluoro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-83573-422399 (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0385] (2S)-2-[(10S)-20-methoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0386] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:18,16- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0387] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4,8]oxadiazacyclopentadecin- 14-yl]propan-1-ol;

[0388] (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:18,16- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0389] (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:16,18- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0390] (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4,8]oxadiazacyclopentadecin- 14-yl]propan-2-ol;

[0391] (2S)-2-[(10S)-20-fluoro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0392] (2S)-2-[(10S)-20-chloro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0393] (2S)-2-[(10S)-19-chloro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0394] (10S)-6,8,10,12,15,22-hexamethyl-2,10,11,12,13,15-hexahydro-8H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine;

[0395] (2S)-2-[(10S)-20-chloro-12-ethyl-6-(methoxymethyl)-8,10,22-trimethyl- 2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0396] (2S)-2-[(10S)-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10,22-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0397] (2S)-2-[(10S)-20-methoxy-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-83573-422399 5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0398] (2S)-2-[(10S)-6,8,10,12,20,22-hexamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0399] (2S)-2-[(10S)-20-ethyl-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol;

[0400] (2S)-2-[(10S)-20-cyclopropyl-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0401] (2S)-2-[(10S)-20-(difluoromethoxy)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0402] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-20-(trifluoromethoxy)-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; and

[0403] (2S)-2-[(10S)-20-(dimethylamino)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;

[0404] or a pharmaceutically acceptable salt thereof.

[0405] In some embodiments, the disclosure provides a compound selected from the group consisting of 2-[(10S)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol;

[0406] (2S)-1-[(10S)-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol;

[0407] (2S)-1-[(10S)-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol;

[0408] (2S)-1-[(10S)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro- 14H-3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0409] (2S)-2-[(10S)-6-(methoxymethyl)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H- 3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-83573-422399 yl]propan-1-ol; and

[0410] (2S)-1-[(10S)-12-ethyl-8,10-dimethyl-20-(propan-2-yl)-2,8,10,11,12,13-hexahydro- 14H-3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol;

[0411] or a pharmaceutically acceptable salt thereof.

[0412] In some embodiments, the disclosure provides a compound selected from the group consisting of (2S)-2-[(11S)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0413] (2S)-2-[(11S)-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0414] (11S)-7,9,11,13,16-pentamethyl-12,13,14,16-tetrahydro-9H,11H-6,3-(azenometheno)- 17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine;

[0415] (2S)-2-[(11S)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;

[0416] (2S)-1-[(11S)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0417] (2S)-2-[(11S)-7,9,11,13,23-pentamethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; and

[0418] (2S)-1-[(11S)-7,9,11,13,23-pentamethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-2-ol;

[0419] or a pharmaceutically acceptable salt thereof.

[0420] In some embodiments, the disclosure provides a compound selected from the group consisting of (2S)-2-[(10S)-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)- 16,18-ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)- yl]propan-1-ol;

[0421] (2S)-1-[(10S)-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)-16,18- ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)-yl]propan-2-ol;

[0422] (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)- 16,18-ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)-83573-422399 yl]propan-1-ol; and

[0423] (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)- 16,18-ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)- yl]propan-2-ol

[0424] or a pharmaceutically acceptable salt thereof.

[0425] The following represent illustrative embodiments of compounds of Formula (I-VIII): Ex # Structure Name (ACD) 1 1 1 183573-422399 Ex # Structure Name (ACD) (2S)-2-[(10S)-6,8,10,12,22- l-83573-422399 Ex # Structure Name (ACD) (2S)-2-[(10S)-12-ethyl-6,8,10,22- - -83573-422399 Ex # Structure Name (ACD) - - l-83573-422399 Ex # Structure Name (ACD) n][1,4,8]oxadiazacyclopentadecin-14- l 1 l - - - -83573-422399 Ex # Structure Name (ACD) n][1,4,11]oxadiazacyclopentadecin- 1 l 1 l83573-422399 Ex # Structure Name (ACD) (2S)-2-[(10S)-20-ethyl-6,8,10,12,22- t thl2 1 1112183573-422399 Ex # Structure Name (ACD) (2S)-2-[(11S)-7,9,11,13,23- t thl11121 14tt h83573-422399 Ex # Structure Name (ACD) 4- -and pharmaceutically acceptable salts thereof.

[0426] 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

[0427] 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.

[0428] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.

[0429] 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.83573-422399

[0430] 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.

[0431] 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.

[0432] 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.

[0433] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form83573-422399 or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg / kg / minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0434] 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.

[0435] For topical applications, the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery.

[0436] 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.

[0437] The term “subject” refers to a mammalian patient in need of such treatment, such as a human.

[0438] 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, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, acute myeloid leukemia (AML), congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, skin83573-422399 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.

[0439] In the inhibitory methods of the disclosure, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to a mutation of one or more kinases as described herein.

[0440] In treatment methods according to the disclosure, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment, such as those described herein having a disease, such as cancer, including those associated with aberrant oncogenic driver mutations such as those described herein, and resistance mutations, such as those described herein. 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).

[0441] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis. DRUG COMBINATIONS83573-422399

[0442] 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.

[0443] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the disclosure, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. For cancer indications, additional such agents include, but are not limited to, kinase inhibitors, such as ALK inhibitors (e.g., crizotinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatories such as NSAIDs. The pharmaceutical compositions of the disclosure may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents. CHEMICAL SYNTHESIS METHODS

[0444] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I)-(VI).

[0445] 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 grams83573-422399 mL milliliters NMR Nuclear Magnetic Resonance83573-422399 CMPP (Triphenylphosphoranylidene)acetonitrile DBAD Di-tert-butyl azodicarboxylate -83573-422399 PE petroleum ether PPh3 Triphenyl phosphine

[0446] The examples described herein are used to prepare the starting materials, intermediates and products of the disclosure. The materials, intermediates and products are either commercially available or prepared via conventional chemistry from commercially available materials. Examples of commercially available materials that can be used in the syntheses of the disclosure include 5-bromo-1H-pyrazolo[3,4-c]pyridine; 5-bromo-7-methyl-1H-pyrazolo[3,4-c]pyridine; 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine; 5-bromo-7-fluoro-1H-indazole; ethyl (2S)-2- hydroxypropanoate; (2R)-propane-1,2-diol; tert-butyl N-[(2R)-2-hydroxypropyl]carbamate; (R)- 2-methyloxirane; ethyl 7-methoxy-2H-indazole-3-carboxylate; methyl 5-bromo-1H-indazole-3- carboxylate; methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate; methyl 6-fluoro-1H- indazole-3-carboxylate; methyl 7-fluoro-1H-indazole-3-carboxylate; 7-chloro-1H-indazole-3- carboxylic acid; 1,3-dimethyl-1H-pyrazol-5-ol; 1-methyl-1H-pyrazol-5-ol; 5-bromo-1H- indazole; 5-bromo-1,2-dihydro-3H-indazol-3-one; (2-bromoethoxy)(tert-butyl)dimethylsilane; 4,4,5,5-tetramethyl-1,3,2-dioxaborolane; ethanamine. Those skilled in the art will recognize that83573-422399 the commercially available materials listed or illustrated herein are not exhaustive, and that additional commercially available materials may also be selected.

[0447] Intermediate Synthesis:

[0448] Intermediate Method I-1A

[0449] Synthesis of 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (I-1-1)

[0450] Step 1. To a solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine (23.0 g, 116 mmol, 1 eq), t- BuOK (26.0 g, 232 mmol, 2 eq) in THF (300 mL) was added a solution of I2 (32.4 g, 127 mmol, 1.1 eq) in THF (100 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 3 hrs. On completion, the mixture was quenched with saturated NaHSO3 (100 mL, aq.), diluted with H2O (300 mL), and extracted with EA (3 × 300 mL). The organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 5-bromo-3- iodo-1H-pyrazolo[3,4-c]pyridine (37.5 g, 115 mmol, 99.7% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.80 (s, 1H), 7.55 (s, 1H).

[0451] Step 2. To a solution of 5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine (25.0 g, 77.1 mmol, 1 eq) in toluene (250 mL) was added TsOH (2.66 g, 15.4 mmol, 0.2 eq) and 3,4-dihydro-2H- pyran (16.2 g, 192 mmol, 2.5 eq). The mixture was stirred at 90 °C for 2 hrs. On completion, the mixture was washed with NH4Cl solution (2 x 100 mL), washed with brine (2 x 100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE / EA= 100 / 8) to give 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazolo[3,4-c]pyridine (22.3 g, 54.6 mmol, 71 % yield) as a yellow solid.

[0452] I-1-2 was prepared in a manner similar to those described in Intermediate Method I-1A starting with 5-bromo-7-methyl-1H-pyrazolo[3,4-c]pyridine.

[0453] I-1-3 was prepared in a manner similar to those described in step 2 of Intermediate Method I-1A starting from 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine.

[0454] I-1-4 was prepared in a manner similar to those described in Intermediate Method I-1A starting from 5-bromo-7-fluoro-1H-indazole and using dioxane in step 2 instead of Toluene.

[0455] Intermediate Table 1.83573-422399 Number Structure LCMS: m / z1H NMR (400 MHz, DMSO-d6) (M+1) I 11 δ 908 1H 772 1H 600 .2 ), 1 4 , ),

[0457] Preparation of (S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol (I-2-3)

[0458] 1 eq) in DCM (50 mL) was added imidazole (8.64 g, 127 mmol, 3 eq), and then TBSCl (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 × 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 (SiO2, PE / EA= 10:1 to 10:1) to give ethyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate (9.70 g, 41.7 mmol, 99% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ = 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).

[0459] 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 THF, 74.8 mL, 2 eq) at 0°C under N283573-422399 atmosphere. The mixture was stirred 25 °C for 4 h. On completion, water (3 mL), 15% solution of NaOH (3 mL) and water (7.5 mL) was added successively, and the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 10:1 to 10:1) to give (S)-2-((tert-butyldimethylsilyl)oxy)propan- 1-ol (4.87 g, 25.6 mmol, 68% yield) as a white oil.

[0460] I-2-4 was prepared in a manner similar to those described in Intermediate Method I-2A step 1 starting from (2R)-propane-1,2-diol and TBDPSCl.

[0461] Intermediate Method I-2B

[0462] Preparation of (R)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl methanesulfonate (I-2-5)

[0463] Step 1. To a solution of (R)-propane-1,2-diol (5.00 g, 65.7 mmol, 1 eq) in DCM (50 mL) was added imidazole (13.4 g, 197 mmol, 3 eq) and TBSCl (9.90 g, 65.7 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was partitioned between DCM (50 mL) and water (100 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 10:1) to give (R)-1- ((tert-butyldimethylsilyl)oxy)propan-2-ol (8.00 g, 64% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 4.54 - 4.39 (m, 1H), 3.76 - 3.53 (m, 1H), 3.31 - 3.27 (m, 1H), 1.02 (d, J = 6.0 Hz, 3H), 0.87 - 0.84 (m, 9H), 0.02 (s, 6H).

[0464] Step 2. To a solution of (R)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (8.00 g, 42.1 mmol, 1 eq) in DCM (100 mL) was added TEA (8.51 g, 84.1 mmol, 2 eq) and Ms2O (10.9 g, 63.1 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the residue was diluted with H2O (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give (R)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl methanesulfonate (11.0 g, 97% yield) as a yellow solid.

[0465] I-2-6 and I-2-7 were prepared in a manner similar to those described in step 2 of Intermediate Method I-2B starting from I-2-4 and tert-butyl N-[(2R)-2- hydroxypropyl]carbamate, respectively.

[0466] Intermediate Method I-2C

[0467] Synthesis of (R)-N-ethyl-2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (I-2-8)83573-422399

[0468] - (100 mL) was added ethanamine (2 M in MeOH, 258 mL, 3 eq). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was concentrated to give (R)-1-(ethylamino)propan-2-ol (8.13 g, 78.8 mmol, 46% yield) as a brown solid.1H NMR (400 MHz, CDCl3) δ = 3.84 - 3.70 (m, 1H), 2.74 - 2.55 (m, 3H), 2.45 - 2.34 (m, 2H), 1.16 - 1.05 (m, 6H)

[0469] Step 2. To a solution of (R)-1-(ethylamino)propan-2-ol (8.13 g, 78.8 mmol, 1 eq) in DCM (80 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (24.8 g, 118 mmol, 16.4 mL, 1.5 eq) and TEA (39.9 g, 394 mmol, 5 eq) at 0 °C, and then the mixture was stirred at 0 °C for 1 h. On completion, the reaction mixture was partitioned between DCM (100 mL × 3) and water (100 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:1 to 1:1) to give (R)-N-ethyl-2,2,2-trifluoro-N-(2-hydroxypropyl)acetamide (7.92 g, 39.8 mmol, 50% yield) as a white solid.

[0470] Preparation of I-2-9 was prepared in a manner similar to those described in Intermediate Method I-2C using methanamine in step 1.

[0471] Intermediate Table 2 Structure LCMS: m / z1(M+1) H NMR (400 MHz, CDCl3) - - . 6 J .83573-422399 Structure LCMS: m / z1(M+1) H NMR (400 MHz, CDCl3) , .1 8-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-carboxylate (I-3-1)1 eq), (R)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (2.38 g, 12.4 mmol, 1.1 eq), PPh3(5.95 g, 22.7 mmol, 2 eq), DBAD (3.92 g, 17.0 mmol, 1.5 eq) in THF (100 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 0 °C for 0.5 hours under N2atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 1:1) to give ethyl (S)-1-(1- ((tert-butyldimethylsilyl)oxy)propan-2-yl)-7-methoxy-1H-indazole-3-carboxylate (250 mg, 636 μmol, 5% yield) as colorless oil. LCMS: m / z 393.1 (M+1)

[0474] Step 2. A mixture of ethyl (S)-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7- methoxy-1H-indazole-3-carboxylate (1.24 g, 3.16 mmol, 1 eq), Bis(pinacolato)diboron (1.36 g, 5.37 mmol, 1.7 eq), 4,4'-di-tert-butyl-2,2'-bipyridine (84.7 mg, 0.315 mmol, 0.1 eq), (1,5- Cyclooctadiene)(methoxy)iridium(I) dimer (104 mg, 0.157 mmol, 0.05 eq) in Hexanes (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 14 hours under N2atmosphere. 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 5:1) to give ethyl (S)-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7-methoxy-83573-422399 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-carboxylate (1.10 g, 2.12 mmol, 67% yield) as yellow oil. LCMS: m / z 519.3 (M+1)

[0475] Intermediate Method I-3A

[0476] Preparation of methyl 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxylate (I-3-2) 1eq), 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (3.80 g, 21.5 mmol, 1.1 eq), and PPh3 (10.2 g, 39.2 mmol, 2 eq) was dissolved in DCM (80 mL). To the mixture was added Di-(4- chlorobenzyl)azodicarboxylate (10.8 g, 29.4 mmol, 1.5 eq) in DCM (20 mL) at 0 °C. Then, the mixture was degassed and purged with N2for 3 times, and then stirred at 25 °C for 0.5 hours under N2 atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 10:1) to give methyl 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-indazole-3-carboxylate (3.63 g, 8.78 mmol, 44% yield) as a colorless oil. LCMS: m / z 413.1 (M+1)

[0478] Step 2. A mixture of methyl 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H- indazole-3-carboxylate (3.63 g, 8.78 mmol, 1 eq), Bis(pinacolato)diboron (3.12 g, 12.2 mmol, 1.4 eq), Pd(dppf)Cl2.CH2Cl2 (717 mg, 0.878 mmol, 0.1 eq), KOAc (2.59 g, 26.3 mmol, 3 eq) in dioxane (50 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N2 atmosphere. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 2-(2-((tert- butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3- carboxylate (4.00 g, 8.69 mmol, 98% yield) as a black oil. LCMS: m / z 461.1 (M+1)

[0479] I-3-3 was prepared in a similar manner to those described in Intermediate Method I-3A starting from methyl 5-bromo-1H-indazole-3-carboxylate and I-2-1.

[0480] I-3-4 was prepared in a similar manner to those described in Intermediate Method I-3A using methyl 5-bromo-1H-indazole-3-carboxylate and I-2-3.

[0481] I-3-5 was prepared in a manner similar to those described in Intermediate Method I-3A from methyl 5-bromo-1H-indazole-3-carboxylate and I-2-4. Note that two regio isomers were83573-422399 formed during step 1 of the synthesis and were separated at that step by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 20:1), first eluting peak was I-3-5.

[0482] Intermediate Method I-3B

[0483] Preparation of Methyl (S)-2-(2-((tert-butyldiphenylsilyl)oxy)propyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxylate (I-3-6) 1eq), ((S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol (4.93 g, 25.9 mmol, 1.1 eq), PPh3 (12.3 g, 47.0 mmol, 2 eq) in DCM (60 mL) was degassed and purged with N2for 3 times. Then, DCAD (12.9 g, 35.2 mmol, 1.5 eq) was added into the mixture at 0 °C, and then the mixture was stirred at 25 °C for 1 hour under N2atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 20:1) to give methyl (S)-5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propyl)-2H- indazole-3-carboxylate (4.05 g, 9.48 mmol, 40% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.19 (s, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 5.15 - 5.04 (m, 1H), 4.75 - 4.66 (m, 1H), 4.43 - 4.32 (m, 1H), 4.03 (d, J = 1.2 Hz, 3H), 1.29 - 1.23 (m, 3H), 0.72 (d, J = 1.2 Hz, 9H), -0.15 (s, 3H), -0.48 (s, 3H).

[0485] Step 2. To a solution of methyl (S)-5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propyl)- 2H-indazole-3-carboxylate (2.00 g, 4.68 mmol, 1 eq) in DCM (10 mL) was added HCl / dioxane (2 M, 2.5 mL, 1 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give methyl (S)-5-bromo-2-(2- hydroxypropyl)-2H-indazole-3-carboxylate (1.40 g, 4.47 mmol, 95% yield) as a white solid. LCMS: m / z 314.7 (M+1).

[0486] Step 3. To a solution of methyl (S)-5-bromo-2-(2-hydroxypropyl)-2H-indazole-3- carboxylate (3.00 g, 9.58 mmol, 1 eq), TBDPSCl (3.16 g, 11.5 mmol, 1.2 eq) in DCM (10 mL)83573-422399 was added TEA (2.91 g, 28.7 mmol, 3 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10:1) to give methyl (S)-5-bromo-2-(2-((tert-butyldiphenylsilyl)oxy)propyl)-2H- indazole-3-carboxylate (3.00 g, 5.44 mmol, 56% yield) as a yellow oil. LCMS: m / z 553.1 (M+1)

[0487] Step 4. A mixture of methyl (S)-5-bromo-2-(2-((tert-butyldiphenylsilyl)oxy)propyl)-2H- indazole-3-carboxylate (3.00 g, 5.44 mmol, 1 eq), bis(pinacolato)diboron (1.66 g, 6.53 mmol, 1.2 eq), Pd(dppf)Cl2(397 mg, 0.543 mmol, 0.1 eq), KOAc (1.60 g, 16.3 mmol, 3 eq) in dioxane (10 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 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10:1) to give methyl (S)-2-(2-((tert- butyldiphenylsilyl)oxy)propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3- carboxylate (2.00 g, 3.34 mmol, 61% yield) as a white solid. LCMS: m / z 599.0 (M+1)

[0488] Intermediate Method I-3C

[0489] Preparation of methyl (S)-2-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxylate (I-3-7)(10.5 g, 39.2 mmol, 1 eq), methyl 5-bromo-1H-indazole-3-carboxylate (10.0 g, 39.2 mmol, 1 eq), K2CO3(16.3 g, 117 mmol, 3 eq) in DMF (100 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N2 atmosphere. On completion, the residue was diluted with H2O (5 mL) and extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 10 / 1) to give methyl (S)-5-bromo-2-(1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-2H-indazole-3-carboxylate (5.00 g, 28% yield) as yellow oil. LCMS: m / z 428.7 (M+1)

[0491] Step 2. Conducted in a similar manner described in step 4 of Intermediate Method I-3B.83573-422399

[0492] I-3-8 was prepared in a similar manner described in Intermediate Method I-3C starting from methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate and I-2-6.

[0493] Intermediate Method I-3D

[0494] Preparation of methyl (S)-2-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxylate (I-3-9)mmol, 1 eq) in ACN (250 mL) was added NBS (21.0 g, 118 mmol, 2.3 eq) and AcOH (309 mg, 5.15 mmol, 0.1 eq). The mixture was stirred at 80 °C for 14 hours. On completion, the mixture was quenched with saturated solution of Na2SO3(20 mL) and extracted with ethyl acetate (50 mL × 3) and water (50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 0:1) to give methyl 5-bromo-6-fluoro-1H-indazole- 3-carboxylate (9.00 g, 32.9 mmol, 64% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 14.20 (s, 1H), 8.33 (d, J = 6.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H).

[0496] Step 2. A mixture of methyl 5-bromo-6-fluoro-1H-indazole-3-carboxylate (3.00 g, 10.9 mmol, 1 eq), (R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-ol (3.80 g, 12.0 mmol, 1.1 eq), DCAD (6.05 g, 16.4 mmol, 1.5 eq), PPh3 (5.76 g, 21.9 mmol, 2 eq) in DCM (80 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 0 °C for 1 hour under N2 atmosphere. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 0:1) to give methyl (S)-5-bromo-2-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-fluoro-2H- indazole-3-carboxylate (1.04 g, 1.83 mmol, 16% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 8.21 (d, J = 6.8 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.27 - 7.2183573-422399 (m, 5H),7.17 - 7.12 (m, 2H), 6.06 (ddd, J = 4.4, 6.8, 8.8 Hz, 1H), 4.01 - 3.95 (m, 1H), 3.93 (s, 3H), 3.84 (dd, J = 4.4, 10.0Hz, 1H), 1.56 -1.45 (m, 4H), 0.78 (s, 9H).

[0497] Step 3. A mixture of methyl (S)-5-bromo-2-(1-((tert-butyldiphenylsilyl)oxy)propan-2- yl)-6-fluoro-2H-indazole-3-carboxylate (1.00 g, 1.76 mmol, 1 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (668 mg, 2.63 mmol, 1.5 eq), Pd(dppf)Cl2(128 mg, 175 μmol, 0.1 eq), KOAc (516 mg, 5.27 mmol, 3 eq) in dioxane (15 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 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 (S)-2-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-fluoro- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxylate (590 mg, 956 μmol, 54% yield) as a yellow oil.

[0498] Intermediate Method I-3E

[0499] Preparation of methyl (S)-2-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxylate (I-3-10)I-3D starting with methyl 7-fluoro-1H-indazole-3-carboxylate.

[0501] Step 2. To a mixture of methyl 5-bromo-7-fluoro-1H-indazole-3-carboxylate (7.00 g, 25.6 mmol, 1 eq), (R)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (5.37 g, 28.2 mmol, 1.1 eq), PPh3(10.0 g, 38.4 mmol, 1.5 eq) in DCM (250 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 0 °C, then DBAD (8.85 g, 38.4 mmol, 1.5 eq) was added into the mixture, and then the mixture was stirred at 25 °C for 2 hours under N2 atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl83573-422399 acetate= 20:1) to give methyl (S)-5-bromo-2-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7- fluoro-2H-indazole-3-carboxylate (7.00 g, 15.7 mmol, 61% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 8.13 (d, J = 1.2 Hz, 1H), 7.61 (dd, J = 1.2, 10.4 Hz, 1H), 6.12 - 6.00 (m, 1H), 4.11 (s, 3H), 4.09 - 4.04 (m, 2H), 1.68 (d, J = 6.4 Hz, 3H), 0.77 (s, 9H), 0.00 (s, 3H), -0.15 (s, 3H).

[0502] Step 3. Conducted in a similar manner described in step 3 of Intermediate Method I-3D.

[0503] Intermediate Method I-3F

[0504] Preparation of methyl (S)-2-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxylate (I-3-11) OH O O OTBS OTBS O646 mmol, 1 eq) in MeOH (1200 mL) was added H2SO4(64.6 mmol, 3.44 mL, 0.1 eq). The mixture was stirred at 60 °C for 16 hours. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with EA (500 mL), adjusted to pH>7 by addition sat. NaHCO3 (500 mL) at 25 °C, and then extracted with EA (2 × 500 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give methyl 7-chloro-1H-indazole-3-carboxylate (100 g, 465 mmol, 72% yield, 98% purity) as a yellow solid. LCMS: m / z 211.1 (M+1).1H NMR (400 MHz, CDCl3) δ = 8.15 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.32 - 7.27 (m, 1H), 4.06 (s, 3H).

[0506] Step 2. A mixture of methyl 7-chloro-1H-indazole-3-carboxylate (119 g, 626 mmol, 1.1 eq), PPh3 (224 g, 854 mmol, 1.5 eq) in THF (1000 mL) was degassed and purged with N2 for 3 times, and then DBAD (157 g, 683 mmol, 1.2 eq) in THF (200 mL) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 0.5 hours under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. And then the residue was purified by column chromatography (SiO2, PE / EA= 100% to 97.5%) to give methyl (S)-2- (1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7-chloro-2H-indazole-3-carboxylate (120 g, 31083573-422399 mmol, 54% yield) as a colorless oil. LCMS: m / z 383.4 (M+1).1H NMR (400 MHz, CDCl3) δ = 7.94 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.07 - 5.96 (m, 1H), 4.14 (t, J = 9.2 Hz, 1H), 4.03 (s, 3H), 3.98 - 3.90 (m, 1H), 1.66 (d, J = 6.8 Hz, 3H), 0.72 (s, 9H), -0.06 (s, 3H), -0.22 (s, 3H).

[0507] Step 3. To a solution of methyl (S)-2-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7- chloro-2H-indazole-3-carboxylate (117 g, 305 mmol, 1 eq) in ACN (1200 mL) was added NBS (108 g, 611 mmol, 2 eq) and AcOH (30.5 mmol, 1.75 mL, 0.1 eq). The mixture was stirred at 60 °C for 2 hours. On completion, the reaction mixture was quenched by addition sat. Na2SO3(2000 mL) at 25 °C, diluted with H2O (1000 mL), and extracted with EA (3 × 2000 mL). The combined organic layers were 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% to 97%) to give methyl (S)-5-bromo-2-(1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-7-chloro-2H-indazole-3-carboxylate (76.0 g, 164 mmol, 53% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 8.13 (s, 1H), 7.70 (s, 1H), 6.00 - 5.86 (m, 1H), 3.98 (s, 3H), 3.95 (d, J = 6.8 Hz, 2H), 1.54 (d, J = 6.8 Hz, 3H), 0.63 (s, 9H), -0.13 (s, 3H), -0.30 (s, 3H).

[0508] Step 4. A mixture of methyl (S)-5-bromo-2-(1-((tert-butyldimethylsilyl)oxy)propan-2- yl)-7-chloro-2H-indazole-3-carboxylate (75.0 g, 162 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (45.3 g, 178 mmol, 1.1 eq), AcOK (31.8 g, 324 mmol, 2 eq) and Pd(dppf)Cl2 (11.8 g, 16.2 mmol, 0.1 eq) in dioxane (750 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 hour under N2 atmosphere. On completion, the reaction mixture was diluted with H2O (1000 mL) and extracted with EA (2 × 1000 mL). The combined organic layers were washed with brine (2 × 1000 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% to 97%) to give methyl (S)-2-(1-((tert-butyldimethylsilyl)oxy)propan- 2-yl)-7-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxylate (80.0 g, 139 mmol, 86% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 8.40 (s, 1H), 7.73 (s, 1H), 6.09 - 5.96 (m, 1H), 4.17 - 4.11 (m, 1H), 4.06 (s, 3H), 3.96 - 3.91 (m, 1H), 1.65 (d, J = 6.8 Hz, 3H), 1.39 (s, 12H), 0.71 (s, 9H), -0.09 (s, 3H), -0.25 (s, 3H).

[0509] Intermediate Method I-3G

[0510] Preparation of methyl 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole-3-carboxylate (I-3-12)83573-422399 mmol,1 eq) mmol, 1.1 eq). The mixture was stirred at 30 °C for 12 h. On completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EA (25 mL × 3). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / THF= 1 / 0 to 3 / 1) to give methyl 5-bromo-1-methyl-1H-indazole-3-carboxylate (4.40 g, 16.4 mmol, 83 % yield) as a yellow solid. LCMS: m / z 291.0 (M+23)

[0512] Step 2. A mixture of methyl 5-bromo-1-methyl-1H-indazole-3-carboxylate (4.40 g, 17.5 mmol, 1 eq), BPD (8.87 g, 35.0 mmol, 2 eq), Pd(dppf)Cl2 (1.28 g, 1.75 mmol, 0.1 eq), KOAc (3.43 g, 35.0 mmol, 2 eq) in dioxane (47 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 1 h under N2 atmosphere. On completion, the reaction mixture was 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 3 / 1) to give methyl 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-carboxylate (5.00 g, 15.8 mmol, 91% yield) as a yellow solid.

[0513] I-3-13 was prepared in a similar manner to those described in Intermediate Method I-3A using methyl 5-bromo-1H-indazole-3-carboxylate and I-2-4. Note that two regio isomers were formed during step 1 of the synthesis and were separated at that step by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 20:1), second eluting peak was I-3-13.

[0514] Intermediate Table 383573-422399 Number Structure LCMS: m / z (M+1)83573-422399 Number Structure LCMS: m / z (M+1)

[0515] Intermediate Method I-4A83573-422399

[0516] Preparation of 5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)-1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7-methoxy-1H-indazole-3-carbaldehyde (I-4-1)

[0517] Step 1. A mixture of ethyl (S)-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7- methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-carboxylate (1.10 g, 2.12 mmol, 1 eq), 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (865 mg, 2.12 mmol, 1 eq), Na2CO3 (674 mg, 6.36 mmol, 3 eq), Pd(dppf)Cl2.CH2Cl2 (173 mg, 0.212 mmol, 0.1 eq) in dioxane (15 mL) and H2O (3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 0.5 hours under N2 atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 0:1) to give ethyl 5-(5-bromo-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-((S)-1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-7-methoxy-1H-indazole-3-carboxylate (880 mg, 1.31 mmol, 61% yield) as a colorless oil. LCMS: m / z 672.2 (M+1).

[0518] Step 2. A mixture of ethyl 5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- c]pyridin-3-yl)-1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7-methoxy-1H-indazole-3- carboxylate (880 mg, 1.31 mmol, 1 eq) in THF (10 mL) was degassed and purged with N2 for 3 times. Then, to the mixture was added DIBAL-H (1 M in THF, 3.9 mL, 3 eq) and was stirred at 0 °C for 0.5 hours under N2 atmosphere. On completion, the mixture was quenched with water83573-422399 (6 mL), and then the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 2:1) to give (5- (5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-((S)-1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-7-methoxy-1H-indazol-3-yl)methanol (325 mg, 0.515 mmol, 39% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.96 (s, 1H), 8.09 (s, 1H), 7.80 (s, 1H), 7.31 (d, J = 1.6 Hz, 1H), 6.00 - 5.76 (m, 1H), 5.55 - 5.36 (m, 1H), 4.07 (s, 3H), 4.04 - 3.80 (m, 3H), 2.64 - 2.50 (m, 1H), 2.19 (d, J = 10.4 Hz, 2H), 1.88 - 1.67 (m, 7H), 1.58 (d, J = 6.8 Hz, 3H), 0.75 (s, 9H), -0.05 (s, 3H), -0.16 (s, 3H). LCMS: m / z 630.0 (M+1).

[0519] Step 3. To a solution of (5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- c]pyridin-3-yl)-1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7-methoxy-1H-indazol-3- yl)methanol (325 mg, 0.515 mmol, 1 eq) in DCM (3 mL) was added DMP (262 mg, 0.618 mmol, 1.2 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was quenched with the saturated Na2S2O3 (5 mL), NaHCO3 (5 mL) and extracted with ethyl acetate (8 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-((S)-1- ((tert-butyldimethylsilyl)oxy)propan-2-yl)-7-methoxy-1H-indazole-3-carbaldehyde (250 mg, 0.397 mmol, 77% yield) as a yellow oil.

[0520] I-4-2, I-4-3, and I-4-4 were prepared in a manner similar to those described in Intermediate Method I-4A using the SMs as listed below in intermediate table 4.

[0521] I-4-5 was prepared in a manner similar to those described in Intermediate Method I-4A step 1 with the SMs as listed below in intermediate table 4.

[0522] I-4-6 was prepared in a manner similar to those described in Intermediate Method I-4A using the SMs as listed below in intermediate table 4.

[0523] I-4-7, I-4-8, I-4-9 and I-4-10 were prepared from the SMs as listed below in intermediate table 4 in a manner similar to those described in step 1 of Intermediate Method I-4A.

[0524] Intermediate Method I-4B

[0525] Preparation of methyl 5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- c]105yridine-3-yl)-2-((S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-2H-indazole-3- carboxylate (I-4-11)83573-422399- 2-yl)-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxylate (1.60 g, 2.67 mmol, 1 eq), 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (1.64 g, 4.01 mmol, 1.5 eq), Pd(dppf)Cl2 (195 mg, 0.267 mmol, 0.1 eq), Cs2CO3 (849 mg, 8.02 mmol, 3 eq) in dioxane (15 mL) and H2O (3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N2 atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 10:1) to give methyl 5-(5-bromo-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazolo[3,4-c]106yridine-3-yl)-2-((S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)- 2H-indazole-3-carboxylate (1.30 g, 1.73 mmol, 64% yield) as a white solid.

[0527] I-4-12 and I-4-13 were prepared in a manner similar to those described in Intermediate Method I-4A step 1 using the SMs as listed below in intermediate table 4.

[0528] I-4-14, I-4-15 and I-4-16 were prepared in a manner similar to those described in Intermediate Method I-4B step 1 using the SMs as listed below in intermediate table 4 and substituting Na2CO3 for Cs2CO3.

[0529] I-4-17 was prepared in a manner similar to those described in Intermediate Method I-4B step 1 using the SMs as listed below in intermediate table 4 and substituting K2CO3 for Cs2CO3.

[0530] I-4-18 was prepared in a manner similar to those described in Intermediate Method I-4B step 1 using the SMs as listed below in intermediate table 4 and substituting Na2CO3 for Cs2CO3 along with decreasing reaction time to 1 hour.

[0531] I-4-19 was prepared in a manner similar to those described in Intermediate Method I-4A step 1 using the SMs as listed below in intermediate table 4.

[0532] Intermediate Table 4.83573-422399 Int # SMs Structure LCMS: m / z (M+1)83573-422399 Int # SMs Structure LCMS: m / z (M+1)83573-422399 Int # SMs Structure LCMS: m / z (M+1)83573-422399 Int # SMs Structure LCMS: m / z (M+1)

[0533] Preparation of tert-butyl (S)-(2-((1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (I-5-2)

[0534] Step 1. To a solution of (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl methanesulfonate (14.0 g, 55.2 mmol, 1 eq) and 1,3-dimethyl-1H-pyrazol-5-ol (4.96 g, 44.2 mmol, 0.8 eq) in DMF (50 mL) was added K2CO3(22.9 g, 165 mmol, 3 eq). The mixture was stirred at 80 °C for 12 hours. On completion, the reaction mixture was quenched by addition H2O (150 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with saturated solution of NaCl (150 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3:1) to give tert-83573-422399 butyl (S)-(2-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (7.50 g, 27.8 mmol, 50% yield) as a white solid. LCMS: m / z 190.8 (M-78)

[0535] Step 2. To a solution of tert-butyl (S)-(2-((1,3-dimethyl-1H-pyrazol-5- yl)oxy)propyl)carbamate (7.40 g, 27.4 mmol, 1 eq) in ACN (30 mL) was added NBS (5.87 g, 32.9 mmol, 1.2 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the reaction mixture was quenched by addition H2O (50 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with saturated solution of NaCl (60 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:1) to give tert-butyl (S)-(2-((4-bromo- 1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (5.50 g, 15.7 mmol, 57% yield) as a white solid. LCMS: m / z 191.1 (M-156)

[0536] Step 3. To a solution of tert-butyl (S)-(2-((4-bromo-1,3-dimethyl-1H-pyrazol-5- yl)oxy)propyl)carbamate (5.00 g, 14.3 mmol, 1 eq) in DMF (30 mL) was added NaH (861 mg, 21.5 mmol, 60% purity, 1.5 eq). The mixture was stirred at 0 °C for 0.5 hours. MeI (3.06 g, 21.5 mmol, 1.5 eq) was added and the mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was quenched by addition H2O (90 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with saturated solution of NaCl (90 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3:1 to 2:1) to give tert-butyl (S)-(2-((4- bromo-1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (5.00 g, 13.8 mmol, 96% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ = 4.86 - 4.65 (m, 1H), 3.53 (s, 3H), 3.46 - 3.06 (m, 2H), 2.91 (d, J = 4.8 Hz, 3H), 2.08 (s, 3H), 1.39 (s, 9H), 1.22 - 1.15 (m, 3H). LCMS: m / z 190.9 (M-170)

[0537] Step 4. To a solution of tert-butyl (S)-(2-((4-bromo-1,3-dimethyl-1H-pyrazol-5- yl)oxy)propyl)(methyl)carbamate (1.00 g, 2.76 mmol, 1 eq) in dioxane (3 mL) was added slowly XPhos (131 mg, 0.276 mmol, 0.1 eq) at 110 °C. After addition, the mixture was stirred at this temperature for 0.5 hours, and then Pinacolborane (1.06 g, 8.28 mmol, 3 eq) and Bis(acetonitrile)dichloropalladium(II) (71.6 mg, 0.276 mmol, 0.1 eq) and TEA (2.76 mmol, 1 eq) was added into the mixture. The resulting mixture was stirred at 110 °C for 2 hours. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 9:1 to 5:1) to give tert-butyl (S)-(2-((1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (1.10 g, 2.69 mmol, 97% yield) as a yellow solid.

[0538] Intermediate Table 5.83573-422399 Intermediate # Structure LCMS: m / z (M+1)

[0540] Preparation of 5-(5-(1,3-dimethyl-5-(((S)-1-(methylamino)propan-2-yl)oxy)-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-((S)-1-hydroxypropan-2-yl)-7-methoxy-1H- indazole-3-carbaldehyde (5-2)

[0541] Step 1. To a solution of tert-butyl ((2S)-2-((4-(3-(1-((S)-1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-3-formyl-7-methoxy-1H-indazol-5-yl)-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,3-dimethyl-1H-pyrazol-5- yl)oxy)propyl)(methyl)carbamate (40.0 mg, 0.0481 mmol, 1 eq) in DCM (0.5 mL) was added HCl / dioxane (2 M, 0.3 mL, 10 eq). The mixture was stirred at 25 °C for 0.1 hour. On completion, the mixture was concentrated to give 5-(5-(1,3-dimethyl-5-(((S)-1-(methylamino)propan-2- yl)oxy)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-((S)-1-hydroxypropan-2-yl)-7- methoxy-1H-indazole-3-carbaldehyde (25.0 mg, 0.0439 mmol, 91% yield, HCl) as a yellow solid. LCMS: m / z 533.2 (M+1)83573-422399

[0542] Deprotection Method D2

[0543] Preparation of (S)-5-(5-(1,3-dimethyl-5-((1-(methylamino)propan-2-yl)oxy)-1H- pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-(2-hydroxyethyl)-2H-indazole-3-carbaldehyde (6-2)(2-((tert- butyldimethylsilyl)oxy)ethyl)-3-formyl-2H-indazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-c]pyridin-5-yl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (50.0 mg, 0.0635 mmol, 1 eq) in DCM (1 mL) was added HCl / EtOAc (2 M, 0.3 mL, 10 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was concentrated to give (S)-5-(5-(1,3-dimethyl-5-((1-(methylamino)propan-2-yl)oxy)-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)-2-(2-hydroxyethyl)-2H-indazole-3-carbaldehyde (30.0 mg, 0.0571mmol, 89% yield, HCl) as a green solid. LCMS: m / z 489.3 (M+1)

[0545] Deprotection Method D3

[0546] Preparation of 1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(5-(1,3-dimethyl-5- (((S)-1-(methylamino)propan-2-yl)oxy)-1H-pyrazol-4-yl)-7-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-indazole-3-carbaldehyde (7-2) N Boc NH

[0547] Step 1. To a solution of tert-butyl ((2S)-2-((4-(3-(1-((S)-1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-3-formyl-1H-indazol-5-yl)-7-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,3-dimethyl-1H-pyrazol-5-83573-422399 yl)oxy)propyl)(methyl)carbamate (20.0 mg, 0.0245 mmol, 1 eq) in DCM (1 mL) was added ZnBr2(16.5 mg, 0.0736 mmol, 3 eq). The mixture was stirred at 25 °C for 0.16 hours. On completion, the reaction mixture was partitioned between dichloromethane (10 mL × 3) and water (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(5-(1,3-dimethyl-5- (((S)-1-(methylamino)propan-2-yl)oxy)-1H-pyrazol-4-yl)-7-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-indazole-3-carbaldehyde (15.0 mg, 0.0237 mmol, 96% yield) as a brown solid. LCMS: m / z 631.2 (M+1)

[0548] Deprotection Method D4

[0549] Preparation of (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-15H- 5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin- 15-yl]propan-1-ol (Ex.7)2-yl]- 6,8,10,12,22-pentamethyl-2-(oxan-2-yl)-2,10,11,12,13,15-hexahydro-8H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (14.0 mg, 0.0227 mmol, 1 eq) in THF (1 mL) was added TBAF (1 M in THF, 0.1 mL, 3 eq). The mixture was stirred at 25 °C for 0.16 hours. On completion, the mixture was filtered and concentrated to give a residue. The filtrate was purified by prep-HPLC purification (column: CD01-Phenomenex luna C18 150*25*10um; mobile phase: [water(FA)-ACN]; gradient: 3%-33% B over 11 min), column: CD07-Daisogel SP-100-8-ODS-PK 150*25*10um;mobile phase: [water( NH4HCO3)- ACN];gradient:27%-57% B over 11 min to give (2S)-2-[(10S)-6,8,10,12,22-pentamethyl- 2,8,10,11,12,13-hexahydro-15H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-15-yl]propan-1-ol (0.290 mg, 0.00057 mmol, 2.54% yield) as an off-white solid.

[0551] Deprotection Method D583573-422399

[0552] Preparation of (2S)-2-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-15H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15- yl]propan-1-ol (Ex.8)2-yl]- 6,8,10,12-tetramethyl-2-(oxan-2-yl)-2,10,11,12,13,15-hexahydro-8H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (20.0 mg, 0.0292 mmol, 1 eq) in DCM (2 mL) was added TFA (3.33 mg, 0.0292 mmol, 1 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent. The crude product was purified by reversed-phase column: CD01-Phenomenex luna C18150 x25x10um; mobile phase: [water(FA)- ACN]; gradient: 1%-31% B over 11 min to give (2S)-2-[(10S)-6,8,10,12-tetramethyl- 2,8,10,11,12,13-hexahydro-15H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-15-yl]propan-1-ol (0.290 mg, 0.000596 mmol, 2.04% yield) as a white solid.

[0554] Deprotection Method D6

[0555] Preparation of (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin- 14-yl]propan-1-ol (Ex.12)

[0556] Step 1. To a solution of (10S)-14-[(2S)-2-{[tert-butyl(diphenyl)silyl]oxy}propyl]- 6,8,10,12-tetramethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (54.0 mg, 0.065783573-422399 mmol, 1 eq) in THF (2 mL) was added pyridinium chloride (7.59 mg, 0.0657 mmol, 1 eq). The mixture was stirred at 25 °C for 0.16 hours. On completion, the mixture was filtered and concentrated to give a residue. The filtrate was purified by prep-HPLC purification (column: CD01-Phenomenex luna C18150 x 25 x 10um; mobile phase: [water(FA)-ACN]; gradient:13%- 43% B over 10 min) to give (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (3.40 mg, 0.0062 mmol, 9.47% yield, FA salt) as a yellow gum.

[0557] Deprotection Method D7

[0558] Preparation of (2S)-1-[(10S)-12-ethyl-22-fluoro-6-(methoxymethyl)-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-14H-3,5:16,18-diethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol (Ex.17)

[0559] Step 1. To a solution of (2S)-1-[(10S)-12-ethyl-22-fluoro-6-(methoxymethyl)-8,10- dimethyl-2-(oxan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5:16,18-diethenotripyrazolo[3,4- f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol (80.0 mg, 0.127 mmol, 1 eq) in MeOH (1 mL) was added conc. HCl (12.0 M, 0.172 mL, 16.3 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: CD01- Phenomenex luna C18150 x 25 x 10 um; mobile phase: [water (FA)-ACN]; gradient: 16%-46% B over 10 minutes. (2S)-1-[(10S)-12-ethyl-22-fluoro-6-(methoxymethyl)-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-14H-3,5:16,18-diethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol (33.37 mg, 0.059 mmol, 40.03% yield, 96.86% purity) as a white solid.

[0560] Deprotection Method D8

[0561] Preparation of tert-butyl ((2S)-2-((4-(3-(3-formyl-2-((S)-2-hydroxypropyl)-2H-indazol- 5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(methoxymethyl)-1- methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (Ex.19-2)83573-422399

[0562] ((S)-2-((tert-- - pyran-2-yl)-1H- pyrazolo[3,4-b]pyridin-5-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (100 mg, 122 μmol, 1 eq) in DMSO (1 mL) was added CsF (92.0 mg, 612 μmol, 5 eq) and stirred at 25 °C for 1 h. On completion, the reaction mixture was diluted with H2O (3 mL) and extracted with EA (1 mL × 3). The combined organic layers were washed with Brine (3 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound of tert-butyl ((2S)- 2-((4-(3-(3-formyl-2-((S)-2-hydroxypropyl)-2H-indazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5- yl)oxy)propyl)carbamate (90.0 mg, crude) was obtained as a yellow oil. LCMS: m / z 703.3 (M+1).

[0563] Deprotection Method D9

[0564] Preparation of (2S)-2-[(5S)-16-fluoro-27,32,35,5,7-pentamethyl-12H,21H,32H-4-oxa-7- aza-2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)-pyrazolacyclooctaphan-12-yl]propan- 1-ol (Ex.21)

[0565] 21- (oxan-2-yl)-12H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)- pyrazolacyclooctaphan-12-yl]propoxy}di(phenyl)silane (made from intermediate 21-1 using Reduction Method R3) (29.0 mg, 34.4 μmol, 1 eq) in THF (1 mL) was added HF / Pyr (28.4 mg, 172 μmol, 70% purity, 5 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 purification (column: CD01-Phenomenex luna C18 150*25*10um;mobile phase: [water(FA)- ACN];gradient:15%-45% B over 10 min) to give (2S)-2-[(5S)-16-fluoro-27,32,35,5,7-83573-422399 pentamethyl-12H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)- pyrazolacyclooctaphan-12-yl]propan-1-ol (1.92 mg, 3.33 μmol, 9.67% yield, 98% purity, FA) as a yellow solid.

[0566] Deprotection Method D10

[0567] Preparation of (5S)-11,27,32,35,5,7-hexamethyl-11H,21H,32H-4-oxa-7-aza-2(3,5)- pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)-pyrazolacyclooctaphane (Ex.37)

[0568] 4-oxa-7-aza- 2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)-pyrazolacyclooctaphan-21-yl]oxane (prepared from intermediate 37-1 using Reduction Method R3) (16.0 mg, 29.6 μmol, 1 eq) in MeOH (0.5 mL) was added HCl / MeOH (2 M, 400 μL, 33.79 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give (5S)-11,27,32,35,5,7-hexamethyl-11H,21H,32H-4-oxa-7-aza-2(3,5)- pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)-pyrazolacyclooctaphane (1.60 mg, 3.50 μmol, 11.84% yield) as an off-white solid.

[0569] Reduction Method R1

[0570] Preparation of tert-butyl ((2S)-2-((4-(3-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3- (hydroxymethyl)-2H-indazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5- yl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (9-1)

[0571] propan-2- yl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-83573-422399 yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-indazole-3-carboxylate (500 mg, 0.634 mmol, 1 eq) in THF (5 mL) was added LAH (2.5 M in THF, 0.126 mL, 0.5 eq). The mixture was stirred at 0 °C for 1 h. On completion, the mixture was sequentially quenched by water (0.01 mL), 15% NaOH (0.01 mL), water (0.03 mL) at 0 °C. The combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:1) to give tert-butyl ((2S)-2-((4-(3-(2-(2- ((tert-butyldimethylsilyl)oxy)ethyl)-3-(hydroxymethyl)-2H-indazol-5-yl)-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (428 mg, 0.562 mmol, 89% yield) as a yellow oil. LCMS: m / z 761.5 (M+1)

[0572] Reduction Method R2

[0573] Preparation of (10S)-14-[(2S)-1-{[tert-butyl(diphenyl)silyl]oxy}propan-2-yl]- 6,8,10,12,22-pentamethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (12-2)2-yl]- 6,8,10,12,22-pentamethyl-2-(oxan-2-yl)-2,11,12,14-tetrahydro-8H-5,3-(azenometheno)-16,18- ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-13(10H)-one (60.0 mg, 0.0716 mmol, 1 eq) in toluene (1 mL) was added LiAlH4 (2.5 M in THF, 0.1 mL, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was sequentially quenched with water (0.1 mL), 15% NaOH (0.1 mL) and H2O (0.1 mL × 3) and then dried over anhydrous sodium sulfate, filtered and concentrated to give (10S)-14-[(2S)-1-{[tert- butyl(diphenyl)silyl]oxy}propan-2-yl]-6,8,10,12,22-pentamethyl-2-(oxan-2-yl)- 2,10,11,12,13,14-hexahydro-8H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecine (55.0 mg, 0.0668 mmol, 93% yield) as a white solid.. LCMS: m / z 823.4 (M+1)

[0575] Reduction Method R3

[0576] Preparation of (2S)-1-[(10S)-12-ethyl-22-fluoro-6-(methoxymethyl)-8,10-dimethyl-2- (oxan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5:16,18-diethenotripyrazolo[3,4-f:3',4'-j:4'',3''-83573-422399 n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol (17-2)

[0577] Step 1. A mixture of AlCl3 (17.3 mg, 0.130 mmol, 7.09 μL, 0.58 eq) in THF (1 mL) was degassed and purged with N2for 3 times, LiAlH4(2.50 M in THF, 0.179 mL, 2 eq) was added at 0 °C and stirred for 10 minutes. (10S)-14-[(2S)-2-{[tert-butyl(diphenyl)silyl]oxy}propyl]-12- ethyl-22-fluoro-6-(methoxymethyl)-8,10-dimethyl-2-(oxan-2-yl)-2,11,12,14-tetrahydro-8H- 3,5:16,18-diethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-13(10H)-one (170 mg, 0.224 mmol, 1 eq) in THF (1 mL) was added at 0 °C, and then the mixture was stirred at 0 °C for 1 hour under N2 atmosphere. On completion, the mixture was sequentially quenched water (0.2 mL): NaOH (15%) (0.2 mL): water (0.6 mL). Then the mixture was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The mixture was not purified and used in next step. (2S)-1-[(10S)-12-ethyl-22-fluoro-6-(methoxymethyl)-8,10-dimethyl-2-(oxan-2-yl)- 2,8,10,11,12,13-hexahydro-14H-3,5:16,18-diethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol (110 mg, 0.174 mmol, 78% yield) was obtained as a yellow oil. LCMS: m / z 632.2 (M+1).

[0578] Preparation of 15-(methanesulfonyl)-8-methyl-2,11,12,15-tetrahydro-8H,10H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole (Ex.1)

[0579] Preparation of 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H- pyrazol-3-one (1-1)

[0580] , SEM-Cl (17.2 g, 103 mmol, 2 eq) and K2CO3 (30.0 g, 217 mmol, 4 eq) in ACN (50 mL) was stirred at 20 °C for 2 h. On completion, the mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH= 1:0 to 20:1) to give83573-422399 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (9.00 g, 39.4 mmol, 77% yield) as a yellow solid. LCMS: m / z 228.8 (M+1).

[0581] Step 2. To the mixture of 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H- pyrazol-3-one (8.96 g, 39.2 mmol, 1 eq) in ACN (180 mL) was added NBS (6.98 g, 39.2 mmol, 1 eq) at 0 °C. The resulting mixture was stirred at this temperature for 1 h. On completion, the reaction mixture was partitioned between ethyl acetate (70 mL × 3) and water (120 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF= 1:0 to 1:1) to give 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (9.67 g, 31.4 mmol, 80% yield) as a white solid. LCMS: m / z 306.8 (M+1).

[0582] Preparation of 1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-pyrazol- 5-ol (1-2)2H- pyran (8.54 g, 101 mmol, 2 eq) and 4-methylbenzenesulfonic acid hydrate (1.93 g, 10.1 mmol, 0.2 eq) in toluene (100 mL) was stirred at 90 °C for 16 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5:0 to 5:1) to give 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (10.0 g, 35.7 mmol, 70% yield) as a yellow oil. LCMS: m / z 196.7 (M+1-85).

[0584] Step 2. To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (9.00 g, 32.0 mmol, 1 eq), Bis(pinacolato)diboron (12.1 g, 48.0 mmol, 1.5 eq), potassium acetate (9.43 g, 96.0 mmol, 3 eq) in dioxane (180 mL) was added Pd(dppf)Cl2 (2.34 g, 3.20 mmol, 0.1 eq). The mixture was stirred at 90 °C for 3 h under N2. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF= 1:0 to83573-422399 5:1) to give 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole (11.5 g, crude) as a yellow gum. LCMS: m / z 328.9 (M+1)

[0585] Step 3. To a mixture of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazole (5.34 g, 16.2 mmol, 1 eq), 4-bromo-2-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (5.00 g, 16.2 mmol, 1 eq), Cs2CO3 (15.9 g, 48.8 mmol, 3 eq) in dioxane (107 mL) and H2O (22 mL) was added Pd(dppf)Cl2(1.19 g, 1.63 mmol, 0.1 eq). Then the mixture was stirred at 90 °C for 3 h under N2. 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 1:1) to give 2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (6.30 g, 14.7 mmol, 90% yield) as a white solid. LCMS: m / z 429.2 (M+1)

[0586] Step 4. To a solution of 2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazol-3-one (6.30 g, 14.7 mmol, 1 eq) in THF (63 mL) was added tetrabutylammonium fluoride (1 M in THF, 73.5 mL, 5 eq). The mixture was stirred at 60 °C for 12 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / (DCM / MeOH= 10:1)=1:0 to 1:1)) to give 1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-pyrazol-5-ol (7.4 g, crude) as a brown solid. LCMS: m / z 298.9 (M+1)

[0587] Preparation of 15-(methanesulfonyl)-8-methyl-2,11,12,15-tetrahydro-8H,10H- 3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole (Ex.1)83573-422399

[0588] Step 1. To a mixture of 5-bromo-1,2-dihydro-3H-indazol-3-one (8.60 g, 40.3 mmol, 1 eq) and propane-1,3-diol (9.22 g, 121 mmol, 3 eq) in toluene (170 mL) was added (Triphenylphosphoranylidene)acetonitrile (24.3 g, 80.7 mmol, 2 eq). The mixture was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 12 h under N2atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM: THF= 1:0 to 3:1) to give 3-((5-bromo-1H- indazol-3-yl)oxy)propan-1-ol (5.80 g, 52% yield) as a white solid. LCMS: m / z 272.5 (M+1)

[0589] Step 2. To a solution of 3-((5-bromo-1H-indazol-3-yl)oxy)propan-1-ol (3.00 g, 11.0 mmol, 1 eq) in DCM (30 mL) was added TEA (5.60 g, 55.3 mmol, 5 eq) and MsCl (7.65 g, 66.7 mmol, 6.04 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was partitioned between DCM (50 mL) and sat. citric acid (50 mL). The separated organic layer was washed with sat. aqueous citric acid (50 mL × 2) and sat. NaCl (50 mL × 2), and dried over Na2SO4, filtered and concentrated to give 3-((5-bromo-1-(methylsulfonyl)-1H-indazol-3- yl)oxy)propyl methanesulfonate (4.80 g, crude) as a white solid. LCMS: m / z 428.4 (M+1)

[0590] Step 3. To a mixture of 3-((5-bromo-1-(methylsulfonyl)-1H-indazol-3-yl)oxy)propyl methanesulfonate (500 mg, 1.17 mmol, 1 eq) and 1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)-1H-pyrazol-5-ol (349 mg, 1.17 mmol, 1 eq) in DMF (8 mL) was added K2CO3 (485 mg, 3.51 mmol, 3 eq). The mixture was stirred at 60 °C for 2 h. On completion, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 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, PE: THF= 1:0 to 1:1) to give 5-bromo-3-(3-((1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1H-pyrazol-5-83573-422399 yl)oxy)propoxy)-1-(methylsulfonyl)-1H-indazole (370 mg, 50% yield) as a colorless oil. LCMS: m / z 630.6 (M+1)

[0591] Step 4. To a mixture of 5-bromo-3-(3-((1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)-1H-pyrazol-5-yl)oxy)propoxy)-1-(methylsulfonyl)-1H-indazole (325 mg, 0.516 mmol, 1 eq) and Bis(pinacolato)diboron (196 mg, 0.774 mmol, 1.5 eq) in dioxane (10 mL) was added KOAc (126 mg, 1.29 mmol, 2.5 eq) and Pd(dppf)Cl2•CH2Cl2(42.1 mg, 0.052 mmol, 0.1 eq). The resulting mixture was stirred at 100 °C for 2 h under N2. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:0 to 1:1) to give 3-(3-((1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)- 1H-pyrazol-5-yl)oxy)propoxy)-1-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-indazole (310 mg, 88% yield) as a yellow oil. LCMS: m / z 677.1 (M+1)

[0592] Step 5. To a solution of 3-(3-((1-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)-1H-pyrazol-5-yl)oxy)propoxy)-1-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazole (290 mg, 0.428 mmol, 1 eq) in DCM (29 mL) was added TFA (8.93 g, 78.3 mmol, 182 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give 3-(3-((4-(1H-indazol-5-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propoxy)-1- (methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (220 mg, 86% yield) as a brown oil. LCMS: m / z 592.8 (M+1)

[0593] Step 6. To a solution of 3-(3-((4-(1H-indazol-5-yl)-1-methyl-1H-pyrazol-5- yl)oxy)propoxy)-1-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole (218 mg, 0.367 mmol, 1 eq) in THF (4 mL) was added tBuOK (412 mg, 3.68 mmol, 10 eq). The resulting mixture was stirred at 0 °C for 0.1 h. After that a solution of I2 (93.3 mg, 0.367 mmol, 1 eq) in THF (2 mL) was added to the mixture, and the mixture was stirred at 25 °C for another 2 h. On completion, the mixture was quenched with aq. Na2SO3 (2 mL) and partitioned between water (25 mL) and ethyl acetate (25 mL × 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, PE:THF= 1:0 to 1:1) to give 3-(3-((4-(3-iodo-1H- indazol-5-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propoxy)-1-(methylsulfonyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (250 mg, 94% yield) as a yellow oil. LCMS: m / z 718.7 (M+1)

[0594] Step 7. A mixture of 3-(3-((4-(3-iodo-1H-indazol-5-yl)-1-methyl-1H-pyrazol-5- yl)oxy)propoxy)-1-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole (200 mg, 0.278 mmol, 1 eq), Cs2CO3 (272 mg, 0.835 mmol, 3 eq) in dioxane (20 mL) and H2O (2 mL) was added Pd(dppf)Cl2.CH2Cl2 (22.7 mg, 0.028 mmol, 0.1 eq). The mixture was83573-422399 degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:0 to 1:2) to give 15-(methanesulfonyl)-8-methyl-2,11,12,15- tetrahydro-8H,10H-3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7- c'']tripyrazole (120 mg, 92% yield) as a yellow solid.

[0595] Preparation of 8-methyl-2,11,12,15-tetrahydro-8H,10H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole (Ex.2)

[0596] Step 1. To a solution of 15-(methanesulfonyl)-8-methyl-2,11,12,15-tetrahydro-8H,10H- 3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole (10.0 mg, 0.022 mmol, 1 eq) in DMSO (0.5 mL) was added K2CO3 (8.93 mg, 0.065 mmol, 3 eq). The mixture was stirred at 80 °C for 1 h. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate C18 150*25mm*5um;mobile phase: [water(TFA)-ACN]; B%: 17%-47%,10min) to give 8-methyl- 2,11,12,15-tetrahydro-8H,10H-3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14- c':6,7-c'']tripyrazole (1.40 mg, 16% yield, 96% purity) as a brown solid.

[0597] Preparation of 2-(8-methyl-2,8,11,12-tetrahydro-10H,15H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazol-15-yl)ethan-1-ol (Ex. 3) and 2-(8-methyl-2,8,11,12-tetrahydro-10H,14H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazol-14-yl)ethan-1-ol (Ex.4)83573-422399

[0598] Step 1. To a mixture of 15-(methanesulfonyl)-8-methyl-2,11,12,15-tetrahydro-8H,10H- 3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole (105 mg, 0.226 mmol, 1 eq) and 3,4-dihydro-2H-pyran (38.0 mg, 0.452 mmol, 2 eq) in toluene (3.5 mL) was added 4-methylbenzenesulfonic acid (7.8 mg, 0.045 mmol, 0.2 eq). The mixture was stirred at 90 °C for 16 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:0 to 1:2) to give 15-(methanesulfonyl)-8-methyl-2-(oxan-2-yl)-2,9,10,11,12,15-hexahydro-8H-3,5:16,18- diethenooxacyclopentadecino[11,10-c:15,14-c':6,7-c'']tripyrazole (36.0 mg, 29% yield) as a yellow solid. LCMS: m / z 549.0 (M+1)

[0599] Step 2. To a solution of 15-(methanesulfonyl)-8-methyl-2-(oxan-2-yl)-2,9,10,11,12,15- hexahydro-8H-3,5:16,18-diethenooxacyclopentadecino[11,10-c:15,14-c':6,7-c'']tripyrazole (30.0 mg, 0.055 mmol, 1 eq) in DMSO (1.8 mL) was added CsF (58.1 mg, 0.382 mmol, 7 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (SiO2, PE:THF= 1:2) to give 8-methyl-2-(oxan-2-yl)-2,11,12,15- tetrahydro-8H,10H-3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7- c'']tripyrazole (20.0 mg, 77% yield) as a yellow solid. LCMS: m / z 471.0 (M+1)

[0600] Step 3. To a mixture of 8-methyl-2-(oxan-2-yl)-2,11,12,15-tetrahydro-8H,10H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole (50.0 mg, 0.106 mmol, 1 eq) and (2-bromoethoxy)(tert-butyl)dimethylsilane (38.1 mg, 0.159 mmol, 1.5 eq) in DMF (2.5 mL) was added Cs2CO3 (103 mg, 0.318 mmol, 3 eq) and NaI (15.9 mg, 0.106 mmol, 1 eq). The mixture was stirred at 60 °C for 1 h. On completion, the mixture was quenched with water (5 mL)83573-422399 and extracted with ethyl acetate (5 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (SiO2, PE:THF= 1:2) to give a mixture of 15-(2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)-8-methyl-2-(oxan-2-yl)-2,11,12,15-tetrahydro-8H,10H- 3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole (30.0 mg, 0.048 mmol, 44% yield) and 14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-8-methyl-2-(oxan-2- yl)-2,11,12,14-tetrahydro-8H,10H-3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11- c:15,14-c':6,7-c'']tripyrazole (5.00 mg, 0.0092 mmol, 8.64% yield) as a yellow oil. LCMS: m / z 629.1 (M+1)

[0601] Step 4. To a mixture of 15-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-8-methyl-2-(oxan-2- yl)-2,11,12,15-tetrahydro-8H,10H-3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11- c:15,14-c':6,7-c'']tripyrazole (30.0 mg, 0.048 mmol, 1 eq) and 14-(2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)-8-methyl-2-(oxan-2-yl)-2,11,12,14-tetrahydro-8H,10H- 3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole (5.00 mg, 0.0092 mmol, 0.192 eq) in DCM (3 mL) was added TFA (20.2 mmol, 1.5 mL, 424 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(TFA)-ACN]; B%: 10%-40%, 10 min) to give 2-(8- methyl-2,8,11,12-tetrahydro-10H,14H-3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11- c:15,14-c':6,7-c'']tripyrazol-14-yl)ethan-1-ol (2.33 mg, 0.00541 mmol, 11.35% yield, 100% purity) as an off-white solid and 2-(8-methyl-2,8,11,12-tetrahydro-10H,15H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazol-15-yl)ethan-1-ol (9.26 mg, 0.021 mmol, 44.19% yield, 98.01% purity) as a grey solid.

[0602] General Method A

[0603] Preparation of (2S)-2-[(10S)-20-methoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13- hexahydro-15H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-15-yl]propan-1-ol (Ex.5)83573-422399 NH N O N N N O N OHdioxaborolan-2-yl)-1H-pyrazol-5-yl)oxy)propyl)(methyl)carbamate (71.6 mg, 0.174 mmol, 1 eq), 5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-((S)-1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-7-methoxy-1H-indazole-3-carbaldehyde (110 mg, 0.174 mmol, 1 eq), Pd(dppf)Cl2 (11.4 mg, 0.0175 mmol, 0.1 eq), and Cs2CO3 (171 mg, 0.524 mmol, 3 eq) in dioxane (1 mL) and H2O (0.2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 0.5 hours under N2 atmosphere. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 0:1) to give tert-butyl ((2S)-2-((4- (3-(1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-formyl-7-methoxy-1H-indazol-5-yl)- 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,3-dimethyl-1H-pyrazol-5- yl)oxy)propyl)(methyl)carbamate (50.0 mg, 0.060 mmol, 34% yield) as a yellow solid.

[0605] Step 2. Performed according to Deprotection Method D1.

[0606] Step 3. To a solution of 5-(5-(1,3-dimethyl-5-(((S)-1-(methylamino)propan-2-yl)oxy)- 1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-((S)-1-hydroxypropan-2-yl)-7-methoxy- 1H-indazole-3-carbaldehyde (25.0 mg, 0.044 mmol, 1 eq, HCl salt) in THF (0.5 mL) and DMF (0.1 mL) was added AcOH (2.64 mg, 0.044 mmol, 1 eq) until the solution pH was between 5-6. The reaction mixture was stirred at 25 °C for 0.05 hour, then NaBH3CN (3.31 mg, 0.053 mmol, 1.2 eq) was added at 25°C and stirred for an additional 0.05 hours. The mixture was stirred at 25 °C for 0.1 hour. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25mm x 10um; mobile phase: [water(FA)-ACN]; gradient: 5%-35% B over 8 min) to give (2S)-2-[(10S)-20-methoxy- 6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-15H-5,3-(azenometheno)-16,18- ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15-yl]propan-1-ol (1.38 mg, 0.0022 mmol, 5.03% yield, 90.08% purity, FA) as a white solid.

[0607] General Method B

[0608] Preparation of (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-15H- 5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin- 15-yl]propan-1-ol (Ex.7)83573-422399

[0610] Step 2. Performed according to Deprotection Method D3.

[0611] Step 3. Conducted in a manner described in General Method A step 3 using only THF as solvent.

[0612] Step 4. Performed according to Deprotection Method D4.

[0613] General Method C

[0614] Preparation of 2-[(10S)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]ethan-1-ol (Ex.9)83573-422399-1H- pyrazolo[3,4-b]pyridin-3-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-indazole-3- carboxylate (1.06 g, 1.72 mmol, 1 eq), 2-methylpyrazol-3-ol (220 mg, 2.24 mmol, 1.3 eq) in 2- MeTHF (10 mL) was added K2CO3 (477 mg, 3.45 mmol, 2 eq) and tBuBrettPhosPdG3 (147 mg, 0.172 mmol, 0.1 eq). The mixture was stirred at 80 °C for 1 h. On completion, the mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, DCM:MeOH= 15:1) to give methyl 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(5-(5-hydroxy-1- methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2H- indazole-3-carboxylate (1.13 g, crude) as a brown solid. LCMS: m / z 632.4 (M+1)

[0616] Step 2. To a solution of methyl 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(5-(5- hydroxy-1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin- 3-yl)-2H-indazole-3-carboxylate (1.06 g, 1.68 mmol, 1 eq), (R)-1-((tert- butoxycarbonyl)amino)propan-2-yl methanesulfonate (2.13 g, 8.39 mmol, 5 eq) in DMF (10 mL) was added K2CO3 (696 mg, 5.03 mmol, 3 eq). The mixture was stirred at 80 °C for 1 h. On completion, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with water (20 mL × 2) and dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF= 1:1) to give methyl 5-(5-(5-(((S)-1-((tert- butoxycarbonyl)amino)propan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-indazole-3- carboxylate (1.10 g, 1.39 mmol, 83% yield) as a yellow oil. LCMS: m / z 789.5 (M+1)

[0617] Step 3. Performed according to Reduction Method R1.83573-422399

[0618] Step 4. To a solution of tert-butyl ((2S)-2-((4-(3-(2-(2-((tert- butyldimethylsilyl)oxy)ethyl)-3-(hydroxymethyl)-2H-indazol-5-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (408 mg, 0.536 mmol, 1 eq) in DCM (4 mL) was added DMP (273 mg, 0.643 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched with sat. Na2SO3 (10 mL) at 0 °C and extracted with DCM (5 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give tert-butyl ((2S)-2-((4- (3-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-formyl-2H-indazol-5-yl)-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (427 mg, crude) as a yellow solid. LCMS: m / z 759.5 (M+1)

[0619] Step 5. Conducted in a manner described in Deprotection Method D3.

[0620] Step 6. To a solution of 5-(5-(5-(((S)-1-aminopropan-2-yl)oxy)-1-methyl-1H-pyrazol-4- yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(2-((tert- butyldimethylsilyl)oxy)ethyl)-2H-indazole-3-carbaldehyde (20.0 mg, 0.0304 mmol, 1 eq) in MeOH (0.5 mL) was added AcOH (0.030 mmol, 1.74 μL, 1 eq). The mixture was stirred at 25 °C for 0.2 h, then NaBH3CN (3.82 mg, 0.061 mmol, 2 eq) was added. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched by water (0.1 mL) and dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH= 10:1) to give (10S)-14-(2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)-8,10-dimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H- 3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (10.0 mg, crude) as a yellow solid. LCMS: m / z 643.4 (M+1)

[0621] Step 7. To a solution of (10S)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-8,10- dimethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-(azenometheno)-16,18- ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (10.0 mg, 0.016 mmol, 1 eq), formaldehyde (0.934 mg, 0.031 mmol, 2 eq) in MeOH (0.3 mL) was added AcOH (0.0156 mmol, 0.89 μL, 1 eq). The mixture was stirred at 25 °C for 0.5 h, then NaBH3CN (2.93 mg, 0.0467 mmol, 3 eq) was added. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched by water (0.1 mL) and dried over Na2SO4, and the mixture was filtered and concentrated to give(10S)-14-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-8,10,12-trimethyl-2- (oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4- f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine (10.0 mg, crude) as a yellow oil. LCMS: m / z 657.4 (M+1)

[0622] Step 8. Conducted in a manner described in Deprotection Method D1.

[0623] General Method D83573-422399

[0624] Preparation of (2S)-1-[(10S)-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H- 3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin- 14-yl]propan-2-ol (Ex.11)b]pyridin-3-yl)-2-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-2H-indazole-3-carboxylate (1.80 g, 2.86 mmol, 1 eq), 1-methyl-1H-pyrazol-5-ol (337 mg, 3.44 mmol, 1.2 eq), potassium carbonate (791 mg, 5.73 mmol, 2 eq), tBuBrettPhos Pd G3(122 mg, 0.143 mmol, 0.05 eq) in 2-MeTHF (15 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, the reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF = 1:0 to 1:1) to give methyl 2-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-5-(5-(5- hydroxy-1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin- 3-yl)-2H-indazole-3-carboxylate (1.10 g, 1.70 mmol, 59% yield) as a white solid. LCMS: m / z 646.3 (M+1)

[0626] Step 2. A mixture of methyl 2-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-5-(5-(5- hydroxy-1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-83573-422399 3-yl)-2H-indazole-3-carboxylate (610 mg, 0.944 mmol, 1 eq), (R)-N-ethyl-2,2,2-trifluoro-N-(2- hydroxypropyl)acetamide (206 mg, 1.04 mmol, 1.1 eq), DBAD (326 mg, 1.42 mmol, 1.5 eq), PPh3 (495 mg, 1.89 mmol, 2 eq) in THF (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 0.5 hours under N2atmosphere. 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 1:1) to give methyl 2-((S)-2-((tert- butyldimethylsilyl)oxy)propyl)-5-(5-(5-(((S)-1-(N-ethyl-2,2,2-trifluoroacetamido)propan-2- yl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3- yl)-2H-indazole-3-carboxylate (780 mg, 0.943 mmol, 99% yield) as a white solid. LCMS: m / z 827.8 (M+1)

[0627] Step 3. To a solution of methyl 2-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-5-(5-(5- (((S)-1-(N-ethyl-2,2,2-trifluoroacetamido)propan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2H-indazole-3-carboxylate (280 mg, 0.338 mmol, 1 eq) in THF (2 mL) and H2O (0.4 mL) was added LiOH.H2O (21.3 mg, 0.507 mmol, 1.5 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 3:1) to give 2-((S)-2-((tert- butyldimethylsilyl)oxy)propyl)-5-(5-(5-(((S)-1-(ethylamino)propan-2-yl)oxy)-1-methyl-1H- pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2H-indazole-3- carboxylic acid (200 mg, 0.278 mmol, 82% yield) as a white solid. LCMS: m / z 717.4 (M+1)

[0628] Step 4. To a solution of 2-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-5-(5-(5-(((S)-1- (ethylamino)propan-2-yl)oxy)-1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-b]pyridin-3-yl)-2H-indazole-3-carboxylic acid (200 mg, 0.278 mmol, 1 eq) in DCM (2 mL) was added HATU (127 mg, 0.334 mmol, 1.2 eq) and DIEA (108 mg, 0.836 mmol, 3 eq). The mixture was stirred at 25 °C for 14 hours. On completion, the reaction 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 (10S)-14-[(2S)-2-{[tert- butyl(dimethyl)silyl]oxy}propyl]-12-ethyl-8,10-dimethyl-2-(oxan-2-yl)-2,11,12,14-tetrahydro- 8H-3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-13(10H)-one (110 mg, 0.157 mmol, 56% yield) as a colorless oil. LCMS: m / z 699.4 (M+1)

[0629] Step 5. Conducted in a manner described in Reduction Method R1.

[0630] Step 6. Conducted in a manner described in Deprotection Method D1.

[0631] General Method E83573-422399

[0632] Preparation of (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H- 5,3:16,18-di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol (Ex.16)D steps 1-4 using intermediates: I-4-12, I-5-3 and I-2-9.

[0634] Step 2. Conducted in a manner described in Deprotection Method D1.

[0635] Step 3. Conducted in a manner described in Reduction Method R2.

[0636] Step 4. Conducted in a manner described in Deprotection Method D6.

[0637] General Method F

[0638] Preparation of (2S)-1-[(10S)-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13- hexahydro-14H-3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol (Ex.19)83573-422399C steps 1-4 using starting materials I-4-7, I-5-4 and I-2-7.

[0640] Step 5. Performed according to Deprotection Method D8.

[0641] Step 6. To a solution of tert-butyl ((2S)-2-((4-(3-(3-formyl-2-((S)-2-hydroxypropyl)-2H- indazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3- (methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (90.0 mg, 128 μmol, 1 eq) in DCM (1 mL) was added TBDPSCl (38.7 mg, 141 μmol, 1.1 eq) and imidazole (26.0 mg, 384 μmol, 3 eq) and stirred at 0 °C for 1 h. On completion, the reaction mixture was diluted with H2O (3 mL) and extracted with DCM (1 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound tert-butyl ((2S)-2-((4-(3-(2-((S)-2-((tert-butyldiphenylsilyl)oxy)propyl)-3-formyl-2H-indazol-5-yl)-1-83573-422399 (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(methoxymethyl)-1-methyl-1H- pyrazol-5-yl)oxy)propyl)carbamate (180 mg, crude) was obtained as a yellow solid. LCMS: m / z 941.2 (M+1)

[0642] Step 7. Conducted in a manner described in Deprotection Method D1.

[0643] Step 8. To a solution of 5-(5-(5-(((S)-1-aminopropan-2-yl)oxy)-3-(methoxymethyl)-1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-((S)-2-((tert- butyldiphenylsilyl)oxy)propyl)-2H-indazole-3-carbaldehyde (140 mg, 185 μmol, 1 eq) in THF (2 mL) was added sodium triacetoxyboranuide (78.4 mg, 370 μmol, 2 eq) and CH3COOH (185 μmol, 10.6 μL, 1 eq) and stirred 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 prep- HPLC (column: CD01-Phenomenex luna C18150*25*10um; mobile phase: [water (FA)-ACN]; gradient: 3%-33% B over 8 min). Compound (2S)-1-[(10S)-6-(methoxymethyl)-8,10-dimethyl- 2,8,10,11,12,13-hexahydro-14H-3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol (1.94 mg, 3.7 μmol, 2% yield, 96.6% purity) was obtained as an off-white solid.

[0644] General Method G

[0645] Preparation of (2S)-2-[(5S)-17-fluoro-27,32,35,5,7-pentamethyl-12H,21H,32H-4-oxa-7- aza-2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)-pyrazolacyclooctaphan-12-yl]propan- 1-ol (Ex.31)83573-422399(((S)-1-((tert- butoxycarbonyl)(methyl)amino)propan-2-yl)oxy)-1,3-dimethyl-1H-pyrazol-4-yl)-7-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-((S)-1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-7-fluoro-2H-indazole-3-carboxylate (1.60 g, 1.85 mmol, 1 eq) in DCM (20 mL) was added ZnBr2 (2.09 g, 9.27 mmol, 5 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:1) to give methyl 2-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(5-(1,3- dimethyl-5-(((S)-1-(methylamino)propan-2-yl)oxy)-1H-pyrazol-4-yl)-7-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-7-fluoro-2H-indazole-3-carboxylate (1.00 g, 1.31 mmol, 70% yield) as a yellow solid. LCMS: m / z 736.5 (M+1)

[0647] Step 2. To a solution of methyl 2-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(5- (1,3-dimethyl-5-(((S)-1-(methylamino)propan-2-yl)oxy)-1H-pyrazol-4-yl)-7-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-7-fluoro-2H-indazole-3- carboxylate (1.00 g, 1.31 mmol, 1 eq) in THF (10 mL) and H2O (2 mL) was added LiOH (164 mg, 3.93 mmol, 3 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction83573-422399 mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, DCM / MEOH= 5:1) to give 2-((S)-1-((tert- butyldimethylsilyl)oxy)propan-2-yl)-5-(5-(1,3-dimethyl-5-(((S)-1-(methylamino)propan-2- yl)oxy)-1H-pyrazol-4-yl)-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)-7-fluoro-2H-indazole-3-carboxylic acid (500 mg, 667 μmol, 50% yield) as a white solid. LCMS: m / z 749.4 (M+1)

[0648] Step 3. To a solution of 2-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(5-(1,3- dimethyl-5-(((S)-1-(methylamino)propan-2-yl)oxy)-1H-pyrazol-4-yl)-7-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-7-fluoro-2H-indazole-3-carboxylic acid (500 mg, 667 μmol, 1 eq) in ACN (3 mL) was added NMI (82.2 mg, 1.00 mmol, 1.5 eq), TCFH (280 mg, 1.00 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 1:1) to give (5S)-12- [(2S)-1-{[tert-butyldi(methyl)silyl]oxy}propan-2-yl]-17-fluoro-27,32,35,5,7-pentamethyl-21- (oxan-2-yl)-12H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)- pyrazolacyclooctaphan-8-one (350 mg, 478 μmol, 71% yield) as a yellow oil. LCMS: m / z 731.3 (M+1)

[0649] Step 4. A mixture of AlCl3 (9.12 mg, 68.4 μmol, 0.5 eq) in THF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 0 °C for 0.1 hour under N2 atmosphere. Then LAH (2.5 M in THF, 0.1 mL, 2 eq) was added into the mixture, and then the mixture was stirred at 0 °C for 0.1 hour under N2 atmosphere. (5S)-12-[(2S)-1-{[tert- butyldi(methyl)silyl]oxy}propan-2-yl]-17-fluoro-27,32,35,5,7-pentamethyl-21-(oxan-2-yl)- 12H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)- pyrazolacyclooctaphan-8-one (100 mg, 136 μmol, 1 eq) was added into the mixture, and the mixture was stirred at 0 °C for 1 hour. On completion, the mixture was sequentially quenched by H2O (0.2 mL), 15% NaOH (0.2 mL), H2O (0.6 mL), dried over Na2SO4, and filtered and concentrated under reduced pressure to give tert-butyl{(2S)-2-[(5S)-17-fluoro-27,32,35,5,7- pentamethyl-21-(oxan-2-yl)-12H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)- indazola-3(4,3)-pyrazolacyclooctaphan-12-yl]propoxy}di(methyl)silane (80.0 mg, 111 μmol, 81% yield) as a yellow solid. LCMS: m / z 717.5 (M+1)

[0650] Step 5. To a solution of tert-butyl{(2S)-2-[(5S)-17-fluoro-27,32,35,5,7-pentamethyl-21- (oxan-2-yl)-12H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)- pyrazolacyclooctaphan-12-yl]propoxy}di(methyl)silane (80.0 mg, 111 μmol, 1 eq) in DCM (2 mL) was added 2 M HCl / dioxane (2 M, 0.5 mL, 8.96 eq). The mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was filtered and concentrated under reduced pressure to83573-422399 give a residue, the residue was purified by prep-HPLC (column: CD24-XPT C18150*25*7um; mobile phase: [water(FA)-ACN]; gradient: 20%-50% B over 15 min) to give (2S)-2-[(5S)-17- fluoro-27,32,35,5,7-pentamethyl-12H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-c]pyridina- 1(5,3)-indazola-3(4,3)-pyrazolacyclooctaphan-12-yl]propan-1-ol (10.54 mg, 20.32 μmol, 18.21% yield, 100% purity, FA) as a white solid.

[0651] General Method H

[0652] Preparation of (5S)-11,27,32,35,5,7-hexamethyl-21-(oxan-2-yl)-11H,21H,32H-4-oxa-7-aza- 2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)-pyrazolacyclooctaphan-8-one (37-1)2-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-1H-indazole-3-carboxylate (1.50 g, 3.10 mmol, 1 eq), 1,3- dimethyl-1H-pyrazol-5-ol (625 mg, 5.57 mmol, 1.8 eq), K2CO3(856 mg, 6.19 mmol, 2 eq), [2- (2-aminophenyl)phenyl]-methylsulfonyloxy-palladium ditert-butyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (265 mg, 310 μmol, 0.1 eq) in 2-MeTHF (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 h under N2atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2,83573-422399 DCM:MeOH= 1 / 0 to 10 / 1) to give methyl 5-(5-(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-7- methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-1H-indazole-3- carboxylate (1.40 g, 2.72 mmol, 88% yield) as a yellow solid. LCMS: m / z 516.2 (M+1)

[0654] Step 2. A mixture of methyl 5-(5-(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-7-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-1H-indazole-3- carboxylate (800 mg, 1.55 mmol, 1 eq), (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N- methylacetamide (575 mg, 3.10 mmol, 2 eq) was added PPh3 (814 mg, 3.10 mmol, 2 eq) and degassed and purged with N2for 3 times, then a solution of DBAD (715 mg, 3.10 mmol, 2 eq) in THF (8 mL) was added dropwise into the mixture, and the mixture was stirred at 25 °C for 1 h under N2atmosphere. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue, the residue was triturated with MTBE at 25 °C for 30 min. The residue was purified by column chromatography (SiO2, PE / THF= 1 / 0 to 1 / 1) to give methyl 5-(5-(1,3-dimethyl-5-(((S)-1-(2,2,2-trifluoro-N-methylacetamido)propan-2-yl)oxy)-1H-pyrazol- 4-yl)-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-1H- indazole-3-carboxylate (450 mg, 659 μmol, 42% yield) as a yellow oil. LCMS: m / z 683.3 (M+1)

[0655] Step 3. To a solution of methyl 5-(5-(1,3-dimethyl-5-(((S)-1-(2,2,2-trifluoro-N- methylacetamido)propan-2-yl)oxy)-1H-pyrazol-4-yl)-7-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-1H-indazole-3-carboxylate (450 mg, 659 μmol, 1 eq) in THF (5 mL) and H2O (1 mL) was added LiOH.H2O (138 mg, 3.30 mmol, 5 eq). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 5-(5-(1,3-dimethyl-5-(((S)-1-(methylamino)propan-2- yl)oxy)-1H-pyrazol-4-yl)-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)-1-methyl-1H-indazole-3-carboxylic acid (300 mg, 524 μmol, 79% yield) as a yellow solid. LCMS: m / z 573.3 (M+1)

[0656] Step 4. To a solution of 5-(5-(1,3-dimethyl-5-(((S)-1-(methylamino)propan-2-yl)oxy)- 1H-pyrazol-4-yl)-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1- methyl-1H-indazole-3-carboxylic acid (200 mg, 349 μmol, 1 eq) in Pyridine (0.5 mL) was added POCl3 (161 mg, 1.05 mmol, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was quenched by addition H2O (0.2 mL) at 25 °C, and then the pH was adjusted to 7 with citric acid (0.5 mL) and extracted with EA (1 mL × 3). The combined organic layers were washed with brine (1 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 1 / 1) to give (5S)-11,27,32,35,5,7-hexamethyl-21-(oxan-2-yl)-83573-422399 11H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)- pyrazolacyclooctaphan-8-one (50.0 mg, 90.0 μmol, 26% yield) as a colorless oil.

[0657] General Method I

[0658] Preparation of (5S)-12-[(2S)-1-{[tert-butyldi(methyl)silyl]oxy}propan-2-yl]-7-ethyl-17- fluoro-35-(methoxymethyl)-27,32,5-trimethyl-21-(oxan-2-yl)-12H,21H,32H-4-oxa-7-aza-2(3,5)- pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)-pyrazolacyclooctaphan-8-one (39-1)materials I-4-16 and I-5-4 with time being increased to 2 hours.

[0660] Step 2 was performed in a similar manner to step 2 of General Method H using I-2-8.

[0661] Step 3 was performed in a similar manner to step 3 of General Method H with time being decreased to 1 hour.

[0662] Step 4. To a solution of 2-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(5-(5-(((S)- 1-(ethylamino)propan-2-yl)oxy)-3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl)-7-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-7-fluoro-2H-indazole-3-carboxylic acid (850 mg, 1.07 mmol, 1 eq) in ACN (10 mL) was added NMI (3.22 mmol, 256 μL, 3 eq) and TCFH (451 mg, 1.61 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 hours. On completion,83573-422399 the reaction mixture was quenched by addition H2O (10 mL) at 25 °C and then diluted with H2O (30 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 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= 5 / 1 to 0 / 1) to give (5S)-12-[(2S)-1-{[tert- butyldi(methyl)silyl]oxy}propan-2-yl]-7-ethyl-17-fluoro-35-(methoxymethyl)-27,32,5-trimethyl- 21-(oxan-2-yl)-12H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-c]pyridina-1(5,3)-indazola-3(4,3)- pyrazolacyclooctaphan-8-one (200 mg, 193 μmol, 18% yield, 75% purity) as a yellow solid.

[0663] General Method J

[0664] Preparation of (5S)-12-(2-{[tert-butyldi(phenyl)silyl]oxy}ethyl)-32,5-dimethyl- 12H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-b]pyridina-1(5,3)-indazola-3(4,3)- pyrazolacyclooctaphane (56-1)83573-422399

[0666] Step 2. A mixture of tert-butyl ((2S)-2-((4-(3-(2-(2-hydroxyethyl)-3-(hydroxymethyl)- 2H-indazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1-methyl-1H- pyrazol-5-yl)oxy)propyl)carbamate (90.0 mg, 139 μmol, 1 eq) in DCM (1 mL) was added MnO2 (181 mg, 2.09 mmol, 15 eq), and then the mixture was stirred at 40 °C for 16 h. On completion, the mixture was quenched with sat. Na2SO3 (2 mL) and extracted with DCM (2 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl ((2S)-2-((4-(3-(3-formyl-2-(2-hydroxyethyl)-2H-indazol-5-yl)-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (89.0 mg, 138 μmol, 99% yield) as a brown solid. LCMS: m / z 645.2 (M+1)83573-422399

[0667] Step 3. To a solution of tert-butyl ((2S)-2-((4-(3-(3-formyl-2-(2-hydroxyethyl)-2H- indazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1-methyl-1H- pyrazol-5-yl)oxy)propyl)carbamate (80.0 mg, 124 μmol, 1 eq) in DCM (1 mL) was added imidazole (25.3 mg, 372 μmol, 3 eq) and TBDPSCl (37.5 mg, 136 μmol, 1.1 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched with H2O (2 mL) and extracted with DCM (2 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF= 1:0 to 2:1) to give tert-butyl ((2S)-2-((4-(3-(2-(2-((tert- butyldiphenylsilyl)oxy)ethyl)-3-formyl-2H-indazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-b]pyridin-5-yl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (70.0 mg, 79.3 μmol, 64% yield) as a yellow oil. LCMS: m / z 883.2 (M+1)

[0668] Step 4 was performed in a similar manner to Deprotection Method D1 with time extended to 1 hour.

[0669] Step 5. To a solution of (S)-5-(5-(5-((1-aminopropan-2-yl)oxy)-1-methyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2H-indazole-3- carbaldehyde (33.0 mg, 44.9 μmol, 1 eq, HCl) in MeOH (0.5 mL) was added DIEA (11.6 mg, 89.8 μmol, 2 eq) and AcOH (2.69 mg, 44.9 μmol, 1 eq) and stirred at 25 °C for 30 mins. Then NaBH(OAc)3 (19.0 mg, 89.8 μmol, 2 eq) was added into the mixture and stirred at 25 °C for 16 h. On completion, the mixture was quenched with water (0.5 mL) and filtered and concentrated to give (5S)-12-(2-{[tert-butyldi(phenyl)silyl]oxy}ethyl)-32,5-dimethyl-12H,21H,32H-4-oxa-7- aza-2(3,5)-pyrazolo[3,4-b]pyridina-1(5,3)-indazola-3(4,3)-pyrazolacyclooctaphane (30.0 mg, 43.9 μmol, 98% yield) as a yellow oil.

[0670] Intermediate Example Scheme 1:83573-422399 Int. SMs LCMS: m / z # Intermediate Method Use (M+1)83573-422399 Int. S LCMS: m / z # Ms Intermediate Method Use (M+1)

[0672] Representative Intermediate General Scheme 2:83573-422399 Int. # SMs Intermediate Method Use LCMS: m / z (M+1)83573-422399 Int. # SMs Intermediate Method Use LCMS: m / z (M+1)83573-422399 Int. # SMs Intermediate Method Use LCMS: m / z (M+1)Step 1 time 2 hours, step 3 time was 1 hourcStep 1 time 3 hours, steps 2-4 time was 2 hour each

[0674] Example Table 1.83573-422399 Ex # Structure LCMS1H NMR(400 MHz, DMSO-d6 ) 1 2 1H 1H ), d, r , ). , r 5 ), ), J 4

[0675] p

[0676] Example Table 2.83573-422399 Interme Methods L1Ex # CMS: H NMR(400 diate Employed Structure m / z (M+1) MHz, DMSO-d6 ) δ 1351 1H , J - 5 , z, , - 3 0 4 = z, 3 - 9 ,83573-422399 Interme Methods1Ex # LCMS: H NMR(400 diate Employed Structure m / z (M+1) MHz, DMSO-d6 ) 244 3H 156 = , - 3 2 , z, , 9 ) = , - - 483573-422399 Interme Methods1Ex # LCMS: H NMR(400 diate Employed Structure m / z (M+1) MHz, DMSO-d6 ) 2H 378 3H , , = 7 J 4 , - 7 J ), z, 5 2 283573-422399 Interme Methods L1Ex # CMS: H NMR(400 diate Employed Structure m / z (M+1) MHz, DMSO-d6 ) 60 H 3H 095 - 2 5 2 4 4 ), 2 1 J ), 2 4 7 7 r83573-422399 Interme Methods L1Ex # CMS: H NMR(400 diate Employed Structure m / z (M+1) MHz, DMSO-d6 ) d 12 H 2H), 9 , ), ), - 2 4 8 9 9 , 0 ), 2 J - 5 683573-422399 Interme Methods LCMS:1Ex # d Struc H NMR(400 diate Employe ture m / z (M+1) MHz, DMSO-d6 ) 1H 301 293 , ), z, ), z, 5 ), ), 7 = 8 , = 3 d, , .2 9 - 3 1 , ), 0 383573-422399 Interme Methods LCM1Ex # oyed St S: H NMR(400 diate Empl ructure m / z (M+1) MHz, DMSO-d6 ) δ 1350 1H), 7 J z, 6 6 - 0 4 , ), 8 = 2 - 4 6 ), J z, = 2 4 583573-422399 Interme Methods LCMS1Ex # ed Stru : H NMR(400 diate Employ cture m / z (M+1) MHz, DMSO-d6 ) 448 442 ), ), 4 J 2 ), z, ), 9 J ), = ), 8 8 ) 6 , J z, 5 0 1 6 = ),83573-422399 Interme Methods LC1Ex # ployed S MS: H NMR(400 diate Em tructure m / z (M+1) MHz, DMSO-d6 ) 280 3H 257 z, ), 4 , 2 4 , ), 2 5 J 3 ), , ), ), 7 J83573-422399 Interme Methods1Ex # LCMS: H NMR(400 diate Employed Structure m / z (M+1) MHz, DMSO-d6 ) δ 1367 1H), 3 J 4 0 3 J ), 0 - 7 7 0 - 1 J83573-422399 x # Interme1E Methods LCMS: H NMR(400 diate Employed Structure m / z (M+1) MHz, DMSO-d6 ) δ 1356 1H 1 J ), 4 7 7 J 1 J - 1 2 J , 1 H)bTemperature was 25 C and time was 40 minutes c Time was 0.5 hours83573-422399 CELLULAR ASSAYS

[0677] Generation of Engineered Ba / F3 Cell Lines with EML4-ALK Fusion Genes

[0678] Ba / F3 (purchased from DSMZ, ACC 300) cells were engineered to express EML4-ALK fusion proteins: The EML4-ALK gene was synthesized at GenScript and cloned into pCDH- CMV-MCS-EF1-Puro plasmid with a lenti-viral backbone (System Biosciences, Inc). Plasmids with ALK mutant cDNAs were made at GenScript by site directed mutagenesis and confirmed by sequencing. Lentivirus carrying EML4-ALK mutations were prepared from the corresponding plasmids with EML4-ALK mutant cDNAs. Ba / F3 cell lines with EML4-ALK gene mutations were generated by infecting Ba / F3 cells with lentivirus containing corresponding ALK mutations. Stable cell lines were selected by puromycin treatment at 2 μg / mL, followed by interleukin-3 (IL- 3) withdrawal.

[0679] Cellular Assays

[0680] PC-9 (purchased from Aldrich-Sigma, #90071810), SK-BR-3 (purchased from ATCC HTB-30), MV4-11 (purchased from ATCC CRL-9591), or Ba / F3 EML4-ALK cells at 1000 cells in 48 µL per well were seeded in 384 well plates (Corning, Inc.).2 µL of compounds were added in a 3 folds titration for 11 doses, starting from 10 µM. Plates were incubated for 3 days at 37 °C and 5% CO2. Cell proliferation was measured using CellTiter-Glo® 2.0 luciferase-based ATP detection assay (Promega) at 18 µL per well following the manufacturer’s protocol. Plates were then read on a Tecan Spark® multimode microplate reader. The IC50 values were determined using GraphPad Prism 10 software (GraphPad, Inc.).

[0681] Cellular EGFR Phosphorylation Assays

[0682] EGFR phosphorylation assays were conducted in NSCLC cells with EGFR activation mutations. PC-9 cells (purchased from Aldrich-Sigma) carry a Glu746-Ala750 deletion (d746- 750) mutation in exon 19 of the EGFR gene and NCI-H1975 cells (purchased from ATCC) carry both L858R activation mutation and T790M gatekeeper mutation in the EGFR gene. A431 cells (purchased from ATCC) with amplification of wildtype EGFR, derived from epidermoid carcinoma, were used to measure the activity against wildtype EGFR. All cells were seeded in 96-well plates. For PC-9 and NCI-H1975 cells, 50 thousand cells were seeded per well. For A431 cells, 30 thousand cells were seeded per well. The next day, cells were exposed to compound for 4 hours at 37°C and 5% CO2. Compounds were diluted in DMSO and added to cells in a 9-dose, 3-fold dilution, titration curve using TECAN d300e liquid dispenser. For A431 cells, 40 ng / mL of EGF was added to the media for the final 10 minutes of incubation. EGFR phosphorylation was measured using phospho-EGFR (Try1068) LANCE Ultra TR-FRET Detection Kit (TRF4015M) from PerkinElmer according to manufacturer’s instructions. In brief, cells were lysed with 40 µL of lysis buffer plus 1x Halt protease and phosphatase inhibitor83573-422399 cocktail (Thermo 78441) and by incubation at room temperature for 1h on a microplate shaker (350 rpm). 15 µL of cell lysate was transferred to 384-well white plate and 5 µL of Europium- and ULight-labeled antibodies diluted in 1x detection buffer was added to each well. After 4-6 hours of incubation at room temperature, plates were then read on a TECAN Sparks multimode microplate reader. Data was analyzed using GraphPad Prism 9 (GraphPad Software, San Diego, CA) to obtain IC50values.

[0683] Table 1. Ex. PC-9 MV-4-11 SK-BR-3 Ba / F3 EML4-ALK IC50, nM IC50, nM IC50, nM IC50, nM

Claims

83573-422399 WHAT IS CLAIMED IS:

1. A compound of the formula I whereinA is a 5- to 10-membered heteroarylene or C6-C10 arylene; B / C is a 9-membered bicyclic heteroarylene, wherein X1is C(R2), N(R3), or N; X2is C(R4), N(R5), or N; X3is C or N; X4is C or N; X5is C(R6) or N; X6is C(R7) or N; and X7is C(R8) or N; provided that at least one of X1to X7is a nitrogen atom; D / E is a 9-membered bicyclic heteroarylene, wherein Y1is C(R9), N(R10), or N; Y2is C(R11), N(R12), or N; Y3is C or N; Y4is C or N; Y5is C(R13) or N; Y6is C(R14) or N; and Y7is C(R15) or N; provided that at least one of Y1to Y7is a nitrogen atom; each L is independently a bond, -C(R16)(R17)-, -O-, -N(R18)C(O)-, -C(O)N(R18)-, -N(R18)-, -N(R18)S(O)-, -S(O)N(R18)-, -N(R18)S(O)2-, -S(O)2N(R18)-, -S-, -S(O)-, or -S(O)2-, provided that (L)mdoes not comprise an -O-O-, -O-S-, -O-N-, -S-S-, or -N-N- bond;83573-422399 each R1, when present and bonded to a carbon atom, is independently deuterium, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, and each R1, when present and bonded to a nitrogen atom, is independently deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; each of R2, R4, R6, R7, R8, R9, R11, R13, R14, or R15, when present, is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; each R3and R5, when present, is independently H, deuterium, C1-C6alkyl, -S(O)2Rc,83573-422399 -S(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd, -P(O)2RcRd, -P(O)2NRcRd, or -P(O)2ORc; wherein each hydrogen atom in C1-C6alkyl is independently optionally substituted by Re, Rf, -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; each R10or R12, when present, is independently H, deuterium, halogen, C1-C6alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -OS(O)NRcRd, -OS(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=NRe)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, -N(C(O)Re)(C(O)Rf), -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NRcS(O)NReRf, -NRcS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -C(=NRf)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; each R16and R17, when present, is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRb)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, -NRaC(=NRb)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRb)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or two of R12and R13, taken together with the carbon or carbons to which they are attached, combine to form C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, -ORe, -OC(O)Re,83573-422399 -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; each R18, when present, is independently H, deuterium, -C(O)Rc, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; or an R14and an R12or an R13, taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRd)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRd)NRcRd,-PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2; each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, C1-C6 alkylene-5- to 10-membered heteroaryl, and C1-C6 alkylene-3- to 7-membered heterocycloalkyl, or Raand Rbor Rcand Rdor Reand Rf, taken together with the atom to which they are attached, form a 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkylene-C6-C10 aryl, 5- to 10-membered heteroaryl, or C1-C6 alkylene-5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O)(H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6alkyl)2, -S(O)N(C2-C6alkylene), -S(O)2N(H or C1-C6alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)- (H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)O(H or C1-C6alkyl), -N(H or C1-C6alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)2(H or C1-C6alkyl), -N(H or C1-C6alkyl)S(O)N(H or83573-422399 C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6alkyl)2, -N(H or C1-C6alkyl)S(O)2N(C2-C6alkylene), -C(O)-(H or C1-C6alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6alkyl)2, -P(O)(C2-C6alkylene), -P(O)2(H or C1-C6alkyl)2, -P(O)2(C2-C6alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(O)O(H or C1-C6alkyl), -P(O)2O(H or C1-C6alkyl), -CN, or -NO2; m is 3, 4, 5, 6, 7, or 8; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, having the formula II whereineach of Z and Z1is independently a bond, -O-, -N(R18)C(O)-, -C(O)N(R18)-, -N(R18)-, -N(R18)S(O)-, -S(O)N(R18)-, -N(R18)S(O)2-, -S(O)2N(R18)-, -S-, -S(O)-, or -S(O)2-; each L1is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, -C(R16)(R17)- C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-; L2is a bond, -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)- C(R16)(R17)-; and p is 1 or 2; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, having the formula III83573-422399 or a pharmaceutically4. The compound of any one of the preceding claims, having the formula IV whereineach of Z and Z1is independently a bond, -O-, -N(R18)C(O)-, -C(O)N(R18)-, -N(R18)-, -N(R18)S(O)-, -S(O)N(R18)-, -N(R18)S(O)2-, -S(O)2N(R18)-, -S-, -S(O)-, or -S(O)2-; each L1is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, -C(R16)(R17)- C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-; L2is a bond, -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)-83573-422399 C(R16)(R17)-; and p is 1 or 2; or a pharmaceutically acceptable salt thereof.

5. The compound of any claim 1, having the formula V or a pharmaceutically6. The compound of any one of claims 1, 2, or 5, having the formula VI whereineach of Z and Z1is independently a bond, -O-, -N(R18)C(O)-, -C(O)N(R18)-, -N(R18)-, -N(R18)S(O)-, -S(O)N(R18)-, -N(R18)S(O)2-, -S(O)2N(R18)-, -S-, -S(O)-, or -S(O)2-;83573-422399 each L1is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, -C(R16)(R17)- C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-C(R16)(R17)-; L2is a bond, -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)- C(R16)(R17)-; and p is 1 or 2; or a pharmaceutically acceptable salt thereof.

7. The compound of any one of the preceding claims, wherein ring B / C is of the formula ,,or a pharmaceutically acceptable salt thereof.

8. The compound of any one of the preceding claims, wherein ring A in the portionis a 5- or 6-memberedeach “ ” represents a point ofcovalent attachment; or a pharmaceutically acceptable salt thereof.83573-422399 9. The compound of any one of the preceding claims, wherein ring A in the portion is a 5- or 6-membered consisting ofN (R1)n,or a pharmaceutically acceptable salt thereof.

10. The compound of any one of the preceding claims, wherein each R1, when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, or methoxymethyl; or a pharmaceutically acceptable salt thereof.

11. The compound of any one of the preceding claims, wherein each R1, when present and bonded to nitrogen, is independently methyl or ethyl; or a pharmaceutically acceptable salt thereof.

12. The compound of any one of the preceding claims, wherein ring A in the portion is selected from the group,83573-422399 apoint of covalent attachment;salt thereof.

13. The compound of any one of claims 1 to 10, wherein ring A in the portionis C6-C10 arylene, n is 0, 1, 2, or 3, a point of covalent attachment;or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 1 to 10, or 13, wherein ring A in the portionis phenylene, n is 0, 1, 2, or 3, anda point of covalent attachment;or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 2, 4, or 6 to 14, wherein each L1, when present, is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)- C(R16)(R17)-; or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 2, 4, or 6 to 15, wherein each L1, when present, is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)- C(R16)(R17)-, wherein one or two of R16is a C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 2, 4, or 6 to 16, wherein each L1, when present, is independently -C(R16)(R17)-, -C(R16)(R17)-C(R16)(R17)-, or -C(R16)(R17)-C(R16)(R17)-83573-422399 C(R16)(R17)-, wherein one or two of R16is a C1-C6 alkyl, and the remaining R16and R17are H or deuterium; or a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 2, 4, or 6 to 17, wherein p is 1; or a pharmaceutically acceptable salt thereof.

19. The compound of any one of claims 2, 4, or 6 to 18, wherein L1, when present, is -C(R16)(R17)- C(R16)(R17)-; or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 2, 4, or 6 to 19, wherein p is 2; or a pharmaceutically acceptable salt thereof.

21. The compound of any one of claims 2, 4, or 6 to 17, or 20, wherein one instance of L1, when present, is -C(R16)(R17)- and another instance of L1, when present, is -C(R16)(R17)-C(R16)(R17)-; or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 2, 4, or 6 to 21, wherein Z, when present, is -O-; or a pharmaceutically acceptable salt thereof.

23. The compound of any one of claims 2, 4, or 6 to 21, wherein Z, when present, is -N(R18)C(O)- ; or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 2, 4, or 6 to 21, wherein Z, when present, is a bond; or a pharmaceutically acceptable salt thereof.

25. The compound of any one of claims 2, 4, or 6 to 24, wherein each Z1, when present, is independently -O- or -N(R18)-; or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 2, 4, or 6 to 25, wherein L2, when present, is a bond; or a pharmaceutically acceptable salt thereof.83573-422399 27. The compound of any one of the preceding claims, wherein -(L)p- or -L2-(Z1-L1)p-Z- is of the formula , , , ,or a pharmaceutically acceptable salt thereof.

28. The compound of any one of the preceding claims, wherein R2, when present, is H or deuterium; or a pharmaceutically acceptable salt thereof.

29. The compound of any one of the preceding claims, wherein R3, when present, is H, deuterium, or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

30. The compound of any one of the preceding claims, wherein R4, when present, is H or deuterium; or a pharmaceutically acceptable salt thereof.83573-422399 31. The compound of any one of the preceding claims, wherein R5, when present, is H, deuterium, or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

32. The compound of any one of the preceding claims, wherein R6, when present, is H or deuterium; or a pharmaceutically acceptable salt thereof.

33. The compound of any one of the preceding claims, wherein R7, when present, is H or deuterium; or a pharmaceutically acceptable salt thereof.

34. The compound of any one of the preceding claims, wherein R8, when present, is H, deuterium, halogen, C1-C6 alkyl, or -NRaRb; or a pharmaceutically acceptable salt thereof.

35. The compound of any one of the preceding claims, wherein R9, when present, is H or deuterium; or a pharmaceutically acceptable salt thereof.

36. The compound of any one of the preceding claims, wherein R10, when present, is H, deuterium, C1-C6 alkyl, or -S(O)2Rc; wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by Re, Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or a pharmaceutically acceptable salt thereof.

37. The compound of any one of the preceding claims, wherein R10, when present, is H, deuterium, methyl, ethyl, or propyl, wherein each hydrogen atom in methyl, ethyl, and propyl is independently optionally substituted by OH.

38. The compound of any one of the preceding claims, wherein R10, when present, is83573-422399 ,, , , or , wherein the “ ” denotes a point of39. The compound of any one of the preceding claims, wherein R11, when present, is H or deuterium; or a pharmaceutically acceptable salt thereof.

40. The compound of any one of the preceding claims, wherein R12, when present, is H, deuterium, C1-C6 alkyl, or -S(O)2Rc; wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by Re, Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or a pharmaceutically acceptable salt thereof.

41. The compound of any one of the preceding claims, wherein R12, when present, is H, deuterium, methyl, ethyl, propyl, or -S(O)2Re, wherein each hydrogen atom in methyl, ethyl, and propyl is independently optionally substituted by OH; or a pharmaceutically acceptable salt thereof.

42. The compound of any one of the preceding claims, wherein R12, when present, is , wherein the “43. The compound of any one of the preceding claims, wherein R14, when present, is H or deuterium; or a pharmaceutically acceptable salt thereof.

44. The compound of any one of the preceding claims, wherein R15, when present, is H, deuterium, halogen, C1-C6 alkyl, or -NRaRb; or a pharmaceutically acceptable salt thereof.83573-422399 45. The compound of any one of the preceding claims, wherein R18, when present, is H or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

46. The compound of claim 1, selected from the group consisting of 15-(methanesulfonyl)-8-methyl-2,11,12,15-tetrahydro-8H,10H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole; 8-methyl-2,11,12,15-tetrahydro-8H,10H-3,5:16,18-dietheno[1,5]dioxacyclopentadecino[10,11- c:15,14-c':6,7-c'']tripyrazole; 2-(8-methyl-2,8,11,12-tetrahydro-10H,15H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazol-15-yl)ethan-1-ol; 2-(8-methyl-2,8,11,12-tetrahydro-10H,14H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazol-14-yl)ethan-1-ol; (2S)-1-[(10S)-12-ethyl-22-fluoro-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13- hexahydro-14H-3,5:16,18-diethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin- 14-yl]propan-2-ol; and (10S)-12-ethyl-22-fluoro-14-[(2S)-2-hydroxypropyl]-6-(methoxymethyl)-8,10-dimethyl- 2,11,12,14-tetrahydro-8H-3,5:16,18-diethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-13(10H)-one; or a pharmaceutically acceptable salt thereof.

47. The compound of claim 1, selected from the group consisting of (2S)-2-[(10S)-20-methoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-15H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15- yl]propan-1-ol; 2-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)-16,18- ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol; (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-15H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15-yl]propan-1-ol; (2S)-2-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-15H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15-yl]propan-1-ol; 2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)-16,18- ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol; (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol;83573-422399 (2S)-1-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol; (2S)-2-[(10S)-12-ethyl-6,8,10,22-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol; (2S)-2-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:16,18- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol; (2S)-2-[(10S)-19-fluoro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol; (2S)-2-[(10S)-20-methoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol; (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:18,16- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4,8]oxadiazacyclopentadecin-14-yl]propan-1-ol; (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:18,16- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol; (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3:16,18- di(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol; (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4,8]oxadiazacyclopentadecin-14-yl]propan-2-ol; (2S)-2-[(10S)-20-fluoro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol; (2S)-2-[(10S)-20-chloro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol; (2S)-2-[(10S)-19-chloro-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-83573-422399 yl]propan-1-ol; (10S)-6,8,10,12,15,22-hexamethyl-2,10,11,12,13,15-hexahydro-8H-5,3-(azenometheno)-16,18- ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine; (2S)-2-[(10S)-20-chloro-12-ethyl-6-(methoxymethyl)-8,10,22-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S)-12-ethyl-20-fluoro-6-(methoxymethyl)-8,10,22-trimethyl-2,8,10,11,12,13- hexahydro-14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S)-20-methoxy-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol; (2S)-2-[(10S)-6,8,10,12,20,22-hexamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol; (2S)-2-[(10S)-20-ethyl-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol; (2S)-2-[(10S)-20-cyclopropyl-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol; (2S)-2-[(10S)-20-(difluoromethoxy)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol; (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-20-(trifluoromethoxy)-2,8,10,11,12,13-hexahydro- 14H-5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol; (2S)-2-[(10S)-20-(dimethylamino)-6,8,10,12,22-pentamethyl-2,8,10,11,12,13-hexahydro-14H- 5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin- 14-yl]propan-1-ol; and (2S)-1-[(5S)-32,35,5,7-tetramethyl-11H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-c]pyridina- 1(5,3)-indazola-3(4,3)-pyrazolacyclooctaphan-11-yl]propan-2-ol; or a pharmaceutically acceptable salt thereof.

48. The compound of claim 1, selected from the group consisting of83573-422399 2-[(10S)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-(azenometheno)-16,18- ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol; (2S)-1-[(10S)-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol; (2S)-1-[(10S)-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol; (2S)-1-[(10S)-12-ethyl-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol; (2S)-2-[(10S)-6-(methoxymethyl)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-1-ol; (2S)-1-[(10S)-12-ethyl-8,10-dimethyl-20-(propan-2-yl)-2,8,10,11,12,13-hexahydro-14H-3,5- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol; and 2-[(5S)-32,5-dimethyl-12H,21H,32H-4-oxa-7-aza-2(3,5)-pyrazolo[3,4-b]pyridina-1(5,3)- indazola-3(4,3)-pyrazolacyclooctaphan-12-yl]ethan-1-ol; or a pharmaceutically acceptable salt thereof.

49. The compound of claim 1, selected from the group consisting of (2S)-2-[(11S)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)- 17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (2S)-2-[(11S)-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)- 17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (11S)-7,9,11,13,16-pentamethyl-12,13,14,16-tetrahydro-9H,11H-6,3-(azenometheno)-17,19- ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecine; (2S)-2-[(11S)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)- 17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; (2S)-1-[(11S)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)- 17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-2-ol;83573-422399 (2S)-2-[(11S)-7,9,11,13,23-pentamethyl-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)- 17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-1-ol; and (2S)-1-[(11S)-7,9,11,13,23-pentamethyl-11,12,13,14-tetrahydro-9H,15H-6,3-(azenometheno)- 17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'-n][1,4,11]oxadiazacyclopentadecin-15- yl]propan-2-ol; or a pharmaceutically acceptable salt thereof.

50. The compound of claim 1, selected from the group consisting of (2S)-2-[(10S)-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)-16,18- ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)-yl]propan-1-ol; (2S)-1-[(10S)-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)-16,18- ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)-yl]propan-2-ol; (2S)-2-[(10S)-6,8,10,12,22-pentamethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)-16,18- ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)-yl]propan-1-ol; and (2S)-1-[(10S)-6,8,10,12,22-pentamethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)-16,18- ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)-yl]propan-2-ol or a pharmaceutically acceptable salt thereof.

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

52. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 51.

53. A compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, for use in a method of treating disease in a subject.

54. Use of a compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease in a subject.

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